<b>Bijsluiter</b>. De hyperlink naar het originele document werkt niet meer. Daarom laat Woogle de tekst zien die in dat document stond. Deze tekst kan vreemde foutieve woorden of zinnen bevatten en de opmaak kan verdwenen of veranderd zijn. Dit komt door het zwartlakken van vertrouwelijke informatie of doordat de tekst niet digitaal beschikbaar was en dus ingescand en vervolgens via OCR weer ingelezen is. Voor het originele document, neem contact op met de Woo-contactpersoon van het bestuursorgaan.<br><br>====================================================================== Pagina 1 ======================================================================

<pre>Cadmium and
selected cadmium
compounds
Evaluation of the effects on reproduction, recommendation for
classification
To: the State Secretary of Social Affairs and Employment
No. 2020/22, The Hague, October 13, 2020
                                                              2 2
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<pre> Contents                                                                      Cadmium and selected cadmium compounds | page 2 of 103
 contents                                                             04 Toxicokinetics (absorption, metabolism,
      Samenvatting3                                                     distribution and elimination) and grouping                          17
                                                                         4.1  Toxicokinetics                                                  18
      Executive summary                                            5    4.2  Grouping                                                        18
 01 Scope7                                                           05 Toxicity for reproduction                                           20
      1.1  Background                                              8    5.1  Adverse effects on sexual function and fertility                21
      1.2  Committee and procedure                                 8    5.2  Short summary and overall relevance of the provided information
      1.3  Classification for effects on or via lactation          9         on adverse effects on sexual function and fertility             42
      1.4  Data                                                  10     5.4  Adverse effects on development                                  51
                                                                         5.5  Short summary and overall relevance of the provided information
 02 Identity of the substances                                   11          on adverse effects on development                               78
      2.1  Name and other identifiers of the substances          13     5.6  Comparison with the CLP criteria                                85
      2.3  Physico-chemical properties of the selected compounds  14    5.7  Lactation                                                       86
                                                                         5.8  Short summary and overall relevance of the provided information
 03 Manufacture and uses                                         15          on effects on or via lactation                                  88
      3.1  Manufacture                                           16     5.9  Comparison with the CLP criteria                                88
      3.2  Identified uses                                       16     5.10 Conclusions on classification and labelling                     88
                                                                         References90
1       Health Council of the Netherlands | No. 2020/22                                                       2                                 3
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<pre> Samenvatting                                                                                Cadmium and selected cadmium compounds | page 3 of 103
samenvatting
Op verzoek van de minister van Sociale Zaken        Gebruik van cadmium                               Als er aanwijzingen zijn dat de stof schadelijke
en Werkgelegenheid (SZW) heeft de                   Cadmium is een metaal, dat vooral gebruikt        effecten heeft, stelt de commissie voor om de
Gezondheids­raad voor cadmium, cadmium­             wordt voor de productie van batterijen. Ook kan   stof in te delen in gevaren­categorieën. Deze
carbonaat, cadmiumchloride, cadmiumfluoride,        het een bestanddeel zijn van pigment voor verf    categorieën zijn afgeleid van EU-verordening
cadmiumhydroxide, cadmiumnitraat, cadmium­          en coatings. Mensen die werkzaam zijn in          (EG) 1272/2008.
oxide, cadmiumsulfaat en cadmiumsulfide             bedrijven waar cadmium wordt geproduceerd of
(hierna aangeduid als ‘cadmium’) beoordeeld of      verwerkt kunnen tijdens hun werk in aanraking     Geraadpleegde onderzoeken
beroepsmatige blootstelling invloed kan hebben      komen met cadmium. Vooral werkzaamheden           Zowel over effecten van blootstelling aan
op de voortplanting. Op basis van deze              zoals lassen en slijpen waarbij cadmium verhit    cadmium op de vruchtbaarheid als over effecten
beoordeling is een classificatievoorstel opgesteld. wordt kunnen risicovol zijn, omdat dan            op de ontwikkeling zijn verschillende onder­
                                                    cadmium­­dampen kunnen vrijkomen.                 zoeken bij mensen beschikbaar. De meeste
Dit advies is opgesteld door de Commissie                                                             onderzoeken laten een verband zien met
Classificatie reproductietoxische stoffen, een      Classificeren naar bewijskracht                   blootstelling aan cadmium, maar leveren geen
subcommissie van de Commissie Gezondheid            Bij de beoordeling van effecten op de voort­      duidelijk bewijs. Er zijn ook veel dierstudies
en beroepsmatige blootstelling (GBBS).              planting, kijkt de commissie zowel naar effecten  gedaan, zowel naar effecten op de vrucht­
Op www.gezondheidsraad.nl staat informatie          op de vruchtbaarheid van mannen en vrouwen        baarheid als naar effecten op de ontwikkeling.
over de taken van deze vaste commissie van de       als naar effecten op de ontwikkeling van het      De beschikbare dierstudies, waarin cadmium­
Gezondheidsraad. De samenstelling van de            nageslacht. Daarnaast worden effecten op de       chloride en cadmiumoxide zijn geëvalueerd,
commissie is te vinden achterin dit advies.         lactatie (productie en afgifte van moedermelk)    laten duidelijke nadelige effecten zien.
                                                    beoordeeld en effecten via de moedermelk op
                                                    de zuigeling.
2      Health Council of the Netherlands | No. 2020/22                                                               2                                 4
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<pre> Samenvatting                                                                                     Cadmium and selected cadmium compounds | page 4 of 103
 Voor effecten van blootstelling aan cadmium op       Classificatievoorstel commissie:
 of via lactatie baseert de commissie zich vooral     • voor effecten op de fertiliteit: classificeren in
 op onderzoeken bij mensen. In die onderzoeken           categorie 1B (stoffen waarvan verondersteld
 zijn concentraties van cadmium in de moeder­            wordt dat zij toxisch zijn voor de menselijke
 melk gemeten waarvan de commissie het                   voortplanting) en te kenmerken met H360F
 mogelijk acht dat ze nadelige gevolgen hebben           (kan de vruchtbaarheid schaden);
 voor de baby na borstvoeding.                        • voor effecten op de ontwikkeling: classificeren
                                                         in categorie 1B (stoffen waarvan verondersteld
 Advies aan de staatssecretaris                          wordt dat zij toxisch zijn voor de menselijke
 Op grond van de beschikbare wetenschappelijke           voortplanting) en te kenmerken met H360D
 gegevens adviseert de commissie om cadmium,             (kan het ongeboren kind schaden);
 cadmiumcarbonaat, cadmiumchloride, cadmium­          • voor effecten op of via lactatie: classificeren
 fluoride, cadmiumhydroxide, cadmiumnitraat,             en kenmerken met H362 (kan schadelijk zijn
 cadmiumoxide, cadmiumsulfaat en cadmium­                via de borstvoeding).
 sulfide, zowel voor effecten op de vrucht­
 baarheid, als voor effecten op de ontwikkeling
 en voor effecten op of via lactatie, in te delen in
 een gevarencategorie.
3        Health Council of the Netherlands | No. 2020/22                                                                 2                             5
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<pre> Executive summary                                                                                Cadmium and selected cadmium compounds | page 5 of 103
 executive summary
 At the request of the Minister of Social Affairs     component of pigments and coatings. Workers          Research consulted
 and Employment, the Health Council of the            in industries that use or produce cadmium and        Epidemiological studies are available on effects
 Netherlands evaluated the effects of cadmium,        cadmium compounds are at risk for increased          on fertility and effects on development. Most of
 cadmium carbonate, cadmium chloride,                 cadmium exposure. In particular, workers whose       these studies show associations with exposure
 cadmium fluoride, cadmium hydroxide, cadmium         jobs involve the heating of cadmium such as          to cadmium, but provide insufficient evidence.
 nitrate, cadmium oxide, cadmium sulphate, and        welding and grinding are at risk of cadmium          In addition, many animal studies have been
 cadmium sulphide, (further referred to as            exposure, as cadmium vapours can be released.        conducted. These studies, which evaluated
 ‘cadmium’) on reproduction. This advisory report                                                          cadmium chloride and cadmium oxide, indicate
 was drafted by the Subcommittee on the               Classification based on evidence                     that cadmium exposure can cause effects on
 Classification of Reproduction Toxic Substances      To assess effects on reproduction, the               fertility and development.
 of the Dutch Expert Committee on Occupational        Committee evaluates the effects on male and
 Safety (DECOS) of the Health Council, hereafter      female fertility and on the development of the       Based on measured cadmium levels in breastmilk
 called the Committee. The Health Council has a       offspring. Moreover, the Committee considers         in humans, the Committee considers it likely that
 permanent task in assessing the hazard of            effects of a substance on lactation and on the       these may cause adverse effects via lactation.
 substances to which man can be occupationally        offspring via lactation. If the data indicate
 exposed. More information about this task can        hazardous properties, the Committee                  Recommendations to the State Secretary
 be found at www.gezondheidsraad.nl.                  recommends classification in a hazard category.      Based on the scientific data available, the
                                                      The classification is performed according to         Committee recommends to classify cadmium,
 Cadmium use                                          EU-regulation (EC) 1272/2008.                        cadmium carbonate, cadmium chloride,
 Cadmium is a metal that is primarily being used                                                           cadmium fluoride, cadmium hydroxide, cadmium
 in batteries, though cadmium can also be a                                                                nitrate, cadmium oxide, cadmium sulphate, and
4        Health Council of the Netherlands | No. 2020/22                                                                   2                                6
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<pre> Executive summary                                      Cadmium and selected cadmium compounds | page 6 of 103
 cadmium sulphide, for effects on fertility, for
 effects on offspring development and for effects
 on or via lactation.
 The Committee’s classification proposal:
 • for effects on fertility: classify these
    substances in category 1B (presumed human
    reproductive toxicant), and label them with
    H360F (may damage fertility);
 • for effects on development: classify these
    substances in category 1B (presumed human
    reproductive toxicant) and label them with
    H360D (may damage the unborn child);
 • for effects during lactation: classify these
    substances for effects on or via lactation and
    label these substances with H362 (may
    cause harm to breastfed babies).
5       Health Council of the Netherlands | No. 2020/22                        2                             7
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<pre> chapter 01 | Scope                                    Cadmium and selected cadmium compounds | page 7 of 103
 01
 scope
6      Health Council of the Netherlands | No. 2020/22                        2                             8
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<pre> chapter 01 | Scope                                                                                  Cadmium and selected cadmium compounds | page 8 of 103
 1.1     Background                                                             on the Classification of Reproduction Toxic Substances, hereafter called
 As a result of the Dutch regulation on registration of substances toxic to     the Committee. The classification is based on the evaluation of published
 reproduction that came into force on 1 April 1995, the Minister of Social      human and animal studies, including those available in the REACH
 Affairs and Employment requested the Health Council of the Netherlands         registration dossiers, concerning adverse effects with respect to fertility
 to classify substances toxic to reproduction. This classification is performed and development as well as lactation.
 by the Health Council’s Subcommittee on the Classification of Reproduction
 Toxic Substances of the Dutch Expert Committee on Occupational Safety           Classification for reproduction (fertility (F) and development (D):
                                                                                 Category 1           Known or presumed human reproductive toxicant (H360(F/D))
 (DECOS). The classification is performed according to European Union               Category 1A       Known human reproductive toxicant
 Regulation (EC) 1272/2008 on classification, labelling and packaging               Category 1B       Presumed human reproductive toxicant
                                                                                 Category 2           Suspected human reproductive toxicant (H361(f/d)
 (CLP) of substances and mixtures. The CLP regulation is based on the            No classification for effects on fertility or development
 Globally Harmonised System of Classification and Labelling of Chemicals         Classification for lactation:
                                                                                                      Effects on or via lactation (H362)
 (GHS). The Subcommittee’s advice on the classification will be applied by                            No classification for lactation
 the Ministry of Social Affairs and Employment to extend the existing list of    Hazard statement codes:
                                                                                 H360F                May damage fertility.
 substances classified as reproductive toxicant (category 1A and 1B and 2)       H360D                May damage the unborn child.
                                                                                 H361f                Suspected of damaging fertility.
 or with effects on or via lactation. The ministry of Social Affairs and
                                                                                 H361d                Suspected of damaging the unborn child.
 Employment asked the Health Council to update the evaluation and                H360FD               May damage fertility. May damage the unborn child.
                                                                                 H361fd               Suspected of damaging fertility. Suspected of damaging the unborn child.
 classification on reproduction toxicity for a series of substances. In this
                                                                                 H360Fd               May damage fertility. Suspected of damaging the unborn child.
 report, such an update was performed for cadmium and selected cadmium           H360Df               May damage the unborn child. Suspected of damaging fertility.
                                                                                 H362                 May cause harm to breastfed babies.
 compounds. An evaluation of these substances was published previously
 in 2000.1
                                                                                The classification and labelling of substances is performed according
 1.2     Committee and procedure                                                to the criteria of the European Union (Regulation (EC) 1272/2008).
 This document contains a recommendation for classification of cadmium          The classification of substances is ultimately dependent on an integrated
 and several cadmium compounds by the Health Council’s Subcommittee             assessment of the nature of all parental and developmental effects
7        Health Council of the Netherlands | No. 2020/22                                                                                   2                                   9
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<pre> chapter 01 | Scope                                                                                      Cadmium and selected cadmium compounds | page 9 of 103
 observed, their specificity and adversity, and the dosages at which the                 between these hormone levels and functional fertility (ability to reproduce)
 various effects occur. The criteria necessarily leave room for interpretation,          are too uncertain.
 dependent on the specific data set under consideration. In the process of
 using the regulation, the Committee has agreed upon a number of                         In 2019, the President of the Health Council released a draft of the report
 additional considerations.                                                              for public review. The Committee has taken these comments into account in
                                                                                         deciding on the final version of the report. These comments, and the replies
    Additional considerations to Regulation (EC) 1272/2008                               by the Committee, can be found on the website of the Health Council.
    •  If there is sufficient evidence to establish a causal relationship between
       human exposure to the substance and impaired fertility or subsequent              1.3      Classification for effects on or via lactation
       developmental toxic effects in the offspring, the substance will be classified in The recommendation for classifying substances for effects on or via
       category 1A, irrespective of the general toxic effects (see Annex B, 3.7.2.2.1.).
                                                                                         lactation is also based on Regulation (EC) 1272/2008. The criteria define
    •  Adverse effects in a reproductive study, reported without information on the
       parental or maternal toxicity, may lead to a classification other than category
                                                                                         that substances which are bioavailable and have been shown to interfere
       1B, when the effects occur at dose levels which cause severe toxicity in          with lactation or which may be present (including metabolites) in breast
       general toxicity studies.                                                         milk in amounts sufficient to cause concern for the health of a breastfed
    •  Clear adverse reproductive effects will not be disregarded on the basis of        child, shall be classified and labelled. Unlike the classification of
       reversibility per se.
                                                                                         substances for fertility and developmental effects, which is based on
    •  The Committee does not only use guideline studies (studies performed
       according to OECD standard protocols) for the classification of substances,
                                                                                         hazard identification only (largely independent of dosage), the classification
       but non-guideline studies are taken into consideration as well.                   for effects during lactation is based on a risk characterization and therefore,
                                                                                         it also includes consideration of the level of exposure of the breastfed child.
 Regarding fertility, the Committee takes into account data on parameters                Consequently, a substance should be classified for effects during lactation
 related to fertility, such as seminal fluid volume and spermatozoa                      when it is likely that the substance would be present in breast milk at
 concentration. The Committee excludes publications containing only data                 potentially toxic levels. The Committee considers a concentration of a
 on sex hormone levels from the assessment, because the associations                     substance as potentially toxic to the breastfed child when this concentration
8         Health Council of the Netherlands | No. 2020/22                                                                          2                                  10
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<pre> chapter 01 | Scope                                                          Cadmium and selected cadmium compounds | page 10 of 103
 leads to exceeding the exposure limit for the general population (including
 sensitive groups), e.g. the acceptable daily intake (ADI).
 1.4     Data
 Starting point for this evaluation was the literature used in the previous
 evaluation.1 An additional literature search using the search terms
 ‘cadmium’ AND ‘repro*’ AND ‘toxic*’ was conducted in PubMed, through
 December 2018. Relevance was subsequently determined based on title
 and abstract. The ECHA database on registered substances was
 consulted as well. In addition, review documents prepared by SCOEL2
 and ATSDR3 were consulted. Publications cited in the selected sources
 were reviewed if considered appropriate.
 The Committee describes both human and animal studies in the text.
 Of each study, the quality and the level of documentation are considered
 in a qualitative manner. The Committee outlines its considerations in the
 text, where appropriate.
9       Health Council of the Netherlands | No. 2020/22                                              2                            11
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<pre> chapter 02 | Identity of the substances               Cadmium and selected cadmium compounds | page 11 of 103
 02
 identity of the
 substances
10     Health Council of the Netherlands | No. 2020/22                        2                             12
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<pre> chapter 02 | Identity of the substances                                                                                  Cadmium and selected cadmium compounds | page 12 of 103
                                                                                                                                      CAS Number           Harmonised classification        Dutch worker
 The Committee previously recommended on a classification for effects on                                                                                   (Annex VI of CLP)                classification
                                                                                                       cadmium                        7440-43-9 [1]        Repr. 2; H361 fd                 Repr. 2; H361fd
 reproduction for ‘cadmium and its compounds’.1 The Committee notes that
                                                                                                       (non-pyrophoric) [1]                                                                 Lactation
 data available on cadmium toxicity mainly involve studies with cadmium                                cadmium (pyrophoric)           7440-43-9            Repr. 2; H361fd                  Repr. 2; H361fd
                                                                                                                                                                                            Lactation
 chloride and cadmium oxide, whereas data on reproduction toxicity of                                  cadmium oxide                  1306-19-0 [2]        Repr. 2; H361fd                  Repr. 2; H361fd
 other cadmium compounds are lacking. Also, no data on bioavailability of                              (non-pyrophoric) [2]                                                                 Lactation*
                                                                                                       cadmium fluoride               7790-79-6            Repr. 1B; H360 FD                Repr. 1B; H30 FD
 other cadmium compounds were retrieved with the literature search.                                                                                                                         Lactation
                                                                                                       cadmium chloride               10108-64-2           Repr. 1B; H360 FD                Repr. 1B; H30 FD
 According to the Guidance on the Application of the CLP Criteria, ‘the                                                                                                                     Lactation
 assumption is that all substances and mixtures are considered to be                                   cadmium sulphate               10124-36-4           Repr. 1B; H360 FD                Repr. 1B; H30 FD
                                                                                                                                                                                            Lactation
 bioavailable to some extent’.4 The Guidance further states that ‘it should                            cadmium sulphide               1306-23-6            Repr. 2; H361 fd                 Repr. 2; H361fd
                                                                                                                                                                                            Lactation*
 be noted that concluding that there is lack of or reduced bioavailability has
                                                                                                       Cadmium compounds                                   None**                           Repr. 2; H361fd
 a high burden of evidence and needs to be supported by robust data and                                except the sulphate,                                                                 Lactation
                                                                                                       fluoride and chloride
 expert evaluation’. The Committee therefore considers the systemic
                                                                                                      * Due to the group classification of cadmium compounds.
 toxicity data on cadmium chloride and cadmium oxide also applicable to                               ** Annex VI of CLP contains a number of additional individual entries for cadmium compounds and an entry for all
                                                                                                         remaining cadmium compounds with some exception which do not include classification for reproductive toxicity.
 other cadmium compounds with an assumed bioavailability.
                                                                                                      The Committee further notes that three other registered cadmium
 For its current classification, the Ministry of Social Affairs and Employment                        compounds (cadmium nitrate, cadmium hydroxide, and cadmium
 requested a re-evaluation of cadmium and cadmium compounds due to                                    carbonate) have an harmonised classification for several toxicological
 some discrepancies between classifications for reproduction toxicity in                              endpoints other than reproductive toxicity (See section 2.4). As outlined
 the Annex VI of CLPa, and classifications for reproduction toxicity applied                          under ‘Grouping’ (Section 4.2), the Committee assumes bioavailability for
 in the Netherlands for workers according to the                                                      all of the above specified cadmium compounds, and applies a group
 “Arbeidsomstandighedenbesluit” (artikel 4.2a, tweede lid)b.                                          approach for its recommendation. When cadmium without further
                                                                                                      specification is used in the text of this advice, it pertains to both cadmium
                                                                                                      metal and the selected cadmium compounds.
 a
   https://echa.europa.eu/nl/information-on-chemicals/annex-vi-to-clp [last accessed June 25th, 2020]
 b
   https://wetten.overheid.nl/BWBR0008498/2020-07-01 [[last accessed June 25th, 2020]
11          Health Council of the Netherlands | No. 2020/22                                                                                                         2                                                13
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<pre> chapter 02 | Identity of the substances                                                             Cadmium and selected cadmium compounds | page 13 of 103
 The identity and physicochemical properties of cadmium and selected
 cadmium compounds are given below.
 2.1      Name and other identifiers of the substances
  EC/EINECS number 231-152-8      208-168-9      233-296-7        232-222-0        244-168-5    233-710-6                 215-146-2         233-331-6             215-147-8
  EC name            Cadmium      Cadmium        Cadmium chloride Cadmium fluoride Cadmium      Cadmium nitrate           Cadmium oxide     Cadmium sulphate      Cadmium sulphide
                                  carbonate                                        hydroxide
  CAS number         7440-43-9    513-78-0       10108-64-2       7790-79-6        21041-95-2   10022-68-1, 10325-94-7 1306-19-0            10124-36-4            1306-23-6
  CAS name           Cadmium                     cadmium chloride Cadmium fluoride                                        Cadmium oxide     Sulfuric acid,        215-147-8
                                                                                                                          (CdO)             cadmium salt (1:1)
  IUPAC name         cadmium      Cadmium(2+)    cadmium          Cadmium fluoride cadmium(2+)  Cadmium(II) nitrate       cadmium oxide     Cadmium sulphate      cadmium(2+)
                                  carbonate      dichloride                        dihydroxide                                                                    sulfanediide
  Synonyms                        Cadmium        Cadmium          Cadmium          Cadmium      Cadmium dinitrate;        Cadmium(II)oxide; Cadmium sulfate       Cadmium
                                  monocarbonate; dichloride;      difluoride;      dihydroxide  nitric acid, cadmium salt Cadmium           hydrate; Sulfuric     monosulfide;
                                  carbonic acid; cadmium(II)      Cadmium(2+)                                             monoxide;         acid, cadmium salt    Cadmium sulfide;
                                  cadmium salt   chloride;        fluoride                                                Monteponite;      (1:1), hydrate (3:8); yellow; Cadmium
                                                 dichlorocadmium                                                          Tienek kadmu      Cadmium(2+)           yellow
                                                                                                                                            sulfate hydrate;
                                                                                                                                            cadmium(2+)
                                                                                                                                            trisulfate
                                                                                                                                            octahydrate
  CLP Annex VI index 048-011-00-X 048-012-00-5   048-008-00-3     048-006-00-2     048-013-00-0 048-014-00-6              048-002-00-0      048-009-00-9          048-010-00-4
  number
  Molecular formula  Cd           CCdO3          CdCl2            CdF2             CdH2O2       Cd(NO3)2                  CdO               Cd.H2O4S              CdS
  Molecular weight   112.414      172.4          183.3            150.4            148.4 g/mol  236.4                     128.4             208.5                 144.5
  Structure
 2.2 Composition of the substances
 Not applicable to mono-constituent substances.
12        Health Council of the Netherlands | No. 2020/22                                                                              2                                           14
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<pre> chapter 02 | Identity of the substances                                                                                                Cadmium and selected cadmium compounds | page 14 of 103
 2.3          Physico-chemical properties of the selected compounds
 In the following table, physico-chemical properties are summarised for
 cadmium, and selected cadmium compounds (in order of water solubility).
                                 Cadmium                   Cadmium               Cadmium sulphate Cadmium nitrate            Cadmium             Cadmium               Cadmium          Cadmium      Cadmium oxide
                                 (7440-43-9)               chloride              (10124-36-4;           (10022-68-1,         hydroxide           sulphide              fluoride         carbonate    (1306-19-0)
                                                            (10108-64-2)         monohydrate)           10325-94-7)          (21041-95-2)        (1306-23-6)           (7790-79-6)      (513-78-0)
   State of the substance Brownish powder or               White powder          White powder           White powder         Greenish white      Orange ochre          Grey or white-   White powder Red ochre powder
   at normal temperature massive metal                                                                                       powder              powder                grey crystals
   and pressure
   Melting/freezing point        In air, the substance     In nitrogen and       105 °C                 In air it starts     186 °C              There is no           1,110 °C         356 °C       There is no
                                 starts oxidizing at ca.   air, the substance                           melting at 48 -61°C.                     melting and no                                      melting and no
                                 270°C (powder) and        starts melting at                            The substance                            decomposition,                                      decomposition,
                                 circa 470°C (cast         553°C.                                       starts decomposing                       sublimation starts at                               sublimation starts
                                 metal)                                                                 at 401 -405°C                            871 -890°C in air.                                  at ca. 950°C in air
   Density                       8.64 g/cm3                3.91 g/cm³            4.69 g/cm³             2.52 g/cm³           4.73 g/cm³          4.81 g/cm³            6.33 g/cm³       4.44 g/cm³   8.26 g/cm³
   Water solubility              2.3 and 8.7 mg/L, for 457 g/L                   767 g/L                507 g/L              69.5 mg/L           12 mg/L               4.3 mg/L         3.2 mg/L     2.1 mg/L
   (at room temperature)         the powder and bar
                                 samples, respectively
 2.4 International classifications#
 EU harmonised classification and hazard statement codes for
 reproduction toxicity (Repr.), carcinogenicity (Carc.), mutagenicity (Muta.),
 and specific target organ toxicity (repeated exposure) (STOT RE):
   Cadmium                    Cadmium chloride Cadmium sulphate                Cadmium nitrate                Cadmium hydroxide Cadmium sulphide          Cadmium fluoride       Cadmium carbonate Cadmium oxide
   (7440-43-9)                (10108-64-2)            (10124-36-4)             (10022-68-1, 10325-94-7)       (21041-95-2)         (1306-23-6)            (7790-79-6)            (513-78-0)          (1306-19-0)
   Repr. 2; H361fd            Repr. 1B; H360FD        Repr. 1B; H360FD         -                              -                    Repr. 2; H361fd        Repr. 1B; H360FD       -                   Repr. 2; H361fd
   Carc. 1B; H350             Carc .1B; H350          Carc. 1B; H350           Carc. 1B; H350                 Carc. 1B; H350       Carc. 1B; H350         Carc. 1B; H350         Carc. 1B; H350      Carc. 1B; H350
   Muta. 2; H341              Muta. 1B; H340          Muta. 1B; H340           Muta. 1B; H340                 Muta. 1B; H340       Muta. 2; H341          Muta. 1B; H340         Muta. 1B; H340      Muta. 2; H341
   STOT RE 1; H372            STOT RE 1; H372         STOT RE 1; H372          STOT RE 1; H372                STOT RE 1; H372      STOT RE 1; H372        STOT RE 1; H372        STOT RE 1; H372     STOT RE 1; H372
 #
   https://echa.europa.eu/nl/information-on-chemicals/cl-inventory-database [last accessed June 25th, 2020]
13           Health Council of the Netherlands | No. 2020/22                                                                                                                2                                          15
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<pre> chapter 03 | Manufacture and uses                     Cadmium and selected cadmium compounds | page 15 of 103
 03
 manufacture
 and uses
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<pre> chapter 03 | Manufacture and uses                                          Cadmium and selected cadmium compounds | page 16 of 103
 3.1     Manufacture
 No data are available.
 3.2     Identified uses
 Since the early 1900s, cadmium and cadmium compounds have been
 used in various commercial and industrial applications.5 Currently,
 cadmium is primarily used in batteries, although other cadmium-containing
 products include pigments, electroplates and coatings, and plastic
 stabilisers. Workers in industries that use or produce cadmium and
 cadmium compounds, such as the battery, pigment, plastics, construction,
 and electroplating industries are at risk of increased cadmium exposure.
 In particular, workers whose jobs involve the heating of cadmium and
 cadmium compounds are at risk of cadmium exposure, as these
 substances release harmful vapours when their temperature is increased.
 The use of cadmium and cadmium compounds has been restricted under
 REACH regulation (https://echa.europa.eu/nl/substances-restricted-under-
 reach/-/dislist/details/0b0236e1807e2518) [last accessed June 25th, 2020].
 Information about the current uses (product categories and process
 categories) can be found on the ECHA website (https://echa.europa.eu/nl/
 information-on-chemicals/registered-substances) [last accessed June 25th,
 2020].
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<pre> chapter 04 | Toxicokinetics and grouping              Cadmium and selected cadmium compounds | page 17 of 103
 04
 toxicokinetics (absorption,
 metabolism, distribution and
 elimination) and grouping
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<pre> chapter 04 | Toxicokinetics and grouping                                                    Cadmium and selected cadmium compounds | page 18 of 103
 4.1      Toxicokinetics                                                      The cadmium concentration in the kidneys is generally between 10 and
 In this section, the Committee provides a short summary based on the         50 mg/kg wet weight (in non-occupationally exposed individuals), while
 evaluations of the SCOEL2 and ATSDR3, with additional considerations of      smokers show 2-5 fold higher values than non-smokers. In the blood,
 the Committee.                                                               90% of the cadmium is localized in erythrocytes. Cadmium can cross the
                                                                              placenta; cadmium blood levels of newborns are approximately half of the
 Cadmium metal and cadmium salts are not well absorbed; absorption            levels in mothers.
 fractions have been reported of approximately 25, 1–10, or <1% of the
 dose following inhalation, oral, or dermal exposure, respectively. Several   Cadmium is excreted very slowly (<0.02% of the total body burden per
 factors can influence inhalation and oral absorption efficiency. Cadmium is  day), equal in quantity in the urine and faeces, resulting in an estimated
 absorbed by the respiratory route dependent on several factors (e.g. the     biologic half-life of 10-30 years in the kidney and 5-10 years in the liver.
 solubility of the cadmium compound involved, the size of the particles       The onset of renal toxicity and tubule loss accelerate the loss of cadmium,
 (dusts or fumes), the disposition pattern and ventilation), and the absorbed particularly in the kidneys. In the absence of occupational exposure, the
 fraction varies between 2 and 50%. The gastrointestinal absorption of        mean urinary cadmium concentration is generally below 1 μg/g creatinine
 cadmium is dependent on the diet composition and the individual iron and/    in adults. In populations with substantial occupational exposure, values
 or calcium status, but is usually less than 5%.                              can increase up to 50 μg/g creatinine.
 Cadmium is transported from its absorption site in the respiratory and
 gastrointestinal tracts to the liver where it accumulates. In the liver,     4.2      Grouping
 cadmium induces the synthesis of metallothionein which sequestrates          The mechanism responsible for cadmium-induced toxicity is suggested
 cadmium. Thereafter the cadmium-metallothionein complex is slowly            to involve several modes of action (reviewed in Rani et al. (2014)6).
 released and transported to the kidneys, the most critical targets after     Cadmium induces toxicity in various systems and tissues, including the
 long-term exposure. Here, cadmium is filtrated through the glomerulus and    reproductive system (addressed in the following chapters), respiratory
 reabsorbed in the proximal tubule where it may dissociate intracellularly.   tract, the urinary, cardiovascular, gastrointestinal and nervous systems
 After long-term low level exposure, approximately half of the cadmium        and the bones. At the cellular level, cadmium induces both the damaging
 body burden is stored in the liver and kidneys (mainly in the cortex).       and repair processes in which the cellular redox status plays a crucial role.
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<pre> chapter 04 | Toxicokinetics and grouping                                                     Cadmium and selected cadmium compounds | page 19 of 103
 Oxidative stress is assumed to be the principal molecular basis underlying    Overall, quantitative differences may exist from different absorption and
 cytotoxicity caused by cadmium.                                               distribution characteristics but the different forms of cadmium have similar
                                                                               toxicological profiles.3 The cadmium compounds specified in Chapter 2
 The cadmium-induced effects on the target sites are attributed to the         have anions with no substantial toxicity and the toxicity of these
 cadmium cation, independently from the anionic species. However, the          compounds can therefore be attributed to cadmium. Furthermore, these
 absorption and the distribution of cadmium to various target sites, and       compounds are water soluble within the range of solubility of cadmium
 subsequently the severity of cadmium induced effects, vary dependent on       chloride and cadmium oxide, for which toxicological data are available and
 the form of cadmium and the route of exposure.3 The Committee notes           systemic availability is demonstrated. Overall, the Committee assumes
 that for its evaluation, the toxicological data available primarily involves  that all specified cadmium compounds are bioavailable to some extent.
 cadmium chloride (on the oral, subcutaneous and intraperitoneal route)        This includes metallic cadmium, as the Committee assumes the release of
 and cadmium oxide (via exposure by inhalation). Cadmium chloride is           cadmium ions following oral or inhalatory absorption. The Committee
 highly soluble in water, whereas cadmium oxide is not. In general, the        therefore considers conclusions based on data on cadmium chloride and
 solubility in water and biological fluids is thought to be an important       cadmium oxide also applicable to cadmium nitrate, cadmium sulphate,
 determinant for the amount of metal cations that can reach the target site    cadmium sulphide, cadmium hydroxide, cadmium fluoride, cadmium
 after exposure via the oral or inhalation route. In case of cadmium           carbonate, and cadmium metal.
 compounds, the ATSDR states that the absorption of cadmium in lung
 differs somewhat among chemical forms, but notes that the pattern does
 not correlate with solubility. The Committee notes that in inhalation studies
 with cadmium oxide, systemic availability was demonstrated both in rats
 and mice.7
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<pre> chapter 05 | Toxicity for reproduction                Cadmium and selected cadmium compounds | page 20 of 103
 05
 toxicity for
 reproduction
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<pre> chapter 05 | Toxicity for reproduction                                                                                   Cadmium and selected cadmium compounds | page 21 of 103
 Adverse effects reported in animal studies are statistically significant                               5.1      Adverse effects on sexual function and fertility
 (p<0.05), unless specified otherwise. In the summary tables, the                                       Summary table of animal studies on adverse effects on sexual function
 substance used in the study is specified whereas in the study summaries,                               and fertility.
 the Committee refers to ‘cadmium’ only. For the purpose of comparison,
 doses are expressed in cadmium equivalents. The results are presented
 in chronological order, separated based on exposure route.
  Reference         Species             Experimental period              Substance Dose                     General toxicity                      Effects on reproductive organs or reproduction
                                        and design
  Oral exposure
  Schroeder and     Mouse, Charles      Multi-generation study;          Cadmium   0 or 10 mg Cd/L          2 maternal deaths in F2               Strain could not be bred beyond F2-generation
  Mitchener         River DC, males and administration continuously in   chloride  (equivalent to 0 or 2.1
  (1971)            females, N=5/group) drinking water                             mg Cd/kg bw)
  Krasovskii et al. Random bred white   Administration: continuously     Cadmium   0, 0.00005, 0.0005 or    0.0005 mg: Changes in biochemical     0.0005 mg: reduced spermatogenesis
  (1976)            rat (males) (N=?)   via drinking water for 6 m       chloride  0.005 mg Cd/kg bw        parameters and in the conditional
                                                                                   (reported by authors to  reflex activity
                                                                                   correspond to 0.001,
                                                                                   0.01 and 0.1 mg Cd/L)
  Dixon et al.      Sprague- Dawley,    Acute, serial breeding; single   Cadmium   0, 6.25, 12.5 or 25 mg   No effects on blood chemistry         No effects on male fertility were observed
  (1976)            rats male (N=10)    dose; sacrifice: up to 6 w after chloride  Cd/kg bw
                                        gavage.
                                        Subchronic administration in               0, 0.001, 0.01 or 0.1    No effects on clinical parameters and • No effects on male fertility
                                        drinking water; 30, 60, 90 d;              mg Cd/L (equivalent to   bodyweight                            • No effect on weights of testis, prostate and seminal
                                        sacrifice: 30, 60, 90 d.                   0, 0.00014, 0.0014 or                                            vesicles
                                        Fertility was assessed by                  0.014 mg Cd/kg bw,                                             • No effect on testis histopathology
                                        housing treated males with                 according to authors)                                          • No effects on serum hormone levels.
                                        virgin females, for periods of 7
                                        days each. Nine days after
                                        breeding period, females were
                                        examined.
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<pre> chapter 05 | Toxicity for reproduction                                                                                Cadmium and selected cadmium compounds | page 22 of 103
  Reference       Species             Experimental period              Substance Dose                     General toxicity                        Effects on reproductive organs or reproduction
                                      and design
  Kotsonis and    Sprague-Dawley rats Administration continuously for  Cadmium   0, 10, 30 or 100 mg      At 30 and 100 mg/L tubular necrosis     • No effect on fertility (fraction of females producing
  Klaassen        (males)(N=6)        24 w in drinking water;          chloride  Cd/L (equivalent to 0,   in kidney                                 offspring; number of foetuses per animal)
  (1978)                              sacrifice: 3, 6, 12, 24 w.                 1.2, 3.7 or 12.2 mg Cd/                                          • No effects on histopathology and weight of testis
                                      Testicular function was                    kg bw)                                                           •
                                      assessed by mating with an
                                      untreated virgin female in the
                                      week prior to sacrifice.
  Laskey et al.   Sprague-Dawley rat  Administration: continuously     Cadmium   0, 0.1, 1.0 or 5.0 mg    • 1.0 mg: PN 130: Decreased liver       5.0 mg; PN 50+130:
  (1980)          (males and females) via drinking water sacrifice: PN chloride  Cd/L (equivalent to 0,     weight                                • Decreased preimplantation loss
                  (N=9-10)            50, 130                                    0.01, 0.13 or 0.64 mg    • 5.0 mg: PN 50+130 depressed liver     • No effect on litter size,
                                                                                 Cd/kg bw)                  weight                                • Reduced sperm count
  Sutou et al.    Sprague-Dawley rat  Administration: 6 w by gavage    Cadmium   0, 0,1, 1.0 or 10 mg Cd/ mid and high dose: reduced body and     10 mg:
  (1980a,b)       (males & females)   prior to mating, mating, and     chloride  kg bw                    organ weight                            • Reduced copulation (statistical significance not
                  (N=13-14)           gestation (NB treated males                                                                                   indicated)
                                      were mated with treated                                                                                     • Reduced average number of total implants per female
                                      females).                                                                                                   • Reduced average number live foetuses per female
  Zenick et al.   Sprague- Dawley rat Administration: 70-80 d in       Cadmium   0, 17.2, 34.4 or 68.8    • Reduction in water intake             • No effect on reproductive system (testes weight;
  (1982)          (males) (N=5)       drinking water prior to mating   chloride  mg Cd/L (equivalent to • No effects on body weight                 cauda weight; sperm count; number of normal sperm
                                      with untreated females.                    of 0, 0.7, 1.3, and 2.6  •                                         cells)
                                      Pregnant females were                      mg/kg bw, assuming 15                                            • No effect on reproductive parameters (mating
                                      sacrificed at GD 20                        mL water intake                                                    success; number of pregnancies; number of
                                                                                 (derived from graph)                                               implantations, corpora lutea) litter size; pup body
                                                                                                                                                    weight)
  Baranski et al. Wistar rats female  Administration for 5 d/w for 5 w Cadmium   0.04, 0.4 or 4 mg Cd/kg No information provided                  No effect on fraction inseminated and pregnant females,
  (1983)          (N=?)               by gavage prior to mating and    chloride  bw                                                               average number of total implantations and corpora lutea
                                      continued thereafter                                                                                        (data not specified)
  Baranski and    Wistar rats female  Administration: 5 d/w for 14 w   Cadmium   0.04, 0.4, 4 or 40 mg    Increased mortality up to 54% after     Increase in the mean duration of the oestrous cycle at
  Sitarek (1987)  (N=11-13/group)     by gavage prior to mating and    chloride  Cd/kg bw                 13-14 w, compared to 0% in controls;    40 mg/kg bw/d after 7-8 weeks and after 13-14 weeks
                                      continued thereafter.                                               decreased body weight
  Bomhard et al.  Wistar rats male    Administration by gavage         Cadmium   0 or 50 mg Cd/kg bw      No increased mortality; no difference   No histopathological alterations in the testis
  (1987)          N=30/ Cd group      Single dose                      chloride                           in appearance, general behaviour or
                  N=10/control group                                                                      food and water consumption from the
                  Supplementary                                                                           control animals. Slight growth
                  studies 25 or 35                                                                        retardation in the first 10 weeks.
                  males/group
                                      10 weekly doses of cadmium                 0 or 5 mg Cd/kg bw       1 x 50 and 10 x 5: No increased         No histopathological alterations in the testis
                                      chloride                                                            mortality; no difference in appearance,
                                                                                                          general behaviour or food and water
                                                                                                          consumption from the control animals.
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<pre> chapter 05 | Toxicity for reproduction                                                                                    Cadmium and selected cadmium compounds | page 23 of 103
  Reference        Species              Experimental period              Substance Dose                      General toxicity                        Effects on reproductive organs or reproduction
                                        and design
                                        Supplementary studies:                     0 or 200 mg Cd/kg bw;     Clinical signs, most animals died       1 x 100 and 1 x 200: Severe lesions in the testis
                                        Administration of a single dose            0 or 100 mg Cd/kg bw      within 3 days (28/35 at 100 mg; 24/25
                                        by gavage                                                            at 200 mg)
  Andersen et al.  CBA/Bom male mice Administration of a single dose     Cadmium   0, 270, 530, 790 μmol     Mortality: 0/16 (0), 2/54 (270), 11/60  Histological lesions of testis at the two highest doses
  (1988)           (N=7-15)             by gavage; sacrifice at 10 d     chloride  Cd/kg bw (0,30,60,90      (530), 36/42 (790). Dose-dependent
                                        after dosing                               mg Cd/kg bw), oral        histological lesions of liver, stomach
                                                                                   (gavage)                  and duodenum, from270 μmol Cd/kg
                                                                                                             bw onwards.
  Borzelleca et    Sprague-Dawley rats Single dose by gavage             Cadmium   0, 25, 51, 107 or 225     Reduced spleen weight and increased No effect on testis or ovary weights
  al. (1989)       (male and female)                                     chloride  mg CdCl2/kg bw            lung weight in males
                   (N=10/group)                                                    (equivalent to 0, 15, 31,
                                                                                   66 and 138 mg Cd/kg
                                                                                   bw)
                                        10 consecutive days by           Cadmium   0, 25, 51, 107 or 225     Dose-dependent effects on mortality,    Histopathological changes in testis; not in ovaries
                                        gavage                           chloride  mg CdCl2/kg bw            body weights, organ weights
                                                                                   (equivalent to 0, 15, 31, (including testis) of male and females.
                                                                                   66 and 138 mg Cd/kg       Histopathological changes in kidney,
                                                                                   bw)                       testis and liver
                                        10 d via drinking water          Cadmium   0 or 13-323 mg CdCl2/L Dose-dependent effects on body             No effect on testis or ovary weights
                                        necropsy: 24 h after last dosing chloride  (equivalent to 1.5, 15.3 weights and organ weights
                                                                                   or 31.3 mg Cd/kg bw)
  Saygi et al.     Wistar rats (control Administration continuously via Cadmium    0 or 10 mg Cd/L           Histopathological effects on liver and  • Histopathological effects on testis
  (1991)           N=8; experimental    drinking water for 52 w to males chloride  (equivalent to 0 or 1.1   kidney                                  • Reduced fertility after 52 weeks cadmium exposure
                   group N=20)          only. Functional fertility was             mg Cd/kg bw)                                                        (100% in controls versus 60% in cadmium-treated
                                        assessed after 52 w. Times of                                                                                  males)
                                        necropsy: 28, 40, 56 w                                                                                       •
  Massanyi et al.  Hyla rabbits         Administration continuously via  Cadmium   0 or 1 mg Cd/kg bw        No information provided                 • Decreased relative volume of growing follicles
  (2007)           (females) (N=8)      diet for 5 m                     chloride                                                                    • Increased stroma
                                                                                                                                                     • Increased number of atretic follicles
                                                                                                                                                     • Ultrastructural alterations
  Hu et al. (2014) Chinese Kun Ming     Administration continuously via  Cadmium   0, 0.975 or 1.95 mg       Slight reduction in body weight         • Reduction in serum testosterone levels in both
                   mice (male)(N=?)     diet for 6 m                     chloride  Cd/mouse (equivalent                                                treatment groups
                                                                                   to 0, 20 or 40 mg Cd/kg                                           •
                                                                                   bw)
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<pre> chapter 05 | Toxicity for reproduction                                                                                 Cadmium and selected cadmium compounds | page 24 of 103
  Reference       Species              Experimental period              Substance Dose                     General toxicity                           Effects on reproductive organs or reproduction
                                       and design
  Nasiadek et al. Wistar rats (female) Administration for 28 d by       Cadmium   0, 0.09, 0.9,1.8, 4.5 mg No effects on body weight or organ         • Changes in catalase (CAT) activity and lipid
  (2014; 2018)    (control: N=10;      gavage. Analysis of uterine      chloride  Cd/kg bw                 weights                                      peroxidation (MDA) levels at a dose of 1.8 and 4.5 mg/
                  Cd-treated: N=8-10)  tissue on the first day and then                                                                                 kg bw, both after 28 days of exposure and 90 days
                                       after 90 days post exposure                                                                                      following the termination of Cd exposure
                                                                                                                                                      • Disturbance in oestradiol and progesterone in plasma
                                                                                                                                                      • Increased cycle length (prolonged diestrous) after
                                                                                                                                                        30-d exposure at 4.5 mg/kg bw
                                                                                                                                                      • Increased increase (not dose dependent and
                                                                                                                                                        reversible) in endometrial thickness at all doses
                                                                                                                                                      • Ovary damage (degeneration of corpora luteum and
                                                                                                                                                        granulosa cells; damage to and reduction of oocytes)
                                                                                                                                                        at the highest dose
  Wang et al.     Sprague-Dawley rats Administration for 28 d by        Cadmium   0, 1, 2.5, 5, 10, or 20  • Reduced body weights at doses            • Decreased weights of prostate and seminal vesicle
  (2014)          (males and females) gavage (Enhanced OECD TG          chloride  mg Cd/kg ·bw               exceeding 2.5 mg/kg bw (males) or          glands at 2.5, 10, 20 mg/kg bw in males.
                                       407)                                                                  1 mg/kg bw (in females).                 • Decreased levels of serum luteinizing hormone and
                                                                                                           • Reduced thyroid weight was at 2.5          testosterone at doses of 10-20 mg/kg bw groups in
                                                                                                             mg/kg bw and higher in males.              males.
                                                                                                           • Clinical signs (listlessness,            • Increased uterus weight and histopathological
                                                                                                             anorexia, low hair-gloss, irritation) at   changes at 10-20 mg/kg bw/
                                                                                                             5, 10 and 20 mg/kg bw in both
                                                                                                             sexes.
                                                                                                           • Effects on haematology or clinical
                                                                                                             biochemistry exceeding 2.5 mg/kg
                                                                                                             bw (females) or 1 mg/kg bw (males)
  Zhao et al.     Sprague Dawley rats Administration every 2 d for 9    Cadmium   0 and 22.15 mg Cd/kg     Information on general toxicity not        • Reduced sperm motility and viability
  (2015)          (male) (N=6/group)   w, and allowed to mate with      chloride  bw                       provided                                   • Increased sperm malformation rate (including large
                                       untreated females                                                                                                heads, decollation, and folding and broken tails)
  Medina et al.   Wistar rats (male)   Administration 5 d/w for 3 m     Cadmium   0 and 10 mg Cd/kg bw     Information on general toxicity not        • Morphological changes in testis (after 2 m) and
  (2017)          (N=6/group)                                           chloride                           provided                                     reduced sperm motility (after 3 m)
  Wang et al.     C57BL/6 mice         Administration for 5 w by        Cadmium   0 and 1.9 mg Cd/kg bw    Information on general toxicity not        • Reduced sperm motility and viability
  (2017)          (male) (N=5/group)   gavage                           chloride                           provided
  Sapmaz-Metin    BALB/c mice          Administration for 30 or 60 d in Cadmium   0 and 200 ppm            Information on general toxicity not        • No effect on cycle length was observed, and no stage
  et al. (2017)   (female) (N=6/group) drinking water                   chloride  (equivalent to 0 and 43  provided                                     specific microscopic alterations were noted (except
                                                                                  mg Cd/kg bw)                                                          the presence of apoptotic cells)
                                                                                                                                                      • Decreases in endometrial thickness and number of
                                                                                                                                                        glands in oestrus phase uteri
                                                                                                                                                      • Decreased endometrial eosinophilia and increased the
                                                                                                                                                        number of mast cells
                                                                                                                                                      • Apoptosis in the uterus and the endometrium (at 60 d)
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<pre> chapter 05 | Toxicity for reproduction                                                                                  Cadmium and selected cadmium compounds | page 25 of 103
  Reference      Species               Experimental period               Substance Dose                    General toxicity                         Effects on reproductive organs or reproduction
                                       and design
  Subcutaneous/intraperitoneal injection
  Kar et al.     Colony bred albino    Single dose subcutaneously;       Cadmium   0 or 10 mg CdCl2/kg bw No information on general toxicity        • Cellular and vascular changes in the ovary(partly
  (1959)         rat (females)(N=?)    sacrifice at                      chloride  (equivalent to 6.1 mg   provided                                   recovered after 96 h, completely recovered after 168 h)
                                       0,6,24,48,96,168,360 h after                Cd/kg bw)                                                        • No effect on uterine weight
                                       injection
  Parízek (1960) Rat (males and        Single dose subcutaneously;       Cadmium   0 or 40 μmol CdCl2/kg   No information on general toxicity       • Decreased weights of testis, seminal vesicles and
                 females) (N=?)        sacrifice: up to 4 months after   chloride  bw (equivalent to 4.5   provided                                   prostate.
                                       injection                                   mg Cd/kg bw)                                                     • Severe histopathological changes of reproductive
                                                                                                                                                      organs
  Nordberg       Male CBA mice         Administration subcutaneously     Cadmium   0 or 2.2 μmol CdCl2/kg  • No abnormal behaviour                  • decreased weight and size of the seminal vesicles
  (1975)         (N=8)                 for 5 d/w for 6 m                 chloride  bw (equivalent to 0.2   • Reduced body weight                    • Indications of a lower secretory capacity of seminal
                                                                                   mg Cd/kg bw)            • Reduced urinary excretion of protein     vesicles.
  Lohiya et al.  Langurs (male adult)  Administration of a single dose   Cadmium   1) 0 or 4 mg CdCl2/kg  No information provided                  2) Testis small and oedematous; weight reproductive
  (1976)         (N=3)                 subcutaneously; sacrifice at 1)   chloride     bw (equivalent to 0                                              organs reduced. 1) + 2) dose depended histological
                                       30 d after injection; 2) 60 d                  or 2.5 mg Cd/kg bw)                                              lesions in testis and epididymis
                                       after injection                                2) 0 or 12 mg CdCl2/
                                                                                      kg bw (equivalent to
                                                                                      0 or 7.4 mg Cd/kg
                                                                                      bw)
  Bomhard et al. Wistar rats male      Administration intraperitoneally. Cadmium   0 or 2.5 mg Cd/ kg bw   • No difference in appearance,           Severe lesions testis
  (1987)         N=10/group            Single dose; Necropsy after       chloride                            general behaviour or food and water
                                       12, 18 and 30 months                                                  consumption
                                                                                                           • Transient inflammatory reaction at
                                                                                                             injection site
                                                                                                           • Leydig cell tumours in all animals
                                                                                                           • Slight growth retardation in the first
                                                                                                             10 w
                 N=10/group            10 weekly doses of cadmium                  0 or 0.25 mg Cd/kg bw                                            None
                                       chloride intraperitoneally.
                                       Necropsy after 12, 18 and 30
                                       months
                 N=?                   Supplementary studies:                      0 or 2 mg Cd/kg bw      Transient inflammatory reaction at       Severe lesions testis
                                       single dose of cadmium                                              injection site and transient decrease
                                       chloride subcutaneously                                             body weight
  Rehm and       hamster (1 strain)    Administration of single dose     Cadmium   0 or 20-47.5 μmol/kg    Mortality due to liver necrosis in all   Haemorrhagic necrosis of the ovaries in all hamsters,
  Waalkes (1988) (N=6-48) mouse (3     subcutaneously, at 21-24 d, or    chloride  bw (equivalent to 2.2   species at the highest dose, in          most groups mice and high dose groups rats
                 strains) (N=5-12) rat 8 w old sacrifice:                          -5.3 mg Cd/kg bw)       particular in immature animals
                 (2 strains) (N=4-35)  1,2,3,4,7,14,28,56 d after
                 (females)             administration
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<pre> chapter 05 | Toxicity for reproduction                                                                                Cadmium and selected cadmium compounds | page 26 of 103
  Reference        Species             Experimental period             Substance Dose                     General toxicity                     Effects on reproductive organs or reproduction
                                       and design
  Wlodarczyket     Golden hamsters     Administration of a single dose Cadmium   0 or 0.5 mg Cd/kg bw     No information provided              • Decreased weights and histopathological changes of
  al. 1995         (males) (N=15)      subcutaneously. Necropsy:       chloride                                                                  testis, epididymis and accessory sex organs
                                       1,4,10 w after treatment                                                                                • Decreased number of sperm cells in epididymis after 4
                                                                                                                                                 weeks of treatment
  Laskey et al.    Sprague-Dawley rats Administration of a single dose Cadmium   0, 1.6, 3.1, 7.4, 16 or  • Mortality at 74 and 152 µmol/kg bw • Reduced weight of testis, seminal vesicles and
  (1984)           (males) (N=10/      subcutaneously. Animals were    chloride  33, 74, or 152 µmol/kg • No effects on body weight at lower     epididymis
                   group)              killed and analysed 14 days               bw (0, 0.18, 0.35, 0.83,   doses                              • Reduced sperm count (at higher doses no sperm was
                                       after dosing                              1.8, 3.7, 8.3 or 17.1 mg                                        present)
                                                                                 Cd/kg bw
  Aoyagi et al.    Sprague-Dawley rats Administration subcutaneously, Cadmium    0 or 0.6 mg Cd/kg bw     There were no differences in the     Reduced number of spermatogonia and spermatocytes
  (2002)           (males) (N=3-6)     daily for 6 w Testicular damage chloride                           testes /bodyweight ratio between the in weeks 2-6
                                       was evaluated every week                                           study and control groups
  Paksy et al.     CFY rats (females)  Administration: single doses    Cadmium   0, 5, 10 or 15 mg        No information provided              • Exp. 1: 10 and 15 mg/kg: increased PRL serum levels
  (1989)                               subcutaneously. Exp.1:          chloride  CdCl2/kg bw                                                     and decreased LH serum levels. 10 mg/kg: decreased
                                       Sacrifice and collection of               (equivalent to 0, 3.1,                                          FSH serum levels
                                       blood samples on 13.00,                   6.1 or 9.2 mg Cd/kg                                           • Exp. 2: 10 and 15 mg/kg: decreased basal secretion
                                       15.00, 16.30 or 18.00. Exp. 2:            bw)                                                             of P; 5, 10 and 15 mg/kg: diminished effect of hCG,
                                       measurement of ovarian blood                                                                            • Increase of anovulatory at all doses
                                       flow, hCG induced hormone                                                                               •
                                       secretion, and ovary histology
                                       at 48 h
  Paksy et al.     CFY rats (females)  Administration: a single dose   Cadmium   0, 2.5, 5 or 10 mg       A reduced bodyweight later during    A Dose-dependent reduction in the fraction of rats
  (1996)                               subcutaneously Groups: A:       chloride  CdCl2/kg bw              pregnancy was observed in all groups mated in groups B and C.
                                       administration at diestrous 2,            (equivalent to 0, 1.5,                                        In group A, a statistically non-significant reduction was
                                       mating after 32 h; B:                     3.1 or 6.1 mg Cd/kg                                           only observed at the highest dose.
                                       administration at oestrous,               bw)
                                       mating after 80 h; C:
                                       administration at D2, mating
                                       after 132 h
  Massanyi et al.  Hyla rabbits        Administration: single dose of  Cadmium   0 or 1.5 mg Cd/kg bw     No information provided              • Decreased relative volume of growing follicles
  (2007)           (females) (N=8)     1.5 mg/kg bw orally via diet.   chloride                                                                • Increased stroma
                                       Animals were sacrificed 48 h                                                                            • Increased number of atretic follicles
                                       thereafter                                                                                              • Ultrastructural alterations
  Wu et al. (2017) Sprague-Dawley rat  Administration of a single dose Cadmium   0, 0.3 or 0.6 mg Cd/kg   A reduced bodyweight at both doses   • Reduced serum testosterone and luteinizing hormone
                   (males) (N=5)       ip of 0, 0.3 or 0.6 mg/kg       chloride  bw                                                              levels
                                       followed by ethane dimethane                                                                            • Reduced number of regenerated Leydig cells in the
                                       sulfonate treatment 20 days                                                                               testis
                                       later to eliminate adult Leydig
                                       cells
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<pre> chapter 05 | Toxicity for reproduction                                                                                  Cadmium and selected cadmium compounds | page 27 of 103
  Reference       Species               Experimental period              Substance Dose                      General toxicity                       Effects on reproductive organs or reproduction
                                        and design
  Inhalation
  Baranski 1984   Wistar rats (females) Exposure to aerosols for 5       Cadmium   0, 0.02, or 0.16 mg Cd/ No information provided                  0, 0.02, or 0.16 mg Cd/m3: Gestation indices of 54%
                  (N=?)                 days a week, 5 h daily for 5     oxide     m3 (equivalent to 0,                                             (15/28), 44% (11/25) and 41% (7/17)
                                        months followed by a                       0.006 or 0.05 mg Cd/kg
                                        maximum period of 3 weeks of               bw)
                                        mating
  Baranski 1985   Wistar rats (female)  Exposure by inhalation for 1) 5  Cadmium   1) 0, 0.02 0.16 mg Cd/    Increased mortality at 1 mg/m3         Decrease in fertility at 1 mg Cd/m3, the magnitude of the
                  (N=?)                 hours a day and 5 days weekly    oxide     m3 (equivalent to 0,                                             fertility effects (gestation index, corpora lutea) are not
                                        for a period of 5 months or 2)             0.004, 0.03 mg Cd/kg                                             specified in the publication
                                        for 4 months                               bw, respectively)
                                                                                   2) 1 mg Cd/m3
                                                                                   (equivalent 0.18 mg
                                                                                   Cd/kg bw)
  Baranski and    Wistar rats (female)  Exposure by inhalation for 20    Cadmium   0.02, 0.16 or 1 mg Cd/ At the highest concentration, an          • Increase in the mean duration of the oestrous cycle
  Sitareka (1987) (N=?)                 weeks, 5 hours/day, 5 days/      oxide     m3 (equivalent to 0.004, increase in mortality and an decrease     mainly due to lengthening of dioestrus at 1 mg Cd/m3.
                                        week                                       0.03, or 0.18 mg Cd/kg in body weight gain was observed          • Increased percentage of females with oestrous cycles
                                                                                   bw)                                                                lasting over 6 days was shown 18 weeks after
                                                                                                                                                      exposure at 0.16 mg Cd/m3
  NTP, (1995)     F344 Rats (male and Exposure by inhalation for 6 h     Cadmium   0, 0.025, 0.05, 0.1,      Enlargement and paleness of the        In males in the 1 mg/m3 group: Reduction spermatid
                  female)               and 20 min/d, 5 d/week for 13    oxide     0.25 or 1 mg CdO/m3       tracheobronchial and mediastinal       heads per gram of testis, spermatid heads per testis and
                                        weeks - OECD Guideline 413                 (equivalent to (0, 0.005, lymph nodes                            spermatid count.
                                        (Subchronic Inhalation Toxicity:           0.01, 0.02, 0.05 and                                             No treatment-related microscopic changes in the testis
                                        90-Day Study)                              0.20 mg Cd/kg bw)                                                or epididymis.
                                                                                                                                                    In females the 1 mg/m3 group: increased oestrous cycle
                                                                                                                                                    length but no treatment related histologic changes in the
                                                                                                                                                    reproductive organs.
  NTP (1995)      B6C3F1 mice (male     Exposure by inhalation for 6 h   cadmium   0, 0.025, 0.05, 0.1,      Reticulocyte numbers were greater in   No effects on reproductive organs
                  and female)(N=10)     and 20 min/d, 5 d/week for 13    oxide     0.25 or 1 mg CdO/m3       exposed females (0.025 mg/m3 and
                                        weeks - OECD Guideline 413                 (equivalent to (0, 0.006, higher); Enlargement of the
                                        (Subchronic Inhalation Toxicity:           0.01, 0.02, 0.06 and      tracheobronchial lymph nodes and
                                        90-Day Study)                              0.23 mg Cd/kg bw)         pale grey mottled lungs (0.25 and 1
                                                                                                             mg/m3 groups); significant differences
                                                                                                             in lung weights occurred from 0.05
                                                                                                             mg/m3
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<pre> chapter 05 | Toxicity for reproduction                                                         Cadmium and selected cadmium compounds | page 28 of 103
 5.1.1   Animal studies                                                          examined microscopically on day 1 and 7 and for 6 succeeding 7-day
 Fertility studies, oral exposure                                                intervals. In addition, in the drinking water study, breeding studies were
 In a multigeneration reproduction study, mice were allowed to breed for         performed. The studies failed to reveal any biologically change in clinical
 6 months during which cadmium was offered continuously in the drinking          serum chemistry or weight of the body, testis, prostate, or seminal
 water at a level of 10 mg/L (an equivalent dose of 2.1 mg/kg bw/d)              vesicles. No effect on male fertility was observed after acute or chronic
 (Schroeder and Mitchener (1971)8). No statistically significant effects on      (data not shown) cadmium administration.
 reproduction were observed. Two maternal deaths occurred in the F2;
 breeding was discontinued as 3 of 5 pairs failed to breed in the F2.            Kotsonis and Klaassen (1978)11 studied the toxicity of cadmium in male
                                                                                 Sprague Dawley rats after oral administration of cadmium in the drinking
 Chronic exposure of groups of random bred white male rats to 0.00005,           water (0, 10, 30 or 100 mg cadmium/L; (equivalent to 0, 1.2, 3.7 or 12.2
 0.0005 or 0.005 mg cadmium/kg body weight in the drinking water (dose           mg cadmium/kg bw/d)) for 24 weeks. Fertility was tested after 3, 6, 12 and
 levels corresponding to 0.001, 0.01 and 0.1 mg cadmium/L, according to          24 weeks and appeared not affected. At necropsy after 24 weeks no effect
 the authors) resulted in the two highest dose group in a reduced                on testis weight and histopathology was observed. At 30 and 100 mg/L,
 spermatogenesis (Krasovskii et al. (1976)9). At these doses, also changes       effects on the kidney were detected.
 in biochemical parameters and in the conditional reflex activity were
 observed. At the highest dose, several alterations, among them loss of          Groups of 9-10 male and female Sprague-Dawley rats were, starting from
 body weight and an increase of number of tubules with cast-off epithelium       conception, chronically exposed to 0, 0.1, 1.0 or 5.0 mg cadmium/L in the
 and with 12th stage meiosis, were noted.                                        drinking water (equivalent doses of 0, 0.01, 0.13 or 0.64 mg/kg bw/d)
                                                                                 (Laskey et al. (1980)12). The F1 offspring was sacrificed either on
 Dixon et al. (1976)10 studied the effects of (I) a single oral dose of 0, 6.25, postnatal day (PND) 50 or around PND 130. Sacrifice on PND 50
 12.5 and 25 mg cadmium/kg body weight or (II) exposure via drinking             revealed a decreased liver weight in the 5.0 mg/L group, and a reduced
 water containing 0, 0.001, 0.01 and 0.1 mg cadmium/L (equivalent to 0,          sperm count. Adult sacrifice showed a decreased liver weight in the 1.0
 0.0001, 0.001, and 0.01 mg/kg bw) for 90 days in male rats. After acute         and 5.0 mg/L groups, and a decreased serum progesterone level and litter
 dosing serial matings were performed for 70 days and testes were                size, and a decreased preimplantation loss in the 5.0 mg/L group.
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<pre> chapter 05 | Toxicity for reproduction                                                                   Cadmium and selected cadmium compounds | page 29 of 103
 Groups of 14 male or female Sprague-Dawley rats were administered 0,                      not affect the average number of total implantations and corpora lutea
 0.1, 1.0 or 10 mg cadmium/kg body weight/day by gavage for 6 weeks                        (data were not specified).
 prior to and during a 3 weeks mating period (Sutou et al. (1980a,b)13,14).
 Body and organ weights of males treated with 1.0 and 10 mg/kg body                        Baranski and Sitareka (1987)17 administered female rats an aqueous
 weight/day were depressed. The females of the mid and high dose groups                    solution of cadmium for 14 weeks, 5 days/week (0, 0.04, 0.4, 4 and 40 mg
 showed mild to overt signs of toxicity as concluded from body weights                     cadmium/kg bw/day). A pronounced increase in the mean duration of the
 (only at 10 mg/kg bw) and organ weights. A decrease was observed in the                   oestrous cycle mainly due to lengthening of dioestrus was noted already 6
 10 mg group in numbers of copulations, pregnancies, and implantation                      weeks after treatment of females at 40 mg cadmium/kg bw/d. At this dose,
 sites.                                                                                    an increase in mortality and a decrease in body weight gain was observed.
 Groups of male Sprague-Dawley rats were exposed to 0, 17.2, 34.4 or                       Bomhard et al. (1987)18 studied the chronic effects of single (1x 50 mg
 68.8 mg cadmium/L (equivalent to 0 of 0, 0.7, 1.3, and 2.6 mg/kg bw/da)                   cadmium/kg bw) and multiple oral cadmium administrations (10x 5 mg/kg
 in the drinking water for 70 days (Zenick et al. (1982)15 Following mating                bw, weekly) on the testis of Wistar rats. Rats treated with cadmium at a
 with untreated females, no differences were observed in mating success                    single dose of 50 mg/kg did not differ in appearance, general behaviour or
 and number of pregnancies. Histological examination of the testis                         food and water consumption from the control animals, although growth
 revealed no differences with the controls.                                                was noted to be slightly retarded. Body weights of the animals treated
                                                                                           10 times with 5 mg cadmium/kg corresponded to those of the control
 Cadmium was administered by gavage to female rats, at doses of 0, 0.04,                   animals. Necropsy at 12, 18 and 30 months revealed no cadmium-related
 0.4 or 4 mg/kg bw/d for 5 weeks (Baranski et al. (1983)16). Thereafter                    lesions (including the testis).
 animals were allowed to mate with untreated males, after which exposure                   Animals having received 1x 100 or 1x 200 mg/kg body weight by gavage
 continued. It was noted that the fraction of inseminated and pregnant                     showed severe lesions of the whole testicular parenchyma with massive
 females was similar in each treatment group, and cadmium exposure did                     calcification of the necrotic tubules and pronounced fibrosis of the
                                                                                           interstitium. Most of the animals died within the first 3 days after
                                                                                           administration.
 a
   Based on 15 mL water intake (derived from publication) and a mean body weight of 400 g.
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<pre> chapter 05 | Toxicity for reproduction                                                      Cadmium and selected cadmium compounds | page 30 of 103
 Andersen et al. (1988)19 studied the effects of a single oral dose of       degeneration was reported in males and females. Testicular and hepatic
 cadmium (0, 270, 530 and 790 μmol cadmium/kg body weight (0, 30, 60         changes were observed in males. In the drinking water study dose-
 and 90 mg Cd/kg) on mortality and tissue damage in CBA/Bom male             dependent changes in body weight gain and absolute and/or organ
 mice. In the 30 mg/kg bw group effects were observed on liver, stomach      weights were observed. However, the testis weights of the cadmium
 and duodenum. Effects on the testis were firstly observed in the 60 mg/kg   dosed males were comparable to those in the controls.
 group. At the highest doses, increased mortality was observed.
                                                                             Male Wistar rats, age 5 weeks, were given 0 or 10 mg cadmium/L in
 Male and female Sprague Dawley derived rats received cadmium by             drinking water (equivalent to 0 or 1.1 mg cadmium/kg bw/d) for 52 weeks
 gavage at doses of 15, 31, 67 and 138 mg/kg body weight/day for 1 or 10     (Saygi et al. (1991)).21 Animals were sacrificed at the end of week 28, 40
 consecutive days, or in drinking water solutions at concentrations of 8-198 and 56 and examined for histopathological examination of testis, kidney
 mg cadmium/L for 10 consecutive days (theoretical doses specified by the    and liver. All cadmium-treated male rats showed pathological testicular
 authors were 1.5, 15, and 31 mg/kg bw/d) (Borzelleca et al.20). After a     alterations, and liver and kidney damage after chronic exposure. Cadmium
 single dose of cadmium, an apparent treatment-related but not statistically levels were found to be highest in the kidney. At the end of the 52-week
 significant decrease in body weight was observed in the males.              period, reproductive capacity of the cadmium-treated rats was investigated
 Furthermore, absolute and relative spleen weights were significantly lower  by mating the treated males with 2 untreated females. All control males
 and lung weights were significantly higher. No effects were observed in     and only 60% (11/18) of the cadmium-treated males were fertile.
 the females after a single dose. Dose-dependent mortality was observed
 in the 10 day gavage study. Body weight gain was reduced in a dose-         Massanyi et al. (2007)22 studied the effects of cadmium on the structure of
 dependent manner in both males and females. Absolute and/or relative        ovary, oviduct and uterus in rabbits. Animals received a dose of 1.0 mg/kg
 brain, liver, spleen, lung, thymus, kidney and testis weights of treated    bw/d for 5 month in pelletized food. A lower relative volume of growing
 males were reduced in a dose dependent manner. In females, absolute         follicles and a higher volume of stroma was observed in the experimental
 and/or relative liver, spleen, thymus and kidney weights were reduced in a  group receiving cadmium, compared to the control group. The number of
 dose dependent manner. Ovary weight was unaffected. Focal necrotic          atretic follicles was higher after administration of cadmium. Histological
 changes were observed in renal tubular epithelium and tubular               analysis revealed structural alterations in the ovaries.
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<pre> chapter 05 | Toxicity for reproduction                                                    Cadmium and selected cadmium compounds | page 31 of 103
 Hu et al. (2014)23 studied the effect of cadmium on serum testosterone      Wang et al. (2014)26 performed an Enhanced OECD TG 407 test in male
 and testicular transcriptome of mice. Mice received 0, 1.95 mg or 0.975     and female rats. Animals were administered with 0, 1, 2.5, 5, 10, or 20 mg
 mg per mouse daily via the diet (doses specified by the authors             cadmium/kg bw/day by gavage for 28 days. Rats in 5, 10, 20 mg/kg·bw
 (presumably erroneously as gram instead of milligram); equivalent to        dose groups showed treatment-related clinical signs, which consisted of
 0, 40 or 20 mg/kg bw/d) for 6 months. A reduction in serum testosterone     listlessness, anorexia, low hair-gloss, irritation, and their severity showed
 level was reported in both treatment groups.                                a dose-dependent trend. Body weights were reduced at doses exceeding
                                                                             1 mg/kg bw/d (in males) or 2.5 mg/kg bw/d (females). Levels of serum
 Nasiadek et al. (2014)24 administered cadmium (0.09, 0.9, 1.8 or 4.5 mg     luteinizing hormone and testosterone were decreased in males at doses
 cadmium/kg bw/d) to female rats by gavage for 28 days. Animals were         of 10-20 mg/kg bw groups. The weights of prostate, thyroids, and seminal
 dissected on the first day or after 90 days post exposure. In the uterus,   vesicle glands were decreased at doses exceeding 1 mg/kg bw/d.
 cadmium accumulation was reported and at the two highest doses an           No significant histological changes were observed in testis; relative testis
 increase in catalase (CAT) activity, and an increase (at 1.8 mg cadmium/    weight was increased only at the highest dose. With respect to female
 kg bw/d) or decrease (at 4.5 mg cadmium/kg bw/d) of lipid peroxidation      reproduction, an increase of uterus weight and histopathological change
 (MDA) levels were observed at both time points.                             were reported at 10-20 mg/kg bw/d. Female animals in all cadmium-
 In another publication, Nasiadek et al. (2018)25 reported on the effects on treated groups showed normal oestrous cycle.
 sex hormones (oestradiol and progesterone) in the plasma and uterus,
 and on oestrous cyclicity and histopathological changes in uterine and      Zhao et al. (2015)27 exposed male rats to cadmium (13.6 mg/kg bw), every
 ovary in female rats exposed to cadmium using the same study design,        two days for 9 weeks in total. The cadmium-treated animals group showed
 and with a post-exposure period of 3 months. No clinical signs of toxicity  lower sperm motility and viability, and higher sperm malformation rate
 and no effect on body weight and brain and uterus weight were observed.     compared to the control group. The reported abnormalities included large
 Cadmium caused hormonal disturbance in plasma (at all doses) but not in     heads, decollation, and folding and broken tails.
 the uterus. Cadmium did not induce oestradiol-like hyperplasia of
 endometrium, but resulted in (reversible) endometrial oedema irrespective   Medina et al. (2017)28 exposed male rats to 10 mg cadmium/kg bw by
 of the dose, and caused damage of the ovaries after the highest dose.       gavage, 5 days per week for week for 3 months. The animals were
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<pre> chapter 05 | Toxicity for reproduction                                                                  Cadmium and selected cadmium compounds | page 32 of 103
 examined after 1, 2, and 3 months of treatment. Treatment resulted in                     Fertility studies, subcutaneous and intraperitoneal exposure
 ultrastructural changes of the testis appearing during the second month.                  A single subcutaneous injection of cadmium 6.1 mg/kg body weight
 The study of sperm with light microscopy showed defects in gamete                         induced profound cellular and vascular changes in the ovaries of
 morphology after 2 months of treatment. In the last month, sperm motility                 prepuberal rats (Kar et al. (1959)31). At 96 hours after treatment some
 was reduced in the cadmium-treated group.                                                 recovery of the ovary changes was observed; by 168 hours the process
                                                                                           of recovery was complete.
 Wang et al. (2017)29 exposed male mice to 0 or 1.8 mg/kg cadmium daily
 by gavage for 5 weeks. Thereafter, several sperm functions including the                  A single subcutaneous injection of cadmium in adult rats (40 μmol
 sperm motility, viability and were examined. Cadmium administration                       cadmium/kg body weight, ~ 4.5 mg/kg bw) resulted in decreased weights
 resulted in a reduced sperm total motility, progressive motility and viability.           of testis, seminal vesicles and prostate and severe histopathological
                                                                                           changes of reproductive organs resulting in complete testicular necrosis
 Sapmaz-Metin et al. (2017)30 studied the adverse effects of exposure to                   (Parizek (1960)32).
 cadmium in drinking water (0 or 200 ppm, equivalent to 0 or 43 mg/kg bw/
 da) for either 30 or 60 days on the uteri of mice. The oestrous cycle and                 Male CBA-mice were exposed to cadmium by subcutaneous injection of
 uterine morphology was assessed, and immunohistochemistry was                             2.2 μmol cadmium/kg body weight (~ 0.2 mg/kg bw) for 5 days/week for
 performed. No effect on cycle length was observed, and no stage specific                  6 months (Nordberg (1975)33). A decrease in normal (testosterone-
 microscopic alterations were noted (except the presence of apoptotic cells).              dependent) proteinuria was shown and morphological examination of the
 Decreases in endometrial thickness and number of glands in oestrus                        seminal vesicles revealed a smaller weight and size as well as histological
 phase uteri were observed. Cadmium decreased endometrial eosinophilia                     indications of lower secretory activity of the epithelium compared to
 and increased the number of mast cells. The apoptotic index increased                     controls. Treated animals did not show clinical signs. After 6 months
 with time, while the proliferation index decreased. In the 60-d treated                   exposure, body weight and urinary excretion of protein were reduced.
 group, increased apoptosis was observed in the endometrium.
                                                                                           Lohiya et al. (1976)34 injected male adult Langurs subcutaneously with
                                                                                           a single dose of 0, 2.5 or 7.4 mg cadmium/kg bw. Animals dosed with
 a
   Assuming a bodyweight of 30 g and a water intake of 6.5 mL/d (based on TGD calculation)
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<pre> chapter 05 | Toxicity for reproduction                                                       Cadmium and selected cadmium compounds | page 33 of 103
 2.5 mg/kg were sacrificed after 30 days and animals dosed with 7.4 mg/kg      with 2.2 to 5.3 cadmium cadmium/kg bw in the dorsal thoracic midline
 were sacrificed after 60 days. No effects of cadmium treatment on body        (Rehm and Waalkens (1988)35). They were killed 1 to 56 days after
 weights were observed. Testes of the 7.4 mg/kg group were small and           administration. Upon sacrifice ovarian necrosis was observed. The lowest
 oedematous; the weight of the reproductive organs was reduced. In the         adverse effect levels depended on species (hamster was the most
 2.5 mg/kg group, no macroscopical effects on organ weights were               susceptible), strain (BALB mice were most, DBA mice were least
 observed. Histological examinations of the testis and epididymis of           susceptible; no difference between the rat strains), and age (immature
 CdCl2-treated animals showed severe lesions in the testis and epididymis      animals were more susceptible).
 which were more severe in the high dose group.
                                                                               Wlodarczyk et al. (1995)36 studied the effect of cadmium on the male
 Bomhard et al. (1987)18 studied the chronic effects of single (0, 2 or 2.5    reproductive system of Golden hamsters. Hamsters were subcutaneously
 mg cadmium/kg bw) and multiple subcutaneous cadmium administrations           injected with a single dose of 0 or 0.5 mg cadmium/kg bw. Five males
 (0, 0.25 mg cadmium/kg bw weekly for 10 weeks) on the testis of Wistar        of each dose group were sacrificed 1, 4 and 10 weeks after treatment.
 rats. Animals having received 1 x 2 or 1 x 2.5 mg/kg bw showed severe         The testis, epididymis and accessory sex glands were weighed and
 lesions of the whole testicular parenchyma with massive calcification of      histologically examined. Epididymal sperm was enumerated and sperm
 the necrotic tubules and pronounced fibrosis of the interstitium. All animals morphology was evaluated. In the cadmium-treated animals decrease in
 receiving 2.5 mg/kg BW subcutaneously had a Leydig cell tumour in at          organ weight and pathological changes of the reproductive organs were
 least one testis. Rats treated with 2.5 mg/kg BW did not differ in            detected at all time intervals but intensified to the end of the experiment
 appearance, general behaviour or food and water consumption of the            (10 weeks). Furthermore, sperm number in the epididymis was decreased.
 control animals; some transient inflammatory reactions were observed at       Lasky et al. (1984)37 studied the reproductive effects of single doses of
 the injection site.                                                           1.6, 3.1, 7.4, 16, 33, 74, 152 µmol cadmium/kg (0.3, 0.6, 1.4, 2.9, 6.0,
                                                                               13.6, 27.9, mg/kg bw/d) in male rats. Fourteen days after dosing,
 Groups of sexually immature and mature female Syrian hamsters                 reproductive organs (including testes, seminal vesicles, and epididymides
 (Cr:RGH), mice (BALB/cAnNCr, DBA/2NCr, C57BL/6NCr, NFS/NCr)                   weights), vas deferens sperm concentration, and hCG-stimulated serum
 and rats (F344/NCr, WF/NCr) received a single subcutaneous injection          testosterone concentration were analysed. Mortality occurred at the two
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<pre> chapter 05 | Toxicity for reproduction                                                       Cadmium and selected cadmium compounds | page 34 of 103
 highest doses and these doses were further excluded from the study.           was measured. From the blood fractions taken, progesterone and
 Rats receiving 33 µmol/kg were noted to have a limited weight gain,           oestradiol were determined, and their secretion rates were calculated. In a
 however no statistical significant difference between groups was noted.       third group of treated animals, the ovaries were excised for histological
 Weights of the tested, seminal vesicles, and epididymides were reduced        examination, and oviducts were flushed for counting oocytes. At the two
 at doses of 16 and 33 µmol cadmium/kg. At these doses, intact sperm           highest doses, decreased serum hormones were measured depending on
 was not found, only separated heads, tails, and other cellular debris were    time point. A reduced blood pressure was found 48 h after administration
 observed. In the 7.4 µmol cadmium/kg group, sperm concentration was           of cadmium, however ovarian blood flow was not affected. In animals
 reduced. Stimulated serum testosterone concentrations were depressed          receiving 10 or 15 mg/kg cadmium chloride a decrease in basal secretion
 in all cadmium dose groups.                                                   of progesterone occurred. hCG-induced secretion was reduced in the
                                                                               5 mg/kg group and absent in the 2 highest doses. Secretion of oestradiol
 Piasek et al. (1994)38 injected female rats subcutaneously on the day of      was not affected. An increase in the number of anovulatory was reported
 dioestrus, or on day 7 or 16 of gestation with a single dose of 0, 3, or 5 mg (independent of dose), but when ovulation occurred normal oocyte
 cadmium/kg bw. Animals were sacrificed 24 h later, and serum                  numbers were found. No altered histology of the ovary was observed.
 progesterone and oestradiol concentrations were determined. Whole
 ovary culture was used to evaluate effects of cadmium on the production       In another study, Paksy et al. (1996)41 administered 0, 1.5, 3.1 or 6.1 mg
 of progesterone, testosterone, and oestradiol. No effects on body weight      cadmium/kg bw subcutaneously to rats, during oestrous or diestrous.
 or reproductive organ weights and no disruption of oestrous cyclicity         After 32, 80 or 128 h, the animals were allowed to mate. A dose-dependent
 were observed.                                                                reduction in the fraction of rats mated was observed in the two highest
 Paksy et al. (1989, 1990)39,40 studied the effects of cadmium on serum        dose groups, however this was only for 80-h (5.0 and 10 mg/kg bw) and
 hormone levels and sex organs in female rats. Animals were                    128-h interval (10 mg/kg bw) groups statistically significant.
 subcutaneously injected with 0, 5, 10 or 15 mg cadmium chloride/kg bw/d
 (equivalent to 0, 3.1, 6.1 or 9.2 mg cadmium/kg bw/d) and blood was           Xu et al. (2001)42 studied the effect of intraperitoneal injection of cadmium
 collected the next day at different time points. An additional group was      (0, 0.2, 0.4, 0.8 mg cadmium/kg bw/d) for 7 days on rat sperm motility
 sacrificed or on the day of the expected oestrous and ovarian blood flow      using computer assisted sperm analysis. The sperm head counts and
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 daily sperm production was decreased in the high dose group. The motility   Compared to controls, cadmium treatment reduced serum testosterone
 of spermatozoa was reduced in the middle group and absent in the            and luteinizing hormone levels. There were fewer regenerated Leydig
 highest dose group.                                                         cells in the testis of cadmium-treated rats. A reduction in bodyweight was
                                                                             observed in the cadmium treated group.
 Aoyagi et al. (2002)43 injected male rats were subcutaneously with 0.6 mg
 cadmium/kg per day for 6 weeks. Testicular damage was evaluated by          Inhalation
 counting the spermatogonia and spermatocytes on one cut-surface of five     Exposure of female rats to cadmium at concentrations of 0, 0.02, or
 seminiferous tubules in stages VII or VIII of spermatogenesis every week.   0.16 mg cadmium/m3 (equivalent to 0, 0.005 or 0.04 mg cadmium/kg
 There were no differences in the testes /bodyweight ratio between the       bw/d) for 5 days a week, 5 h daily for 5 months followed by a maximum
 study and control groups. The number of spermatogonia and                   period of 3 weeks of mating, resulted in gestation indices of 54% (15/28),
 spermatocytes was diminished in the exposed group.                          44% (11/25) and 41% (7/17)(Baranski, 1984).45 The low indices were
                                                                             attributed to the relative old age of the animals.
 Massannyi et al. (2007)22 studied the effects of cadmium on the structure
 of ovary, oviduct and uterus in rabbits. In one experiment, cadmium was     Female rats were exposed to cadmium at a concentration of 0, 0.02 or
 administered intraperitoneally (1.5 mg/kg bw) and sacrificed 48 h later for 0.16 mg cadmium/m3 (equivalent to 0.005 or 0.04 mg/kg bw/d) for 5 hours
 the assessment of acute effects. Similar results were found as for a group  a day, 5 days weekly for a period of 5 months, or 1 mg cadmium/m3
 receiving Cd via the diet for 5 months, namely a lower relative volume of   (equivalent to 0.23 mg cadmium/kg bw/d) for 4 months (Baranski, 1985).46
 growing follicles and a higher volume of stroma when compared to the        Exposure to cadmium resulted in an increased mortality (55.1% at 1 mg/
 control group.                                                              m3 versus 6.5% in controls). A decrease in fertility was only reported to be
                                                                             observed at the maternally toxic concentration of 1 mg cadmium/m3, but
 Wu et al. (2017)44 investigated the effect of cadmium exposure on Leydig    the magnitude of the fertility effects (gestation index, corpora lutea) was
 cell regeneration in the rat. Rats received a single dose of 0, 0.3 or      not specified in the publication.
 0.6 mg/kg of cadmium intraperitoneally, followed by ethane dimethane
 sulfonate treatment to eliminate adult Leydig cells 20 days later.
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<pre> chapter 05 | Toxicity for reproduction                                                                                   Cadmium and selected cadmium compounds | page 36 of 103
 Baranski and Sitareka (1987)17 exposed females rats to cadmium for 20                                     related histologic changes in the reproductive organs. There were no
 weeks, 5 hours/day, 5 days/week to 0, 0.02, 0.16 or 1 mg cadmium/m3                                       histopathologic lesions indicative of toxicity to the reproductive system.
 (equivalent to 0.005, 0.04, or 0.23 mg cadmium/kg bw/d)a. An increase in
 the mean duration of the oestrous cycle mainly due to lengthening of                                      In the NTP, also a repeated dose inhalation toxicity study in mice was
 dioestrus was noted already 6 weeks after treatment of females at 1 mg                                    performed (NTP, 1995)7. Male and female mice were exposed to 0, 0.02,
 cadmium/m3. Only at this concentration, an increase in mortality and a                                    0.04, 0.09, 0.22 and 0.88 mg cadmium/m3 (0.007, 0.014, 0.027, 0.068 and
 decrease in body weight gain was observed. In the 0.16 mg cadmium/m3                                      0.27 mg cadmium/kg bw/d) using the study design as described above.
 group, an increased percentage of females with oestrous cycles lasting                                    No effects on reproductive organs were reported.
 over 6 days was shown 18 weeks after exposure compared to controls.
                                                                                                           Other studies on effects on fertility
 In an inhalation 13-w repeated dose study of the National Toxicology                                      Various studies have been conducted with the purpose to study the
 Program (NTP), male and female rats were exposed 6h/d; 5 d/week to 0,                                     protective effect of a substance or agent on cadmium-induced reproduction
 0.02, 0.04, 0.09, 0.22 and 0.88 mg cadmium/m3 (0.005, 0.010, 0.020, 0.050                                 toxicity in mainly male rats and mice.47-68 In addition to an untreated control
 and 0.20 mg cadmium/kg bw/db) (NTP, 1995)7. Females were evaluated for                                    group, these studies included a control group treated with cadmium only,
 necropsy body weight, oestrous cycle length and the percent of cycle                                      using various routes (oral, intraperitoneal, subcutaneous). In males, adverse
 spent in the various stages; male rats were evaluated for necropsy body                                   effects of cadmium on testicular tissue, sperm parameters and testosterone
 and reproductive tissue weights, spermatozoal data and spermatogenesis.                                   levels were reported. In female mice, effects on uterus and ovaries, and
 In males in the 1 mg/m3 group, spermatid heads per gram of testis,                                        on the viability of follicles and progesterone levels were reported.57,69-71
 spermatid heads per testis and spermatid count were lower than those of                                   These studies are of limited value for classification purposes, as usually
 control males. There were no treatment-related microscopic changes in                                     only a (single) high dose is applied and general toxicity was not assessed.
 the testis or epididymis. In females, there was a greater oestrous cycle                                  Therefore, these studies are not further considered by the Committee.
 length than the controls at the 1 mg/m3 exposure level, but no treatment
 a
   Assuming an inhalatory volume of 150 mL/min (for 90-d study) and a body weight of 200 g
 b
   Assuming an inhalatory volume of 175 mL/min, and a body weight of 275 g for males and females combined.
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<pre> chapter 05 | Toxicity for reproduction                                                        Cadmium and selected cadmium compounds | page 37 of 103
 5.1.2    Human data                                                            asked to complete interviews and to provide blood specimens for the
 Humans may be exposed to cadmium either occupationally, via smoking            quantification of cadmium. The couples were followed for 12 months or
 of tobacco, or via the diet and drinking water. Exposure via food is the       until pregnant. The longest time-to-pregnancy was observed for the
 main route for the non-smoking population.                                     highest tertile of cadmium levels for both men (0.23-3.64 µg/L) and
                                                                                women (0.28, 2.87 µg/L), with women in the highest tertile being more
 Studies on reproductive function                                               likely to not achieve pregnancy within 12 months. A reduced fecundability
 In a cross-sectional study with retrospective data collection, Gennart et al.  odds ratio (FOR; ratio of the odds of conception per menstrual cycle) of
 (1992)72 compared male reproductive function in Belgian cadmium                0.78 (95% CI 0.63–0.97), adjusted for age, parity, body mass index, serum
 smelters (N=83) to reproductive function in workers from nearby factories      cotinine, serum lipids, and lead and mercury concentrations, was observed
 not occupationally exposed to cadmium (N=138). The mean urinary                per standard deviation increase in cadmium concentration among women,
 cadmium level in exposed workers was 6.9 µg per g creatinine and mean          while the adjusted FOR for male cadmium exposure was 0.85 (95% CI:
 duration of exposure was 24 years (range 1.1-53.2), whereas the mean           0.71–1.02). The FORs for couple fecundability, with all female and male
 urinary cadmium level in unexposed workers was 0.7 µg per g creatinine.        co-variables included in the model, were 0.80 (0.64–1.00) and 0.94 (0.77–
 Fertility in these workers was assessed by examination of birth rates          1.13) for female and male cadmium exposure, respectively.
 among their wives using logistic regression analysis. Several
 characteristics that influenced birth rate, including smoking habits, were     Kim et al. (2014)74 measured mercury, cadmium and lead in seminal plasma
 included as confounders. No differences in fertility were observed             collected from 30 men using in vitro fertilization, to evaluate associations
 between the exposed and unexposed populations. Within the exposed              with semen quality parameters and IVF outcomes, such as fertilization,
 population, variables reflecting different intensities or duration of exposure implantation, and ultrasound confirmed pregnancy. Multivariable linear
 were not related to the probability of a live birth.                           and Poisson regression analyses were used to adjust for smoking, age,
 In a prospective cohort study, Buck Louis et al. (2012)73 studied              and co-exposure to mercury. Due to multicollinearity, lead exposure could
 associations between levels of metals (including cadmium) in blood and         not be adjusted for. No statistically significant results were observed for
 various parameters of couple fecundity. In 2005–2009, couples (N=501)          semen cadmium concentration and sperm cadmium concentration.
 desiring pregnancy and discontinuing contraception were recruited and
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<pre> chapter 05 | Toxicity for reproduction                                                        Cadmium and selected cadmium compounds | page 38 of 103
 Tulic et al. (2018)75 investigated the associations of cadmium and other        Studies on semen parameters
 metal concentrations in blood and the outcome of IVF (achieving                 Xu et al. (1993)77 determined the concentrations of cadmium and other
 pregnancy) in 104 consecutive female patients. Serum samples were               trace elements (lead, selenium and zinc) in blood and seminal plasma of
 obtained before the IVF procedure. Based on the outcome of IVF, all             men (N=221) undergoing initial screening for infertility. In this cross-
 subjects were divided into groups of pregnant (N=41) and non-pregnant           sectional study, the authors detected an inverse correlation between
 women (N=63). Higher concentrations of cadmium were found in the                cadmium concentrations in blood and sperm density (r=-0.15, P<0.05),
 non-pregnant women compared to the pregnant women (1.83±5.44 vs                 but not with other parameters of semen quality. The inverse correlation
 0.51±0.13, P=0.012). In univariable logistic regression analyses, a 89.4%       (r=-0.23, P<0.05) was only observed among oligozoospermic (N=99) men
 (95% CI: 14.8-98.7) decreased chance of achieving pregnancy was                 (sperm density below 20 million/mL), but not among normospermic (N=91)
 observed for women with cadmium concentrations ≥ 0.5 µg/L. Cadmium              men. Higher cadmium concentrations in seminal plasma were correlated
 was not retained in the multivariable analyses including lead and               with lower semen volume (r=-0.29, P<0.05) in a subgroup of 73 men for
 magnesium concentrations, age, and IVF parameters, such as                      whom seminal plasma concentrations were measured.
 gonadotropin dose, number of fertilized oocytes, and embryo class.
 Adjustment for these IVF parameters, which are potential intermediate           In a cross-sectional study, Keck et al. (1995)78 did not find correlations
 factors, may have led to overadjustment, however.                               (not further specified) between cadmium levels in seminal plasma and
                                                                                 semen parameters (semen volume, count, motility and morphology) and
 García-Fortea et al. (2018)76 analysed the associations between the             fertility among 12 men with proven fertility, 44 normozoospermic infertility
 concentration of four toxic elements, including cadmium, in hair and diverse    patients, and 118 unselected patients of an infertility clinic in Germany.
 reproductive outcomes (e.g. number of oocytes collected, proportion of
 fertilized oocytes, clinical pregnancy) in a cohort of 194 women with fertility Taha et al. (2013)79 evaluated cadmium levels in seminal plasma of 30
 disorders undergoing IVF. Multivariable analyses for in vitro fertilization     men with idiopathic oligo- and/or asthenozoospermia and 30 fertile healthy
 outcomes and cadmium concentrations in hair - adjusting for age, body           controls, and correlated these levels with conventional semen parameters,
 mass index and cigarette smoking – did not show any associations.               sperm hypo-osmotic swelling (HOS), sperm DNA fragmentation
 However, the cadmium concentrations measured were extremely low.                percentage, and semen reactive oxygen species (ROS) levels.
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<pre> chapter 05 | Toxicity for reproduction                                                       Cadmium and selected cadmium compounds | page 39 of 103
 Subjects smoking or occupationally exposed to heavy metals and patients        Mendiola et al. (2011)81 assessed the associations between seminal and
 with diseases impairing reproductive capacity were excluded. Among the         hormonal parameters and the concentrations of cadmium, lead, and
 infertile men, higher seminal lead (44.4 ± 8.6 µg/L versus 21.7 ± 2.6 µg/L)    mercury in seminal plasma, whole blood, and blood plasma. Sixty one
 and cadmium levels (3.8 ± 0.3 µg/L versus 2.8 ± 0.5 µg/L) were observed        men of couples attending infertility clinics in Spain were divided into
 in comparison to the controls (p<0.001). Negative correlations were            30 cases with oligo-astheno-teratozoospermia and 31 normospermic
 reported between seminal lead and cadmium levels and progressive               controls according to the WHO criteria. No differences were found
 sperm motility and sperm vitality (HOS), whereas positive correlations         between cases and controls in the concentrations of heavy metals in any
 were seen for the percentages of sperm DNA fragmentation and semen             of the three body fluids. In multivariable linear regression analyses,
 ROS levels in both infertile and fertile men (p<0.01).                         adjusted for age, body mass index and number of cigarettes per day,
                                                                                no associations were found between serum hormone levels and metal
 Pant et al. (2014)80 assessed the associations between seminal levels of       concentrations, but the percentage of immotile sperm was associated with
 several environmental toxicants and serum hormone levels (FSH, LH, and         seminal plasma levels of lead and cadmium (p≤0.05).
 testosterone), semen quality, and DNA damage in semen among 60 male
 partners of couples attending a medical institute to assess their inability to De Franciscis et al. (2015)82 measured cadmium levels in both blood and
 conceive in India. Subjects occupationally exposed or with a medical history   seminal plasma and analysed the associations between cadmium
 (‘mainly testicular dysfunction/history of urogenital abnormality/mumps,       concentrations and lifestyle and semen parameters. In this cross-sectional
 tuberculosis, or surgical operation; using drugs known to affect gonadal       study, 50 healthy male patients of a fertility clinic were recruited to provide
 function’) were excluded. Although several associations with cadmium           semen and blood samples. Each patient completed an extensive
 appeared to be present, the results of the multivariable linear regression     questionnaire. Cadmium blood levels were higher (p<0.05) in men from
 analyses, adjusting for other toxicants (lead and phthalates), age, BMI,       industrialised areas and in current smokers, but were not correlated with
 tobacco chewing, smoking, alcohol, and diet, showed that cadmium was not       cadmium semen levels. Increasing cadmium blood levels were correlated
 associated with any of the outcome parameters independently.                   with an increase in the number of immotile spermatozoa and with the
                                                                                teratozoospermia index (TZI; the total number of abnormalities (head,
                                                                                mid-piece, and tail abnormalities) divided by the number of abnormal
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<pre> chapter 05 | Toxicity for reproduction                                                    Cadmium and selected cadmium compounds | page 40 of 103
 spermatozoa) (p<0.05). Inverse correlations (p<0.05) were also found       Riaz et al. (2016)84 studied the antioxidant status of serum and seminal
 between cadmium concentrations in blood and fast- and straight-moving      plasma and the associations with several heavy metals, including
 spermatozoa, and the fractions of fast- and straight-moving and slow       cadmium, in 20 fertile and 20 infertile men. Confounders were not taken
 straight-moving spermatozoa.                                               into account. In fertile men, total oxidant status was increased in both
                                                                            seminal plasma and in serum, compared to infertile men. Compared to
 Jeng et al. (2015)83 studied associations between concentrations of        fertile men, infertile men had elevated levels of cadmium in both seminal
 cadmium, copper, lead, zinc, arsenic, and selenium in seminal plasma and   plasma (9.11 ± 2.34 µg/L versus 1.43 ± 0.85 µg/L) and serum (6.44 ± 2.72
 urine and semen quality parameters in 196 male human subjects              µg/L versus 1.89 ± 0.79 µg/L).
 screened for an annual health examination in a municipal hospital in
 Taiwan. Subjects were included when they did not have treatment            Another cross-sectional, environmental study by Li et al. (2016)85 involved
 affecting spermatogenesis, self-reported diabetes mellitus, liver disease, 587 men without a history of reproductive disorders and not occupationally
 malignant disease, use of mood stabilisers, endocrine disrupting           exposed to cadmium, from three provinces in China. The median serum
 medication, or obesity. Fertility status was not included as a criterion.  cadmium level was 1.9 µg/L (P25-P75: 1.1-2.9). When outliers were
 Binary linear regression analyses were performed for semen parameters      excluded (values > 6.3 µg/L (P95)) and the semen parameters were
 and all metals, including the covariables age, smoking, drinking, and BMI. logarithmically transformed, increasing serum cadmium levels were
 Higher urinary cadmium concentrations were found to be associated with     associated with a reduction in semen volume, progressive motility, and
 lower sperm concentration (p=0.051) and viability (p=0.006), next to       fraction of sperm with normal morphology (p≤0.0002). This was observed
 associations between sperm concentration and urinary lead and arsenic      for the entire group, after adjusting for age group, occupation, season of
 concentrations. In multivariable analyses including all metals and         semen sample collection, abstinence intervals, smoking, alcohol drinking,
 covariables, none of the other metals were associated with the sperm       and body mass index, but not in all three provinces separately.
 quality parameters, but seminal cadmium was retained in the regression     Wang et al. (2016)86 recruited 1,052 men from a fertility clinic in Wuhan,
 model for sperm concentration and urinary cadmium in the model for         China. Each man provided one semen sample and two urine samples.
 sperm viability, although the contribution to the models was small.        Men with azoospermia, occupational exposure to metals, or self-reported
                                                                            diseases that may adversely affect the reproductive system or urinary
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<pre> chapter 05 | Toxicity for reproduction                                                      Cadmium and selected cadmium compounds | page 41 of 103
 excretion of chemicals were excluded. Semen quality parameters and           analyses, in which other metals/metalloids were also considered, inverse
 urinary levels of 18 metals, including cadmium, were determined.             associations were found between cadmium level quartiles and progressive
 Associations between urinary cadmium levels and semen quality                (p=0.002) and total sperm motility (p=0.02).
 parameters were assessed using multivariable linear and logistic
 regression analyses, adjusted for various potential confounders, such as     In a study by Famurewa and Ugwuja (2017)88, 75 male partners of
 age, BMI, smoking status, daily cigarette consumption, alcohol use,          Nigerian couples with infertility were categorised using the WHO
 and abstinence time, as well as for multiple comparisons. The urinary        guidelines into normospermia, oligospermia, and azoospermia. Lead and
 cadmium levels were associated inversely with progressive sperm motility     cadmium levels were determined in blood and seminal plasma. Men with
 and total motility (both P = 0.03), with a ten-fold increase in urinary      genital infections or testicular varicocele, with chronic illnesses including
 cadmium being associated with a decline of 6.15 (95% CI: 1.89-10.41) %       endocrine diseases, or using contraceptives or fertility drug were excluded
 in progressive sperm motility and 7.00 (2.19-11.84) % in total motility.     from the study. Smoking, chronic alcohol intake, micronutrient
 In addition, increased odds ratios (with 95% CIs not including unity) were   supplementation for the last three months, surgery, and occupational
 found for below-reference progressive sperm motility and total motility      exposure to heavy metals were exclusion criteria as well. Seminal and
 (p=0.07 adjusted for multiple comparisons). A ten-fold increase in urinary   blood plasma cadmium levels were higher in azoospermic and
 cadmium levels resulted in ORs of 2.07 (95% CI: 1.19-3.63) and 1.90          oligospermic men compared to normospermic men (p<0.01). Inverse
 (1.12-3.21), respectively. After additional adjustment for all other metals, associations were found between blood and seminal cadmium levels and
 very similar effect estimates were found with a slightly higher OR for       sperm count, total motility, and morphology (p<0.01).
 below-reference total motility (OR 2.17, 1.27-3.68).
 In the same population, reduced to 746 men by exclusion of 306 men           Sukhn et al. (2018)89 studied the associations of levels of heavy metals in
 with inadequate semen volumes, Wang et al. (2017)87 also studied             blood and urine with various semen quality parameters in male partners of
 associations between concentrations of metals in seminal plasma and          couples attending a fertility clinic in Lebanon. Non-occupationally exposed
 semen quality (N=746), sperm apoptosis (N=331), and DNA integrity            men were categorised in low- or normal-quality semen groups, based on
 (N=404). Both in the single-element linear regression analyses adjusted      the WHO criteria for sperm quality. Associations between metal
 for confounders and multiple comparisons and in the multiple-element         concentration in quartiles and continuous semen quality outcome
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<pre> chapter 05 | Toxicity for reproduction                                                   Cadmium and selected cadmium compounds | page 42 of 103
 measures were assessed using multivariable linear regression for each      associations between low cadmium levels in hair and various outcome
 metal separately with age, cigarette smoking, alcohol consumption, and     parameters in female IVF patients.
 period of sexual abstinence as confounders. Men with low-quality semen
 had higher cadmium concentrations in the seminal fluid than men with       Most other reports involve clinical or environmental cross-sectional studies
 normal-quality semen (p<0.05). In addition, associations were observed     on associations between cadmium-levels in blood (serum), seminal fluids
 between low sperm viability and higher blood cadmium (p<0.05) and          and/or urine and sperm quality (e.g. motility, concentration, viability).
 higher seminal cadmium (p<0.003) levels.                                   The majority of these studies reported associations between increased
                                                                            cadmium levels and reduced sperm quality (Xu et al. (1993)77; Taha et al.
 5.2     Short summary and overall relevance of the provided                (2013)79; Mendiola et al. (2011)81; De Franciscis et al. (2015)82; Jeng et al.
         information on adverse effects on sexual function and              (2015)83; Riaz et al. (2016)84; Li et al. (2016)85; Wang et al. (2016)86; Wang
         fertility                                                          et al. (2017)87; Famurewa et al. (2017)88; Sukhn et al. (2018)89) whereas
 Various publications concerning the effects of cadmium on human fertility  no associations were reported in only two studies (Keck et al. (1995)78;
 were found. In some studies, functional fertility was assessed. Gennart et Pant et al. (2014)80). Taking co-exposure to multiple metals into account,
 al. (1992)72 did not find an association between urinary cadmium levels    independent associations for cadmium were observed in the studies by
 and birth experiences of their wives in male workers exposed to cadmium.   Jeng (2015)83 and Wang (2016, 2017)86,87.
 From a prospective cohort study with adjustment for confounders and
 other metals, Buck Louis (2012)73 reported associations between long       In animals, effects of oral administration of cadmium on functional fertility
 time-to-pregnancy and reduced fecundability and increased cadmium          parameters in males were mainly assessed in rats. Dixon et al. (1976)10
 blood levels, especially for women. Kim et al. (2014)74 did not find an    reported no effects on male fertility in a breeding experiment with rats
 association between seminal cadmium levels and negative outcome of         (no details were provided), either 6 weeks after a single oral dose up to
 IVF treatment in a small cross-sectional study. In female IVF patients,    25 mg/kg or after exposure up to 0.014 mg/kg via drinking water for up to
 Tulic et al. (2017)75 found an association between blood cadmium levels    90 days. Kotsonis and Klaassen (1978)11 observed no reduced fertility
 and a negative IVF outcome. Garcia-Fortea (2017)76 did not find            (as fraction of pregnant females after mating and number of foetuses per
                                                                            pregnant animal) in male rats exposed to cadmium up to 12.2 mg/kg bw/d
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<pre> chapter 05 | Toxicity for reproduction                                                          Cadmium and selected cadmium compounds | page 43 of 103
 for 24 weeks. Zenick et al. (1982)15 reported no effects on fertility of male    (2017)29), effects on testis and/or spermatogenesis have been reported at
 rats (as mating success/number of pregnancies) exposed up to 3.2 mg/kg           various dosing schedules. However, Kotsonis and Klaassen (1978)11,
 bw/d for 70-80 days. Laskey et al. (1980)12 reported decreased                   Bomhard et al. (1987)18, and Zenick et al (1982)15 did not observe effects
 preimplantation loss after exposing male and female rats from mating at a        on sperm parameters/reproductive organs in rats. In general, effects on
 dose of 0.6 mg/kg via drinking water. Sutou et al (1980a,b)13,14 exposed         sperm parameters or reproductive organs are either observed in
 male rats for 6 weeks by gavage to 0.1, 1 or 10 mg/kg bw and reported no         combination with effects on body or organ weights, or data on general
 reduced copulation and no reduced number of implants. A reduction in             toxicity is lacking.
 these parameters was only observed when females also were exposed at             In rats, inhalation exposure to cadmium for 90 days at an equivalent dose
 the highest dose. Saygi et al. (1991)21 administered male rats cadmium in        of 0.20 mg Cd/kg bw/d resulted in effects on spermatids, but also in
 drinking water at an equivalent dose of 1.1 mg/kg bw/d for 52 weeks and          enlargement and paleness of the tracheobronchial and mediastinal lymph
 observed reduced fertility.                                                      nodes. No effects on reproductive organs were observed in mice with a
 Male and female mice, continuously exposed during multiple generations           similar exposure.(NTP, 1995)7
 to 2.1 mg/kg bw/d for multiple generations failed to bred beyond the
 F2b-generation (Schroeder and Mitchener, 1971)8 All reported effects on          Two studies are available on functional fertility in female animals. Baranski
 functional fertility were observed at doses at which reduced body weight         et al. (1983)16 treated female rats for 5 d/w for 5 weeks with cadmium
 and/or toxicity to other organs were noted as well.                              (0.04, 0.4 or 4 mg cadmium/kg bw/d) prior to mating (and continued
                                                                                  thereafter) and reported no effect on the fraction inseminated and
 Inconsistent data are available on the effects of cadmium treatment on           pregnant females. Inhalation exposure of female rats to a dose of 0.18 mg
 male reproductive organs or sperm parameters after oral (gavage,                 cadmium/kg bw/d for 4 months was reported to result in reduced fertility
 drinking water or diet) or subcutaneous administration of cadmium. In            (otherwise not specified), but also increased mortality.(Baranski, 1985)46
 studies with male rats (Parizek (1960)32; Krasovskii et al. (1976)9; Laskey      Oral exposure of female rats to cadmium resulted in a prolonged oestrous
 et al. (1984)37; Borzelleca et al. (1989)20, Aoyagi et al. (2002)43; Wang et al. cycle at a daily dose of 40 mg/kg bw for 14 weeks (Baranski and Sitarek
 (2014)26; Zhao et al. (2015)27; Medina et al. (2017)28; Wu et al. (2017)44       1987)17; effects on follicles and stroma at 1 mg/kg bw/d for 5 months
 and male mice (Nordberg (1975)33; Andersen et al. (1988)19, Wang et al.          (Massanyi et al 2007)22, biochemical changes in the uterus and increased
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 uterus weight at a dose exceeding 0.9 mg/kg bw/d for 28 days (Nasiadek                     In inhalation studies with cadmium, a prolongation of the oestrous cycle
 et al. 2014)24; and increased uterus weight and histopathological changes                  has been observed in rats (Baranski and Sitareka (1987); NTP (1995)7,17).
 at a dose exceeding 5 mg/kg bw for 28 days (Wang et al 2014)26.
 Adverse effects on the endometrium and uterus were observed in female                      The adverse effects on sexual function and fertility observed in animal
 mice exposed up to 60 days to a high dose of cadmium (43 mg/kg bw/d).                      studies are summarised in the following tables:
 (Sapmaz-Metin 2017)30 Kar et al. (1959)31 reported cellular and vascular
 changes in the ovaries of prepuberal rats. Only in the study of Nasiadek et
 al. (2014)24, effects on reproductive organs were reported at doses at
 which no general toxicity (effects on body or organ weights) were apparent.
 Males
  Ref.                     Species Exposure duration     Exposure route        Effects on fertility                                          General toxicity
  Krasovskii et al. (1976) Rat     6-m                   Oral (drinking water) Reduction spermatogenesis                                     Changes biochemical parameters and in the
                                                                                                                                             conditional reflex activity
                                                                               NOAEL=0.00005 mg/kg                                           NOAEL=0.00005 mg/kg
  Dixon et al. (1976)      Rat     90-d                  Oral (drinking water) No effects on functional fertility (serial breeding) reported No information provided
                                                                               NOAEL=0.01 mg/kg                                              NOAEL=0.01 mg/kg
                                   6 w (single dose)     Oral (gavage)         No effects on functional fertility (serial breeding) reported No general toxicity reported
                                                                               NOAEL=25 mg/kg (single dose)                                  NOAEL=25 mg/kg (single dose)
  Kotsonis and Klaassen    Rat     24-w                  Oral (drinking water) No effect on functional fertility and testis weight and       Tubular necrosis in the kidney
  (1978)                                                                       histopathology
                                                                               NOAEL = 12.2 mg Cd/kg                                         NOAEL=1.2 mg/kg
  Laskey et al. (1980)     Rat     130-d                 Oral (drinking water) Reduced sperm count, (decreased preimplantation loss only     Decreased liver weight
                                                                               when females were also exposed)
                                                                               NOAEL = 0.6 mg Cd/kg bw/d                                     NOAEL=0.01 mg/kg
  Sutou et al. (1980a,b)   Rat     6-w                   Oral (gavage)         Reduced copulation, pregnancy and implantation sites          Reduced body and organ weight
                                                                               (females were also exposed)
                                                                               NOAEL = 1 mg/kg                                               NOAEL=0.1 mg/kg
  Zenick et al. (1982)     Rat     70-d                  Oral (drinking water) No effects on mating success or number of pregnancies; no     No effect on body weight
                                                                               effect on testis
                                                                               NOAEL=3.2 mg/kg                                               NOAEL=3.2 mg/kg
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  Ref.                     Species Exposure duration              Exposure route        Effects on fertility                                           General toxicity
  Bomhard et al. (1987)    Rat     10-w (weekly administration);  Oral (gavage)         No effect on testis                                            No effect on body weight
                                   duration experiment up to 30                         NOAEL=5 mg/kg                                                  NOAEL=5 mg/kg
                                   m
  Bomhard et al. (1987)    Rat     Single dose; duration          Oral (gavage)         No effect on testis                                            Slight growth retardation
                                   experiment up to 30 m                                NOAEL=50 mg/kg                                                 LOAEL=50 mg/kg
  Borzelleca et al. (1989) Rat     10-d                           Oral (gavage)         Testicular atrophy; relative testis weight                     Mortality, kidney toxicity
                                                                                        NOAEL=31 mg/kg                                                 LOAEL=15 mg/kg
                           Rat     10-d                           Oral (drinking water) No effect on testis                                            reduced body/organ weight
                                                                                        NOAEL=31 mg/kg                                                 NOAEL=1.5 mg/kg
  Saygi et al. (1991)      Rat     52-w                           Oral (drinking water) Reduced fertility after 52 w; histopathological changes testis Histopathological changes liver/kidney
                                                                                        LOAEL=1.1 mg/kg                                                LOAEL=1.1 mg/kg
  Wang et al. (2014)       Rat     28-d                           Oral (gavage)         Decrease weight of prostate and seminal vesicles               Reduced body weight
                                                                                        NOAEL=1 mg/kg                                                  NOAEL=1 mg/kg
  Zhao et al. (2015)       Rat     9-w (administration every 2 d) Oral (gavage)         Various abnormalities in sperm                                 No information provided
                                                                                        LOAEL=13.6 mg/kg (every 2 days)
  Medina et al. (2017)     Rat     3 m (5 d/w)                    Oral (gavage)         Morphological changes in testis; sperm motility                No information provided
                                                                                        LOAEL=10 mg/kg
  Schroeder and Mitchener  Mouse   Multi-generation               Oral (drinking water) Strain could not be bred further after 3 generations (exposure 2 maternal deaths; no further information
  (1971)                                                                                to both males and females)                                     provided
                                                                                        LOAEL=2.1 mg/kg                                                LOAEL=2.1 mg/kg
  Anderson et al. (1988)   Mouse   10 d (single dose)             Oral (gavage)         Histological lesions of the testis                             Histological lesions of intestinal tract
                                                                                        NOAEL=30 mg/kg                                                 LOAEL=30 mg/kg
  Haffor and Abou-Tarboush Mouse   4-w                            Oral (gavage)         Damage to testicular tissue                                    No information provided
  (2004)                                                                                LOAEL=1 mg/kg
  Hu et al. (2014)         Mouse   6m                             Oral (diet)           Reduced testosterone levels                                    No reduced body weight
                                                                                        NOAEL=20 mg/kg                                                 NOAEL=20 mg/kg
  Wang et al. (2017)       Mouse   5w                             Oral (gavage)         Reduced sperm motility and viability                           No information provided
                                                                                        LOAEL=1.9 mg/kg
  Laskey et al. (1984)     Rat     14 d (single dose)             subcutaneous          Reduced sperm count                                            No effect on body weight
                                                                                        NOAEL=0.3 mg/kg                                                NOAEL=3.7 mg/kg
  Bomhard et al. (1987)    Rat     10-w (weekly administration)   intraperitoneal       No histological alterations in the testis                      No lesions observed at necropsy
                                                                                        NOAEL=0.25 mg/kg                                               NOAEL=0.25 mg/kg
                                   10 w (single dose)                                   Lesions in the testis                                          No effect on bw and behaviour
                                                                                        LOAEL=2.5 mg/kg                                                NOAEL= 2.5 mg/kg
  Aoyagi et al. (2002)     Rat     6-w                            subcutaneous          Reduction in spermatogonia and spermatocytes                   Decrease in body weight gain
                                                                                        LOAEL=0.6 mg/kg                                                LOAEL=0.6 mg/kg
  Parizek (1960)           Rat     4 m (single dose)              subcutaneous          Decreased weight reproductive organs                           No information provided
                                                                                        LOAEL=4.5 mg/kg
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  Ref.                      Species Exposure duration              Exposure route         Effects on fertility                                              General toxicity
  Xu et al. (2001)          Rat     7d                             intraperitoneal        Decrease motility                                                 No information provided
                                                                                          NOAEL=0.2 mg/kg
  Wu et al. (2017)          Rat     76 d after a single dose       intraperitoneal        Impaired regeneration Leydig cells after EDS treatment            Reduction in bodyweight
                                                                                          LOAEL=0.3 mg/kg                                                   LOAEL=0.3 mg/kg
  Nordberg (1975)           mouse   6m                             subcutaneous           Decreased weight/size seminal vesicles                            Decreased body weight
                                                                                          LOAEL=0.2 mg/kg                                                   LOAEL=0.2 mg/kg
  Wlodarczy et al. (1995)   Hamster Up to 10 w (single dose)       subcutaneous           Decrease number of sperm cells/weight reproductive organs         No information provided
                                                                                          LOAEL=0.5 mg/kg
  Lohiya et al. (1976)      Langurs Up to 60 d (single dose)       subcutaneous           Histological lesions reproductive organs                          No information provided
                                                                                          LOAEL=2.5 mg/kg
  NTP (1995)                Rat     13-w                           Inhalation             Reduced number spermatid heads per testis and spermatid           Lesions in larynx
                                                                                          count (no histopathologic lesions)
                                                                                          NOAEL=0.01 mg/kg                                                  LOAEL=0.005 mg/kg
  NTP (1995)                mouse   13-w                           Inhalation             No effect on reproductive organs                                  Lesions in the lung
                                                                                          NOAEL=0.9 mg/kg                                                   NOAEL=0.007 mg/kg
 Females
  Ref.                     Species                Exposure duration       Exposure route         Effects on fertility                                            General toxicity
  Baranski et al. (1983)   Rat                    5-w                     Oral (gavage)          No effect on functional fertility observed                      No information provided
                                                                                                 NOAEL=4 mg/kg                                                   NOAEL=4 mg/kg
  Baranski and Sitarek     Rat                    5-w                     Oral (gavage)          Increase oestrous cycle                                         Increased mortality; decreased body weight
  (1987)                                                                                         NOAEL=4 mg/kg                                                   gain
                                                                                                                                                                 NOAEL=4 mg/kg
  Nasiadek et al. (2014;   Rat                    28-d                    Oral (gavage)          Biochemical changes uterus                                      No effects on body weight or organ weights
  2018)                                                                                          NOAEL=1.8 mg/kg                                                 NOAEL=4.5 mg/kg
  Wang et al. (2014)       Rat                    28-d                    Oral (gavage)          Increased uterus weight; histopathological changes              Reduced body weight; clinical signs
                                                                                                 NOAEL=5 mg/kg                                                   NOAEL=2.5 mg/kg
  Sutou et al. (1980a,b)   Rat                    6-w                     Oral (gavage)          Reduced copulation, pregnancy and implantation sites            Reduced body and organ weight
                                                                                                 (males were also exposed)
                                                                                                 NOAEL = 1 mg/kg                                                 NOAEL=0.1 mg/kg
  Borzelleca et al. (1989) Rat                    10-d                    Oral (gavage)          No effect on ovary weight                                       Mortality, kidney toxicity
                                                                                                 NOAEL=66 mg/kg                                                  NOAEL=15 mg/kg
                                                  10-d                    Oral (drinking water) No effect on ovary weight                                        No effect on body/organ weight
                                                                                                 NOAEL=31 mg/kg                                                  NOAEL=31 mg/kg
  Schroeder and            Mouse                  Multi-generation        Oral (drinking water) Strain could not be bred further after 3 generations (males      2 maternal deaths; no further information
  Mitchener (1971)                                                                               were also exposed)                                              provided
                                                                                                 LOAEL=2.1 mg/kg                                                 LOAEL=2.1 mg/kg
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  Ref.                   Species                 Exposure duration      Exposure route        Effects on fertility                                         General toxicity
  Sapmaz-Metin et al.    Mouse                   30-60 d                Oral (drinking water) Apoptosis in uterus and endometrium                          No information provided
  (2017)                                                                                      LOAEL=43 mg/kg
  Massanyi et al. (2007) Rabbit                  5-m                    Oral (diet)           Effects on follicles and stroma                              No information provided
                                                                                              LOAEL=1 mg/kg
  Kar et al. (1959)      Rat                     Up to 360 h (single    Subcutaneous          Cellular and vascular changes in ovary (reversible)          No information provided
                                                 dose)                                        NOAEL=6.1 mg/kg
  Paksy et al. (1989)    Rat                     48 h (single dose)     Subcutaneous          Reduced effect of hCG; increased anovulatory                 No information provided
                                                                                              LOAEL=3.1 mg/kg
  Paksy et al. (1996)    Rat                     32-132 h (single dose) Subcutaneous          Reduced fraction mated                                       No information provided
                                                                                              NOAEL=1.5 mg/kg
  Rehm and Waalkes       Rat (several strains;   Up to 56 d (single     Subcutaneous          Necrosis in ovaries                                          Mortality
  (1988)                 mature and immature)    dose)                                        LOAEL=2.2 kg/bw                                              NOAEL=2.2 kg/bw
                         Mouse (several strains;                                              NOAEL=2.2 kg/bw                                              NOAEL=2.2 kg/bw
                         mature and immature)
                         Hamster (several                                                     LOAEL=2.2 kg/bw                                              NOAEL=2.2 kg/bw
                         strains; mature and
                         immature)
  Massanyi et al. (2007) Rabbit                  48h (single dose)      Subcutaneous          Adverse effect follicles                                     No information provided
                                                                                              LOAEL=1.5 mg/bw
  Baranski (1984)        Rat                     5-m; followed by 3 w   Inhalation            No effects on fertility observed                             No information provided
                                                 mating period                                NOAEL=0.04 mg/kg
  Baranski (1985)        Rat                     4-6-m; continued       Inhalation            Reduced fertility (not further specified)                    Increased mortality
                                                 during mating                                NOAEL=0.04 mg/kg                                             NOAEL=0.04 mg/kg
                                                 4-m; continued during
                                                 mating
  Baranski and Sitareka  Rat                     20-w                   Inhalation            Increased incidence of females with prolonged oestrous cycle Mortality and decreased body weight
  (1987)                                                                                      NOAEL=0.005 mg/kg                                            NOAEL=0.04 mg/kg
  NTP (1995)             Rat                     13-w                   Inhalation            Increased oestrous cycle length                              Respiratory tract lesions in the lungs
                                                                                              NOAEL=0.05 mg/kg                                             LOAEL=0.005 mg/kg
  NTP (1995)             mouse                   13-w                   Inhalation            No effect on fertility observed                              Respiratory tract lesions in the lungs
                                                                                              NOAEL=0.2 mg/kg                                              LOAEL=0.007 mg/kg
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<pre> chapter 05 | Toxicity for reproduction                                                     Cadmium and selected cadmium compounds | page 48 of 103
 5.3 Comparison with the CLP criteria                                        compounds. Saygi et al. (1991)21 reported a reduced fertility in rats at 1
 As many animal and epidemiological studies evaluated the effects on         mg/kg bw. This dose also resulted in adverse effects on kidney and liver.
 male or female sexual function and fertility, the results were assessed     In the study of Sutou (1980a,b)13,14 in rats, copulation and pregnancy was
 separately for effects on males and females.                                reduced at a dose of 10 mg/kg bw, which also reduced body and organ
                                                                             weights. Schroeder and Mitchener (1971)8 reported impaired breeding and
 Male fertility                                                              noted some maternal mortality in mice exposed to 2 mg/kg bw. In the
 Three studies on cadmium exposure in men and impaired reproductive          studies of Sutou and Schroeder and Mitchener, females were also
 function are available, of which one large study suggests an association    exposed to cadmium. The studies by Kotsonis and Klaassen (1978)11
 (Buck Louis et al. (2012)73), whereas two small studies do not (Gennart et  and Zenick et al. (1982)15 used higher or comparable dose levels and
 al. (1992)72; Kim et al. (2014)74. Most other human data involve studies on exposure durations, but no effect on fertility was observed. Several other
 associations between cadmium levels in biological fluids and parameters     studies using lower dose levels or shorter exposure periods after which
 of the sperm quality. The majority of these studies reported associations   exposed males were mated, did not result in effects on fertility.
 between increased cadmium levels and reduced sperm quality. Most of
 these studies have several limitations, in particular the presence of       Several studies assessed the male reproductive organs and/or sperm
 possible co-exposures. The Committee notes that in three studies on         parameters after oral exposure to soluble cadmium compounds.
 cadmium exposure and reduced sperm quality (Jeng et al. (2015)83;           Studies in rats showed inconsistent results, with adverse effects mainly
 Wang et al. (2016)86, (2017)87; related to the same population)),           seen in studies with higher exposure levels. Generally, general toxicity
 independent associations were found after adjustment for co-exposure to     was observed or information on general toxicity was lacking in these
 multiple metals. Overall, the Committee concludes that the epidemiological  studies. Results in mice are more consistent as all reported studies
 studies suggest an association between cadmium exposure and adverse         showed effects on the testis or sperm parameters. However, the
 effects on male fertility.                                                  information on general toxicity in these studies is limited. The NTP studied
                                                                             the effect of 13-weeks of inhalation exposure to cadmium in rats and
 In three animal studies a decrease in fertility was reported, in the        mice.7 No effects on the reproductive organs were observed in mice.
 presence of general toxicity, after prolonged exposure to cadmium           However, at the top concentration in rats, effects on sperm counts were
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<pre> chapter 05 | Toxicity for reproduction                                                   Cadmium and selected cadmium compounds | page 49 of 103
 observed, but no microscopic changes of the testis. The general toxicity   effects are dose-dependent. Reductions in fertility were only observed at
 was limited and was related to the respiratory tract.                      higher dose levels, also inducing maternal toxicity up to mortality. Several
                                                                            studies assessed the effects on the female reproductive organs or the
 Studies using subcutaneous/intraperitoneal exposure also revealed          oestrous cycle after oral exposure. Effects on the oestrous cycle were only
 effects of cadmium on the testis or sperm cells, at relatively low dose    observed at lethal dose levels. Effects on the ovary were reported in
 levels. These results deviate from the results after oral exposure that    several studies at dose levels in the range of 1 to 43 mg/kg bw/day in the
 showed only effects at higher dose levels and prolonged exposure in        presence of general toxicity.
 some studies. This difference may be explained by the sequestration of
 cadmium in the liver after oral exposure (first pass effect). Since the    Other studies assessed the effects on the female reproductive organs,
 intraperitoneal and subcutaneous exposure routes are not considered        the oestrous cycle, or mating behaviour after a single subcutaneous
 relevant, studies in which cadmium was administered via these routes       exposure. Most studies showed effects on these parameters. However,
 are attributing less weight and can only be supportive, at most, for       as noted above, these exposure routes are not relevant and have limited
 classification purposes.                                                   value for the recommendation of a classification.
                                                                            Three inhalation studies with cadmium by the group of Baranski showed a
 Female fertility                                                           reduction in gestation index at 0.006 and 0.05 mg/kg bw/day and a
 Associations were reported between increased cadmium blood levels in       decrease in fertility at 0.18 mg/kg bw/day.45,46,90 However, the highest dose
 women and long time-to-pregnancy and reduced fecundability (Buck Louis     level also induced mortality. Furthermore, the effect on gestation was not
 2012)73, and between female blood cadmium levels and a negative IVF        reported in a repeat study. The percentage of females showing prolonged
 outcome (Tulic 2018)75. Only the results in the study by Buck Louis et al. oestrous cycles was increased after exposure to 0.03 mg/kg bw/day.
 (2012)73 were properly adjusted for co-exposures and other confounders,    However, these studies have several limitations in reporting. Studies by
 as well as for paternal variables.                                         the NTP (1995)7 during 13 weeks according to OECD TG 413 showed
                                                                            increased oestrous cycle length without treatment-related histologic
 Several animal studies assessed the effects on female functional fertility changes in the reproductive organs in rats but not in mice. The severity of
 after oral exposure to cadmium. The combined results suggest that the      the general toxicity was limited.
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 Conclusion                                                                     Therefore, it is assumed that the observed fertility effects are relevant
 The Committee concludes that in several studies associations were found        for humans. In line with CLP paragraph 3.7.2.2.3, the Committee
 between cadmium exposure and adverse effects on fertility and cadmium          recommends to classify for effects on sexual function and fertility in
 exposure in men, and in one study, in women. The Committee considers           category 1B (presumed human reproductive toxicant) and to label with
 these associations insufficient for classification in Category 1A.             H360F (may damage fertility) based on the associations found between
 The associations found in humans are consistent with both functional           cadmium exposure and reduced sperm quality and reduced fertility in
 effects (in males and females) and effects on testis and sperm observed        epidemiological studies, and effects on sexual function and fertility
 in animal studies. In these studies, general toxicity was observed or not      observed in animal studies for males and females. This proposal for
 specifically addressed. The Committee considers it likely that effects on      classification relates to cadmium, cadmium carbonate, cadmium chloride,
 fertility or sexual function in animals may occur in the presence of adverse   cadmium fluoride, cadmium hydroxide, cadmium nitrate, cadmium oxide,
 effects on the kidneys (the critical organ in cadmium-induced toxicity).       cadmium sulphate, and cadmium sulphide (See section 4.2 for an
 It is unclear whether or not effects on fertility are a non-specific secondary explanation of the selection of substances).
 effect of the general toxicity. No information is available regarding the
 mechanism for the effects on fertility and its relevance to humans.
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 5.4       Adverse effects on development
 Summary table of animal studies on adverse effects on development
 Oral route
  Reference        Investigated  experimental period and design    Substance Dose and method of                   Maternal toxicity          developmental toxicity
                   species                                                   administration
  Schroeder and    Mouse,        Continuous exposure in multi-     Cadmium   0 or 10 mg Cd/L (equivalent to 0 or • 2 maternal deaths in      • Increased deaths before weaning (87/285 versus
  Mitchener (1971) Charles River generation study, continuous      chloride  2.1 mg Cd/kg bw) via drinking water    treated F2                 2/687 in controls) in F1 and F2
                   DC (N=5       breeding                                                                         •                          • Increased number of animals with runts (34/285
                   pairs/group)                                                                                                                versus 2/687 in controls)
                                                                                                                                             • Strain could not be bred beyond F2b-generation
  Sutou et al.     Rat, Sprague- Administration to males and       Cadmium   0, 0.1, 1.0, and 10 mg Cd/kg bw by   Several signs of general   At 10 mg/kg bw:
  (1980)           Dawley        females for 6 w, during mating up chloride  gavage                               toxicity at the highest    • Reduced foetal body weight and length
                   (N=14/group)  to GD 20                                                                         dose:                      • Anaemia and malnutrition foetuses
                                                                                                                  • Reduced food intake      • Increased placenta weight
                                                                                                                  • Reduced body weight      • Decreased numbers of implantation sites and live
                                                                                                                    gain                       foetuses
                                                                                                                  • Depilation, whitening of • Increased number of resorptions
                                                                                                                    the incisors, salivation
                                                                                                                  • Abnormal haematology     No malformations were observed
  Zenick et al.    Rat, Sprague- Administration for 70-80 d in     Cadmium   0, 17.2, 34.4 or 68.8 mg Cd/L in     Reduced water intake in    No developmental effects were observed
  (1982)           Dawley, males drinking water (corresponding to  chloride  drinking water (equivalent doses of  all exposed groups
                   (N=5/group)   the time for transition of a                0, 0.7, 1.3, and 2.6 mg Cd/kg bw)
                                 spermatogonium to a mature
                                 sperm cell)
  Baranski et al.  Rat, Wistar   Administration from GD 7-16 of    Cadmium   0, 2, 4, 8, 12 and 40 mg Cd/kg bw,   • Decreased body weight    • At all doses: increased number of foetuses with
  (1982)           (N=17-25/     gestation. At GD 21, animals were chloride  by gavage                              gain during pregnancy at   delayed ossification
                   group)        sacrificed                                                                         all doses                • At 8 mg/kg and higher: Decreased foetal weight
                                                                                                                  • Increased adrenal        • At 20 and 40 mg/kg: effects on soft tissue
                                                                                                                    weight at ≥ 4 mg/kg        morphology (subcutaneous haemorrhages,
                                                                                                                  • Reduced bw ≥ 8 mg/kg       hydropericardium)
                                                                                                                  • Mortality (13/25) at 40  • At 40 mg/kg: Reduced number of live foetuses per
                                                                                                                    mg/kg                      litter; increased number of resorptions per litter;
                                                                                                                                               increased number of foetuses with a lack of
                                                                                                                                               forelimbs and sirenomelia
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  Reference       Investigated  experimental period and design        Substance Dose and method of                    Maternal toxicity         developmental toxicity
                  species                                                       administration
  Baranski et al. Rat, Wistar   Administration for 5 days/week,       Cadmium   0, 0.04, 0.4 and 4.0 mg Cd/kg bw      Paradoxically, no effects • No differences reported in average numbers of total
  (1983)          (number not   for 5 weeks, then during mating       chloride  by gavage                             on survival were reported   implantations, corpora lutea, live foetuses,
                  specified)    and gestation. One subgroup was                                                       but some deaths in the      resorptions, foetal body weight
                                sacrificed on GD 21 for the                                                           highest dose group were   • At 0.4 mg/kg: increased fraction of litters with
                                assessment of the foetuses,                                                           noted                       foetuses with subcutaneous oedema
                                whereas another subgroup was                                                                                    • All treatment groups: Decreased locomotor activity
                                allowed to deliver. At the age of 2                                                                               of female offspring
                                months, locomotor activity was                                                                                  • At 0.4 and 4 mg/kg: Decreased locomotor activity of
                                assessed.                                                                                                         male offspring
                                                                                                                                                Data were not specified
  Baranski (1985) Rat, Wistar   Pregnant rats received cadmium        Cadmium   0, 2, 12 and 40 mg Cd/kg bw by        Reduced maternal bw gain At 12 mg/kg and 40 mg/kg:
                  (N=18-6/      from GD 7-16. Females were            chloride  gavage                                at all doses              • Reduced foetus weight
                  group)        sacrificed and analysed on GD 21.
                                                                                                                                                At 40 mg/kg:
                                                                                                                                                • Reduced number of live foetuses per litter
                                                                                                                                                • Increased number of resorptions per litter
  Baranski (1986) Rat, Wistar   Administration from day 1 to day      Cadmium   0 and 60 ppm cadmium in drinking      No information provided   • Reduced brain weight in 2-w old offspring
                  (N=13/group)  20 of gestation. Females were         chloride  water (equivalent to 0 and 8.5 mg                               • No effect on litter size, body weight at birth, body
                                allowed to deliver and nurse their              Cd/kg bw)                                                         weight gain, viability, and food and water
                                progeny until weaning at 28 days.                                                                                 consumption in offspring
                                                                                                                                                • No change in performance of surface and air
                                                                                                                                                  righting reflexes, negative geotaxis and forepaw
                                                                                                                                                  suspension.
                                                                                                                                                • Reduced exploratory locomotor activity dependent
                                                                                                                                                  on age and sex, reduced grooming activity in
                                                                                                                                                  males, depressed avoidance acquisition.
  Baranski (1987) Rat, Wistar   Administration from day 1 to day      Cadmium   0, 60 and 180 ppm cadmium in          Reduced body weight gain • No effect on implantations, corpora lutea, live
                  (N=13/group)  20 of gestation                       chloride  drinking water (equivalent to 0, 9.2  and food/water intake       foetuses, resorptions, and post-implantation loss
                                                                                and 27.7 mg Cd/kg bw)                                           • No gross malformations
                                                                                                                                                • At 60 and 180 ppm: Reduced foetal length and
                                                                                                                                                  body weight
  Whelton et al.  CF1 mice      Administration via diet during 6      Cadmium   0.25, 5.0 or 50 ppm cadmium           No information provided   Results for sufficient diet, at 50 ppm (compared to
  (1988)          (N=10 and     consecutive 42-d rounds of            chloride  (equivalent doses of 0.05, 1.0, and                             0.25 ppm):
                  100           gestation-lactation. Diets sufficient           10.4 mg Cd/kg bw for females, and                               • 15% decrease in litter size
                  respectively) and insufficient in vitamins were               0.06, 1.1, and 11.4 mg Cd/kg bw for                             • 25% decrease in pup growth at 50 ppm
                                tested.                                         males). No control group was
                                                                                included.
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<pre> chapter 05 | Toxicity for reproduction                                                                                   Cadmium and selected cadmium compounds | page 53 of 103
  Reference          Investigated  experimental period and design       Substance     Dose and method of                   Maternal toxicity            developmental toxicity
                     species                                                          administration
  Sorell and         Rat, Sprague- Administration: from GD1-20. At      Cadmium       0. 5, 50 or 100 ppm in drinking      Reduced body weight at       • No effect on litter size
  Graziano (1990)    Dawley        GD20, animals were sacrificed        chloride      water (equivalent to 0, 0.4, 4 or 8  50 and 100 ppm               • Reduced body weight at 50 and 100 ppm
                     (N=42-66/                                                        mg Cd/kg bw)
                     group)
  Andersson et al.   Rat, Sprague- From the day of partus (day 0),      Cadmium       5 mg/L cadmium in drinking water     No effect on food/water      • Increased levels of plasma nitrogen only in pups
  (1997)             Dawley        dams were exposed via drinking       chloride      (equivalent to 0.70, 0.97, and 1.06  intake and mean body           exposed post-weaning.
                     (N=16/group)  water and/or to PND 17, and/or                     mg Cd/kg bw during the first,        weights,                     • No obvious neuropathological effects.
                                   during lactation until postnatal day               second, and third weeks of the                                    • Cortical serotonin levels were reduced in pups of all
                                   42                                                 lactation period for dams, and                                      exposed groups
                                                                                      0.8-1.2 mg Cd/kg bw in pups).                                     • No effect on body weight offspring
  Nagymajtenyi et    Rat, Wistar   Administration: 5 d/w during         Cadmium       0, 3.5, 7.0 or 14.0 mg Cd/kg bw by   No information provided      • No effects on pup body weights, no visible
  al. (1997)         (N=5-10)      pregnancy, lactation and 8 weeks chloride          gavage                                                              malformations and no clinical signs
                                   after weaning for 3 generations                                                                                      • 3.5 mg/kg and higher: open field exploration
                                   (females 7 d/w from start mating                                                                                       affected
                                   until weaning). Investigations were                                                                                  • 7 and 14.0 mg/kg: most behavioural and
                                   performed at 12 w of age                                                                                               electrophysiological parameters; reduced bw in
                                                                                                                                                          generation 2 and 3
                                                                                                                                                        • 14.0 mg/kg: reduced kidney and spleen weights in
                                                                                                                                                          generation 3
  Corpas and         Rat, Wistar   Administration during gestation      Not specified 10 mg/L in drinking water            No information provided      At day 0 and PND 5:
  Antonio (1998)     (N=10)        and early lactation until delivery                 (equivalent to 1.13 mg Cd/kg bw                                   • Reduced pup, testicular and ovary weights
                                   and (5 days after parturition)                     according to the authors)                                         • Decreased seminiferous tubule diameter and
                                                                                                                                                          reduced number of prospermatogonia Reduced
                                                                                                                                                          DNA/RNA ratio ovary and testis
  Desi et al. (1998) Rat, Wistar   Dams were treated according to       Cadmium       0, 3.5, 7.0 or 14.0 mg Cd/kg         No visible clinical signs of • No (statistical significant) effect on litter size, new
                     males (N=10)  three different treatment            chloride      cadmium by gavage                    chronic cadmium                born body weight, malformations
                                   schedules: GD 5–15; GD 5–15 + 4                                                         intoxication were found in
                                   w of lactation; GD 5–15 + 4 weeks                                                       any of the treated groups    All treatment groups:
                                   of lactation followed by the same                                                                                    • Reduced kidney weight; further not specified
                                   oral treatment of male rats of the                                                                                   • Dose-dependent changes in electrocorticogram
                                   F1 generation for 8 weeks.                                                                                             (not statistically significant)
                                                                                                                                                        • Treatment GD 5-15, lactation and 8 weeks (at 14
                                                                                                                                                          mg/kg):
                                                                                                                                                        • Statistically significant changes in
                                                                                                                                                          electrocorticogram
                                                                                                                                                        Treatment GD 5-15 and lactation (7 and 14 mg/kg):
                                                                                                                                                        • Decreased horizontal ambulation; decreased
                                                                                                                                                          rearing
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<pre> chapter 05 | Toxicity for reproduction                                                                                Cadmium and selected cadmium compounds | page 54 of 103
  Reference         Investigated  experimental period and design    Substance    Dose and method of                     Maternal toxicity        developmental toxicity
                    species                                                      administration
  Salvatori et al   Rat, Wistar   Administration from GD6 to GD14.  Likely       0 and 20 mg Cd/kg bw by gavage         Decreased food           • No effect on number of implantation sites, number
  (2004)            (N=10-12      One subgroup was sacrificed and   cadmium                                             consumption; however no    of resorptions, number of live foetuses/litter,
                    group)        analysed for effects on the       sulphate                                            effect on body weight      number of corpora lutea, foetal weight and
                                  foetuses. Another treatment       (cadmium                                                                       placental weight
                                  subgroup and control group were   chloride                                                                     • reduced metacarpus ossification in 2 litters;
                                  allowed to give birth and pups    specified in                                                                   reduced weight in these litters
                                  were assessed for physical and    M&M, results                                                                 • Increased anomalies and malformations (cleft
                                  reflex development at PND21.      specified as                                                                   palate (23/126) and renal cavitation (10/62)) in all
                                                                    cadmium                                                                        litters
                                                                    sulphate)                                                                    • Abnormal sexual behaviour in males and females
  Kuriwaki et al.   Rat, Wistar   Administration from GD9-19.       Cadmium      0, 1 and 10 mg Cd/kg bw by             No information provided  • No effect on the number of foetuses
  (2005)            (N=5/group)   Then, animals were sacrificed and chloride     gavage (doses appear to relate to                               • Reduced foetal liver weight
                                  organs and foetuses were                       cadmium equivalents)
                                  collected.
  Ishitobi et al.   Mouse,        Administration from conception    Cadmium      0, 1 and 10 ppm Cd in the drinking     No effect on body weight • No effect on length of gestation, litter size, sex ratio,
  (2005)            C57BL/6J Jcl  until PND10. Pups were left until chloride     water (equivalent to 0.2 and 2.0 mg    gain                       births weight, number of live births, stillbirths.
                    (N=6/group)   PND21, subsequently, pups were                 Cd/kg bw)                                                       • Non-statistically significant increase in postnatal
                                  separated and housed according                                                                                   deaths
                                  to sex until PND70.                                                                                            • Non-statistically delay in day of vaginal opening
                                                                                                                                                 •
  Jacquillet et al. Rat, Wistar   Administration during whole       Cadmium      0 and 0.5 mg Cd/kg bw by gavage        No information provided  • Reduced pup weight up to 6 days
  (2007)            (N=6-7/group) gestation period. Renal function  chloride                                                                     • Increased arterial pressure at PND21, PND45, and
                                  was assessed from PND2-60                                                                                        PND60
                                                                                                                                                 • Reduced glomerular filtration rate at PND60
                                                                                                                                                   associated with other signs of kidney toxicity
  Ronco et al.      Rat, Wistar   Administration during gestation,  Cadmium      0, 3, 15, 30, 50 ppm in drinking       No effect on body weight • No differences in the offspring number, size and
  (2009)            (N=6–9/group) until GD20. Then, pups were       chloride     water (equivalent to 0, 0.5, 1.8, 3.9                             placenta’s weight
                                  delivered by caesarean section.                and 5.3 mg Cd/kg bw, as specified                               • At 50 ppm: decreased body weight at birth
                                                                                 by the authors)                                                 • At 50 ppm: Increased levels of corticosterone in
                                                                                                                                                   dams (plasma and placenta; GD20) and offspring
                                                                                                                                                   (plasma)
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<pre> chapter 05 | Toxicity for reproduction                                                                           Cadmium and selected cadmium compounds | page 55 of 103
  Reference         Investigated experimental period and design     Substance Dose and method of                   Maternal toxicity          developmental toxicity
                    species                                                   administration
  Couto-Moraes et   Rat, Wistar  Administration on GD 18 and 21     Cadmium   0, 10 and 20 mg Cd/kg bw, by         • 10 and 20 mg/kg:         • 10 and 20 mg/kg: Reduced pup weight and weight
  al. (2010)        (N=8 or 16/  and daily from the PND 1 to PND    chloride  gavage                                 Reduced body weight        gain at PND1 and PND21
                    group)       7.                                                                                  gain during pregnancy in • 20 mg/kg: Reduced mean body length at PND1 and
                                                                                                                     both treatment groups      PND21
                                                                                                                   • 20 mg/kg: Reduced        • 20 mg/kg: reduced anogenital index in pups and
                                                                                                                     body weight gain during    delayed physical and reflexes development
                                                                                                                     lactational period and
                                                                                                                     reduced food
                                                                                                                     consumption
  Samuel et al.     Rat, Wistar  Administration on GD9-21. After    Cadmium   0, 50 and 200 ppm in drinking water Reduced water intake and    At 50 and 200 ppm:
  (2011)            (N=18/group) birth, female pups were left with  chloride  (equivalent to 5.8 and 17.7 mg Cd/ final body weight            • Increased number of resorption sites
                                 the mothers. After weaning, on               kg bw)                               Decrease gravid uterine    • Effects on haematological parameters
                                 PND10 and 21, pups were killed                                                    weight                     • Delayed pubertal onset
                                                                                                                                              • Oestrous cycle extended in metoestrus and
                                                                                                                                                dioestrus stage
                                                                                                                                              • Disruption of ovarian histoarchitecture
                                                                                                                                              At 200 ppm:
                                                                                                                                              • Reduced number of foetuses
                                                                                                                                              • Reduced number of implantation sites
  Zhao et al.       Rat, Sprague Male rats were administered        Cadmium   0 and 22.15 mg CdCl2/kg bw (13.6     No information provided    Differences observed in various behavioural tests:
  (2015)            Dawley (N=6/ cadmium, every 2 days for 9        chloride  mg Cd/kg bw, orally by gavage)                                  • surface‑righting reflex (PND3-9)
                    group)       weeks. Then, the animals were                                                                                • air‑righting reflex (PND3-9)
                                 mated with unexposed females.                                                                                • Cliff avoidance (PND4,5,7 and 9)
                                 Neuromotor maturation                                                                                        • negative geotaxis reflex (PND2-10)
                                 assessment was done on various
                                 days after partus
  Luo et al. (2015) Rat, Sprague Pregnant rats were administered    Cadmium   0, 1, 5 and 10 ppm in drinking water No effect on maternal      No effect on:
                    Dawley       cadmium from GD0-21. Litter size   chloride  (0, 0.089, 0.439, 0.955 mg Cd/kg     body weight                • gestation length, number of pups or sex ratio
                    (N=10/group) and live pups were followed for 12           bw)                                                             • Physical development
                                 weeks                                                                                                        • Sperm parameters/oestrus cycle in offspring
                                                                                                                                              5 and 10 ppm:
                                                                                                                                              • reduced body weight
                                                                                                                                              10 ppm:
                                                                                                                                              • reduced liver and kidney weights
  Mikolic et al.    Rat, Wistar  Pregnant rats were administered    Cadmium   0 and 50 ppm cadmium in drinking     No effect on maternal      No effect on:
  (2014)            (N=5-15/     cadmium during 20 days of          chloride  water (equivalent to 7.5 mg Cd/kg    body weight                • Foetal weight
                    group)       gestation. On day 20, animals      hydrate   bw, according to the authors)                                   • Number of corpora lutea
                                 were killed and analysed                                                                                     • Number of live or dead foetuses
54         Health Council of the Netherlands | No. 2020/22                                                                                            2                                          56
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<pre> chapter 05 | Toxicity for reproduction                                                                                  Cadmium and selected cadmium compounds | page 56 of 103
  Reference          Investigated   experimental period and design      Substance    Dose and method of                    Maternal toxicity              developmental toxicity
                     species                                                         administration
  Tian et al. (2017) Rat, Sprague-  Rats were administered cadmium Cadmium           0, 1, or 5 mg Cd/kg bw by gavage      No data provided               • No effect on pup weight
                     Dawley         from GD0-PND21. At PND21, 35        chloride                                                                          1 mg/kg:
                     (N=not         or 56, F1 male rats were sacrificed                                                                                   • Reduced testis to body weight ratio at PND21
                     specified)     and testes were removed and                                                                                           • Reduced levels steroid hormones at PND35 and 56
                                    blood samples were collected.                                                                                         5 mg/kg:
                                                                                                                                                          • Reduced testis to body weight ratio at PND21, 35
                                                                                                                                                            and 56
                                                                                                                                                          • Reduced levels steroid hormones at PND21, 35
                                                                                                                                                            and 56
                                                                                                                                                          •
  Li et al. (2018)   Rat, Sprague-  Cadmium was administered from       Cadmium      0, 1, or 5 mg Cd/kg bw by gavage      Maternal survival not          No effect on pup weight
                     Dawley         GD 0 to PND 21. F1 female rats      chloride                                           affected                       1 and 5 mg/kg:
                     (N=12-14/      were allowed to mate with to                                                                                          • Increased ratio of uterus to bw
                     group)         obtain the F2 generation
                                                                                                                                                          5 mg/kg:
                                                                                                                                                          • Increased ratio of ovary to body weight
                                                                                                                                                          • Advanced day of vaginal opening and first oestrus
                                                                                                                                                            F1 female offspring
                                                                                                                                                          • Reduced number of primordial follicles; increased
                                                                                                                                                            number of secondary follicles in F1
                                                                                                                                                          • Increased litter size
 Other routes
  Reference           Investigated        experimental period and        Substance Dose and method of       Maternal toxicity          developmental toxicity
                      species             design                                   administration
  Parizek (1964)      Rats, Wistar        Pregnant rats were injected at Cadmium   0 and 0.04 mmol/kg bw No information provided       •  Progressive placental changes, mainly in pars foetalis
                      substrain           GD17-21. No further            chloride  (4.5 mg Cd/kg bw)                                   •  Slight changes in pars maternal, slight oedema and hyperaemia
                      Konarovice (N=70;   information was provided                 subcutaneously                                      •  Haemorrhage into the uterine cavity, even by external bleeding
                      12 controls)                                                                                                     •  Interruption of pregnancy (either by delivery of the dead conceptus
                                                                                                                                          or resorption)
  Ferm et al. (1968) Golden hamsters      Pregnant hamsters were         Cadmium   0, 2 and 4 mg Cd/kg      At >10 mg/kg: 100%         2 and 4 mg/kg: Various degrees of facial malformations, including cleft
                      (N=20/14 per        injected on GD8. Most          sulphate  bw (no control group)    mortality. No noticeable   lip and complete palate clefts
                      group)              animals were sacrificed at               intravenously            effect was apparent at a   2 mg/kg:
                                          GD12.                                                             dose of 5-10 mg/kg         • 248 embryos; 33 resorptions; 73 normal; 142 abnormal
                                                                                                                                       4 mg/kg:
                                                                                                                                       • 190 embryos; 88 resorptions; 16 normal; 86 abnormal
                                                                                                                                       5-10 mg/kg: Nearly 100% resorption
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<pre> chapter 05 | Toxicity for reproduction                                                                              Cadmium and selected cadmium compounds | page 57 of 103
  Reference         Investigated        experimental period and        Substance Dose and method of      Maternal toxicity       developmental toxicity
                    species             design                                   administration
  Samarawickrama    Rat, Wistar-Porton  Cadmium was administered       Cadmium   0, 1.1 and 1.25 mg Cd/  No information provided 1.1 mg/kg: No effects observed
  and Webb (1979)                       on different days of gestation chloride  kg intravenously                                1.25 mg/kg: Increased of resorptions, presence of abnormal foetuses,
                                        (GD8-15). Animals were                                                                   malformations (including hydrocephalus, an- and microphthalmia,
                                        sacrificed on GD20.                                                                      gastroschisis and umbilical hernia).
  Saltzman et al.   Rat, Wistar         Groups of mated female rats    Cadmium   40 and 50 µmol/kg bw    No information provided Administration at GD12 (4.5 mg/kg):
  (1989)            [Crl:(WI)BR] (N=4-8 received an injection of ~ 4.5 chloride  (equivalent to 4.5 or                           • No adverse effects on foetal viability or growth
                    group)              or 5.6 mg cadmium/kg bw on               5.6 mg Cd/kg bw)                                • Reduced blood flow chorioallantoic placenta (-35%) at 16/18 h
                                        GD 12. Blood flow was                    subcutaneously                                    post-treatment; unaffected at 38-43 h.
                                        determined 16-43 h later in                                                              • No effect on foetal viability or growth
                                        placenta and uterus. Other
                                        groups were treated at PND                                                               Administration at GD12 (5.6 mg/kg):
                                        18. Animals were sacrificed                                                              • No adverse effects on foetal growth; 12% foetal lethality (manifested
                                        were sacrificed on GD19/20.                                                                as resorptions only)
                                                                                                                                 • 1 case of cleft palate
                                                                                                                                 Administration at GD18 (4.5 or 5.6 mg/kg):
                                                                                                                                 • Foetus lethality (manifested as resorptions and dead foetuses) at
                                                                                                                                   both doses (53 and 82%, respectively)
  Pelletier and     Rat (Roman          Pregnant rats received         Cadmium   0.075 mg Cd/kg bw       No effect on maternal   • No effect on length of gestation, litter size at birth and weaning,
  Satinder (1991)   HighAvoidance       injections once per day        chloride  and 0.225 mg Cd/kg      weight gain and food      foetal mortality and physical development
                    (RHA), Roman Low    throughout gestation (GD                 bw subcutaneously       consumption             • Abnormal results on behavioural tests
                    Avoidance (RLA)     0-20). Animals were weaned
                    and Satinder’s      and thereafter behavioural
                    Heterogeneous       studies were performed at
                    stock (SHS))(N=9/   various endpoints
                    group)
  Soukupova and     Mouse, ICR (N=?)    Pregnant mice were treated     Cadmium   2, 4 and 6 mg Cd/kg     No information provided At 6 mg/kg (compared to 4 mg/kg):
  Dostal (1991a)                        once during GD8-14. On         chloride  bw subcutaneously (no                           • Increased mortality
                                        GD18 animals were sacrificed             control group included)                         • Reduced thymus weight (2 mg group not analysed)
                                        and foetuses were analysed
                                                                                                                                 Fraction of embryos with (right-sided) limb malformations appeared to
                                                                                                                                 be increased, Inconsistent findings of haemorrhagic bullae,
                                                                                                                                 exencephaly, cleft palate, open eyelids and tail deformities were
                                                                                                                                 reported (no apparent dose-response). No results of control group
                                                                                                                                 were provided.
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<pre> chapter 05 | Toxicity for reproduction                                                                               Cadmium and selected cadmium compounds | page 58 of 103
  Reference         Investigated      experimental period and         Substance Dose and method of      Maternal toxicity       developmental toxicity
                    species           design                                    administration
  Soukupova and     Mouse, ICR (N=4/  Pregnant mice were treated      Cadmium   2.5, and 5 mg Cd/kg     No information provided At 3.1 mg/kg:
  Dostal (1991b)    group)            once on GD16. At the age of     chloride  bw subcutaneously (no                           • Increased lymphoproliferation response of spleen lymphocytes was
                                      4 w, proliferative responses of           control group included)                            in male offspring 4 weeks after birth
                                      spleen cells were tested.
                                                                                                                                At 1.5 mg/kg bw
                                                                                                                                • Increased titre of haemaglglutination antibodies to sheep red blood
                                                                                                                                   cells in the offspring (both sexes)
  Hartsfield et al. Hamster, golden   Pregnant animals were           Cadmium   0, 2 and 3 mg Cd/kg     Reduced bodyweight at   2 and 3 mg/kg bw:
  (1992)            Syrian (N=10/     injected on GD 8. Foetuses      chloride  bw intravenously        3 mg/kg bw              • Increased number of non-viable foetuses
                    group)            were analysed at GD 15.                                                                   • Increased proportion of malformed foetuses (mainly neural tube
                                                                                                                                   defects and oral—facial clefts)
                                                                                                                                • Decreased foetal weights
                                                                                                                                • Decreased foetal crown—rump length
  De et al. (1993)  Mouse, CD-1       Mice were injected on either    Cadmium   0, 2.8 and 4.3 mg Cd/   No information provided 2.8 and 4.3 mg/kg bw;
                    (N=3-15/group)    GD 2 or GD 4, and killed        chloride  kg bw subcutaneously                             Injection at GD 2:
                                      either on GD 5 or GD 8 to                                                                 • Reduction of number mice with implantation sites at GD 5, but not at
                                      examine implantation sites.                                                                  GD 8
                                                                                                                                Injection at GD 4
                                                                                                                                • Reduced number of mice with implantation sites/implantation sites
                                                                                                                                   per uterus at GD 5 and GD 8
                                                                                                                                • Blastocyst degeneration at GD 5
                                                                                                                                •
  Piasek and        Rat, Sprague      Pregnant animals were           Cadmium   0, 3 and 5 mg Cd/kg     No effect on maternal   No disruption of oestrous cyclicity; no effect on live implants,
  Laskey (1994)     Dawley (N=10-16/  injected on the day of          chloride  bw subcutaneously       body weight             resorptions, and foetal weight
                    group)            dioestrus, or on GD 7 or 16.
                                      Dams and foetuses were
                                      analysed 24 h later.
  Paksy et al.      Rat, CFY (N=9-13/ Female rats were treated        Cadmium   0, 1.5, 3.1 and 6.1 mg  Reduced maternal body   6.1 mg/kg:
  (1996)            group)            during oestrus or dioestrus     chloride  Cd/kg bw                weight in all groups,   Reduced percentage of rats mated at 80 and 128h post-treatment
                                      and allowed to mate. Foetal               subcutaneously          dependent on treatment  3.1 mg/kg:
                                      outcome was assessed at GD                                        schedule                Reduced percentage of rats mated at 80h post-treatment
                                      10, or post-natally up to day                                                             No effect on litter number and weight, and fraction of males/females
                                      21.                                                                                       up to GD 21.
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<pre> chapter 05 | Toxicity for reproduction                                                                              Cadmium and selected cadmium compounds | page 59 of 103
  Reference         Investigated        experimental period and        Substance Dose and method of    Maternal toxicity        developmental toxicity
                    species             design                                   administration
  Piasek et al.     Rat, Sprague-       Pregnant rats were fed diet    Cadmium   0, 3 and 5 mg Cd/kg   Reduced maternal body    High foetal mortality and placental destruction at 3 and 5 mg/kg in
  (2004)            Dawley (N=6-16/     with either high or low iron   chloride  bw subcutaneously     weight at 3 and 5 mg/kg  acute treatment group (not further quantified)
                    group)              level (240 or 10 mg/kg diet)                                   in acute treatment group
                                        and exposed to cadmium
                                        from GD 1-15 (subchronic
                                        study) or only at GD 15 (acute
                                        study). At GD 19 animals
                                        were killed and analysed.
  Nampoothiri and   Rat, Charles Foster Animals were treated during    Cadmium   0 and 0.024 mg Cd/kg  No effect on maternal    Changes in implantation enzymes and steroidogenic enzymes of ovary
  Gupta (2008)      (N=14/group)        the gestational period, with   acetate   bw subcutaneously     body weight, no toxicity and placenta, but no effect on:
                                        pretreatment of 5 days prior                                   observed                 • Litter size
                                        to mating. At GD 19, animals                                                            • Number of dead/resorbed foetuses
                                        were killed and analysed.                                                               • Litter weight
                                                                                                                                • Ovarian/placental weight
  Lee et al. (2009) Rat, F344 Fisher    Pregnant rats were treated     Cadmium   0, 0.2 and 2.0 mg Cd/ No information provided  At 0.2 and 2.0 mg/kg (dose dependent):
                    (N=10/group)        from GD 11-19 and were         chloride  kg subcutaneously                              • Decreased number of trophoblast cells
                                        sacrificed on GD 20 and                                                                 • Increased resorptions and dead foetuses
                                        developmental parameters                                                                • Increased post-implantation loss
                                        were assessed and placentas                                                             • Reduced average foetal and placental weights
                                        analysed.                                                                               • Changes in placental lactogens and genes involved in placental
                                                                                                                                  function
                                                                                                                                • Chromosomal DNA fragmentation in the placental junctional zone
  Wang et al.       Mouse, ICR (N=10/   Pregnant mice were injected    Cadmium   0 and 2.8 mg Cd/kg bw No effect on maternal    • Reduced placental weight and histological placental alterations
  (2012)            group))             on GD 9 and sacrificed on GD chloride    intraperitoneally     body weight gain         • Increased markers of oxidative stress
                                        18.
                                                                                                                                No effect on:
                                                                                                                                • Number of implantation sites, resorptions per litter, live foetuses per
                                                                                                                                  litter and dead foetuses per litter
  Del Diaz et al.   Rat, Wistar (N=10/  Pregnant rats were treated     Cadmium   0 and 10 mg Cd/kg bw  Congestion,              In all treatment groups:
  (2014)            group)              with a single injection at GD  chloride  intraperitoneally     haemorrhages,            • Reduced total implantations (except in the GD 7 group)
                                        4, 7, 10 or 15 and sacrificed                                  inflammation and         • Increased total resorption/resorptions per dam
                                        at GD 20.                                                      necrosis in livers,      • Skeletal malformations (including amelia, brachygnathia,
                                                                                                       kidneys and lungs          omphalocele, cauda, and anotia)
                                                                                                                                • Necrosis of the placenta
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<pre> chapter 05 | Toxicity for reproduction                                                                         Cadmium and selected cadmium compounds | page 60 of 103
  Reference       Investigated      experimental period and      Substance Dose and method of      Maternal toxicity         developmental toxicity
                  species           design                                 administration
  Wang et al.     Rat, Sprague-     Pregnant rats were exposed   Cadmium   0, 0.25 and 0.5 mg Cd/  At 0.5 mg/kg:             At 0.5 mg/kg:
  (2014)          Dawley (N=6-8/    to cadmium from GD 5-19.On   chloride  kg bw intraperitoneally • Decreased maternal      • Increased prenatal losses (due to resorption and/or stillbirth)
                  group)            GD 20 animals were                                               body weight             • Reduced foetal body weight
                                    sacrificed and maternal-                                       • Increased systolic      • Reduced litter size of and viable foetuses
                                    placental-foetal parameters                                      blood pressure          • Decreased foetal weight/placental weight ratio and crown rump
                                    linked to preeclampsia were                                    • Increased urine protein   length
                                    evaluated.                                                       excretion               • Increased placental corticosterone production and maternal and
                                                                                                                               foetal plasma corticosterone levels
                                                                                                                             • Changes in expression of placental enzymes involved in
                                                                                                                               corticosteroid synthesis
  Zhang et al     Rat, Wistar (N=5/ Pregnant rats were injected  Cadmium   0 and 0.125 mg Cd/kg    • Increased systemic      • Damage to placenta and decidua
  (2016a)         group)            on GD 9-14. Urine protein    chloride  intraperitoneally         blood pressure          • Reduced foetal weight
                                    was measured on GD 3-19,                                       • Histopathological       Decreased crown-rump length
                                    systolic blood pressure from                                     lesions of the kidney
                                    GD 0 to PND 6. For                                               and proteinuria
                                    evaluation of the foetuses
                                    and placenta, dams were
                                    sacrificed at GD 21.
  Zhang et al.    Mouse, ICR (N=12/ Pregnant mice were injected  Cadmium   0, 1.5 and 3.1 mg Cd/   No effect on maternal     No effect on litter size, live foetuses, and resorptions
  (2016b)         group)            on GD8. On GD 18, the dams   chloride  kg intraperitoneally    body weight gain          At 3.1 mg/kg bw:
                                    were sacrificed on GD18 and                                                              • Increased number of dead foetuses per litter
                                    live, dead and resorbed
                                    foetuses were counted and                                                                At 1.5 and 3.1 mg/kg bw:
                                    Placentas were collected for                                                             • Reduction in foetal weight and crown-rump length
                                    histological examination.                                                                • Increased number of neural tube defects
                                                                                                                             • Reduced placental weight, diameter, and blood sinusoids
  Zhang et al.    Rat, Sprague-     Pregnant rats were injected  Cadmium   0, 0.25 and 0.5 mg Cd/  At 0.25 and 0.5 mg/kg:    At 0.25 and 0.5 mg/kg:
  (2016c)         Dawley (N=8-10/   on GD 4-19. Systolic blood   chloride  kg intraperitoneally    • Increased urine protein • Reduced number of live foetuses
                  group)            pressure was monitored on                                        levels
                                    GD 3, 11, and 18. On GD 20,                                                              At 0.5 mg/kg:
                                    rats were sacrificed and                                       At 0.5 mg/kg:             • Increased number of dead foetuses
                                    tissues were collected.                                        • Decreased maternal      • Decreased foetal weight
                                                                                                     body weight
                                                                                                   • Increased systolic      At 0.25 mg/kg (0.5 not assessed):
                                                                                                     blood pressure          • Morphological changes in placenta
                                                                                                                             • Increased markers of oxidative stress in placenta
                                                                                                   At 0.25 mg/kg (0.5 not
                                                                                                   assessed):
                                                                                                   • Morphological
                                                                                                     changes in kidney
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  Reference          Investigated      experimental period and             Substance  Dose and method of       Maternal toxicity           developmental toxicity
                     species           design                                         administration
  Li et al. (2018)   Rat, Sprague-     Dams received a single              Cadmium    0, 0.25, 0.5, and 1.0    No effect on maternal       At 0.25 and 0.5 mg/kg (but not at 1.0 mg/kg):
                     Dawley (N=6/      injection on GD 12. On GD           chloride   mg Cd/kg                 bodyweight                  • Decreased foetal bodyweight
                     group)            20, animals were sacrificed                    intraperitoneally
                                       and the testes of the male                                                                          At 0.25 and 0.5 mg/kg:
                                       foetuses were weighed and                                                                           • Reduced testosterone levels
                                       analysed.                                                                                           • Reduced number of Leydig cells
 Inhalation route
  ref                 Investigated      experimental period and             Substance  Dose and method of       Maternal toxicity            developmental toxicity
                      species and sex   design                                         administration
  Baranski (1983;     Rat, Wistar       Female rats were exposed for Cadmium           0, 0.02, 0.16, 1.0 mg    At 1.0 mg/m3:                • No foetal mortality or malformations
  1984; 1985)         (N=17-28/group)   5 h/d, 5 d/w for 5 months (high oxide          Cd/m3 (equivalent to 0,  Mortality (55.1% vs 6.5%
                                        dose group for 4 months),                      6, 48 and 300 µg Cd/     in control group)            At 0.02 and 0.16 mg/m3:
                                        during mating and from GD                      kg bw bw)                                             • Retarded ossification
                                        1-20. Toxicity to the foetuses                                                                       • Decreased exploratory motor activity in males
                                        was assessed at GD 21.                                                                               • Reduced avoidance acquisition in both males and females
                                        Remaining animals were
                                        allowed to deliver offspring, on                                                                     At 0.16 mg/m3:
                                        which behavioural tests were                                                                         • Reduced pup viability on PND 4
                                        performed at various at                                                                              • Reduced bw gain after birth
                                        different time points after birth.                                                                   • Decreased exploratory motor activity in males and females
                                                                                                                                             • Impaired open field-behaviour in males
  NTP (1995)          Rat, Sprague-     Pregnant rats were exposed          Cadmium    0, 0.044, 0.44 or 1.75   At 1.75 mg/m3:               No effect on foetal mortality, resorptions, litter size
                      Dawley (N=26-30/  for 6 h/d, 7 d/w days per week, oxide          mg Cd/m3 (equivalent     Decreased body weight        At 1.75 mg/m3:
                      group)            on gestation Day 4 through                     to 0, 0.008, 0.08, and   Dyspnoea and                 • Reduced foetal bw
                                        19.                                            0.34 mg Cd/kg bw)        hypoactivity                 • Reduction of skeletal ossifications
                                                                                                                                             •
  NTP (1995)          Mouse, Swiss      Pregnant rats were exposed          Cadmium    0, 0.044, 0.44 or 1.75   At 1.75 mg/m3:               At 0.44 and 1.75 mg/kg:
                      (CD-1) (N=32-4/   for 6 h/d, 7 d/w days per week, oxide          mg Cd/m3 (equivalent     Decreased body weight        • Reduced foetal body weights
                      group)            on gestation Day 4 through                     to 0, 0. 0.014, 0.14,    Decreased gravid
                                        17.                                            and 0.59 mg Cd/kg bw)    uterine, liver, and kidney   At 1.75 mg/m3:
                                                                                                                weights                      • Reduced fraction live male foetuses
                                                                                                                Dyspnoea, hypoactivity,      • Increased total resorptions/litter
                                                                                                                Lower pregnancy rate
                                                                                                                (30% vs. 97% in the
                                                                                                                control group).
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   ref                Investigated            experimental period and           Substance Dose and method of        Maternal toxicity              developmental toxicity
                      species and sex         design                                      administration
   Jacobo-Estrada     Rat, Wistar             Pregnant rats were exposed        Cadmium   0 and 17.43 mg/m3         No effect on weight gain       • No effect on number of foetuses per litter
   et al. (2016)      (numbers not            during GD 8–20 to cadmium         chloride  (equivalent to 0 and      No effect on liver and         • No malformations
                      specified)              chloride mist. On GD 21,                    1.48 mg Cd/kg bw          kidney weights                 • No effect on kidney, liver or placental weight
                                              dams were euthanized,                       (specified by the                                        • Reduced foetal bw
                                              markers for kidney toxicity                 authors)                                                 • Increased kidney injury biomarkers; histological tubular damage
                                              were quantified in amniotic                                                                            and precipitations in the renal pelvis
                                              fluid samples and foetal                                                                             •
                                              kidneys were examined.
 5.4.1       Animal studies                                                                                  decreased, and the number of resorptions was increased in the 10 mg
 Oral exposure                                                                                               group. No malformations were observed. The females of the mid and high
 Schroeder and Mitchener (1971)8 conducted a multigeneration                                                 dose groups showed mild to overt signs of toxicity. The treated males also
 reproduction study with CD mice in which cadmium was offered                                                mated with untreated females which showed no effects upon sacrifice.
 continuously in the drinking water at a level of 10 mg/L (an equivalent                                     Untreated female Sprague-Dawley rats were mated to males, previously
 dose of 2.1 mg/kg bw/da). An increase in young deaths and in number of                                      exposed to 0, 17.2, 34.4 or 68.8 mg cadmium/L in drinking water
 runts were observed in F1 and F2.                                                                           (equivalent to 0, 0.7, 1.3, and 2.6 mg/kg bw/db). (Zenick et al., 1982)15
                                                                                                             Some females were sacrificed on GD 20. No adverse effects were observed.
 Sutou et al. (1980)13,14 administered 0, 0.1, 1.0 or 10 mg cadmium/kg bw/                                   The other females were allowed to litter; the resulting offspring was
 day for 6 weeks by gavage to groups of 14 female and 14 male Sprague-                                       followed for general and behavioural changes, which were not detected.
 Dawley rats, after which they were mated. Exposure continued during
 mating and gestation up to GD 20, when the females were sacrificed.                                         Baranski et al. (1982)91 administrated cadmium (0, 2, 4, 8, 12, 20 and
 Adverse effects were observed in the 10 mg/kg group on foetal body weight                                   40 mg/kg bw/d) by gavage to pregnant Wistar rats, from day 7 to day 16 of
 and length; the foetuses were anaemic and malnourished, and the placenta                                    gestation. Body weights were measured on day 1 and day 21 of gestation.
 weight was increased. Numbers of implantation sites and live foetuses were                                  On day 21, pregnant rats were euthanized and organs were collected.
                                                                                                             b
                                                                                                               Calculated based on a mean water intake of 15 mL (derived from graph) and mean body weight estimated on the
 a
    Assuming a body weight of 35 gram, and a calculated 7.3 mL water intake/day                                weights reported in the publication
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 The number of corpora lutea was counted and the number of live           subcutaneous oedema was noted. At all doses, a reduction of locomotor
 foetuses, dead foetuses, and early and late resorption sites were        activity at 2 months in females was observed. In males, this was observed
 recorded. All doses of cadmium caused a decrease in body weight gain of  at the two highest doses.
 rats from day 1 to day 21 of pregnancy. From doses of 2 mg/kg bw/d and
 higher, delayed ossification was observed. Foetal body weight was        In another publication, Baranski (1985)46 reported results of a study in
 reduced at doses 8-40 mg/kg bw. At the highest dose, the number of live  pregnant rats exposed to 0, 2, 12 or 40 mg/kg bw from GD 7-16. Animals
 foetuses was decreased and the number of resorptions per litter was      were sacrificed at GD 21. A reduced body weight was noted at all doses.
 increased. Effects on gross external and soft tissue morphology of       At 12 and 40 mg/kg bw/d, the foetus weights were reduced. At the highest
 foetuses were observed at the two highest doses. Decreased maternal      dose, the number of live foetuses per litter was reduced and the number
 body weight gain was observed at all doses, whereas absolute body        of resorptions per litter was increased.
 weight was decreased at 8 mg/kg bw and higher. The highest dose          In another study, Baranski (1986)92 administered cadmium in drinking
 resulted in maternal deaths.                                             water (0 and 60 ppm cadmium; equivalent to 0 and 8.5 mg/kg bw/da) to
                                                                          pregnant rats from day 1 to day 20 of gestation. Females were allowed to
 Baranski et al. (1983)16 also exposed female rats to cadmium by gavage   deliver and nurse their progeny until weaning at 28 days. Litter size was
 (0, 0.04, 0.4, and 4 mg cadmium/kg bw) for 5 days/week for 5 weeks       not affected, and body weight at birth, body weight gain, viability, and food
 before, and throughout gestation. At gestation day 21, animals were      and water consumption in the control group and the exposure group were
 divided in two subgroups. One group was sacrificed and foetuses were     similar. The absolute weight of the whole brain was reduced, and ratio
 analysed while another group was allowed to deliver progeny. After two   liver weight/body weight was increased in 2-w old male offspring, absolute
 months, locomotor activity was measured in the offspring. No effect on   weights of liver and kidneys were not affected. Prenatal exposure to
 survival of the F0 females was noted, however some mortality in the      cadmium led to changes in several parameters in behaviour tests.
 highest dose group was also mentioned. No effect on the number of        In a follow up study, Baranski (1987)90 administered cadmium at levels
 resorptions was found, also foetal length and body weight, and placental of 0, 60 and 180 ppm drinking water (equivalent to 0, 9.2 and 27.7 mg
 weight was similar in all treatment groups. No malformations were
 reported, however, at 0.4 mg cadmium/kg bw an increase in foetal         a
                                                                             Assuming a body weight of 175 g, and a calculated 24.8 mL water intake/day.
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<pre> chapter 05 | Toxicity for reproduction                                                                                                  Cadmium and selected cadmium compounds | page 64 of 103
 cadmium/kg bw/da) from day 1 to day 20 of gestation. The female rats                                               foetal and maternal weights were slightly reduced in the 50- and 100-ppm
 were sacrificed on day 21 of gestation. Increased cadmium intake with                                              groups, but not in the 5-ppm group. Average litter size was not affected.
 drinking water containing 60 and 180 ppm cadmium did not affect the                                                Andersson et al. (1997)95 administered cadmium in the drinking water
 survival of pregnant rats. Body weight gain and daily food and water                                               (5 mg/Ld) to female Sprague Dawley rats during the lactation period,
 intake were reduced. The average numbers of live and dead foetuses,                                                from parturition to postnatal day 17, and/or to the offspring until PND 42.
 resorptions, and postimplantation losses were not different in cadmium-                                            Mean body weights of the dams and offspring, food and water intake were
 treated and control groups. The haematocrit was reduced in foetal blood                                            comparable to controls. Relative weights of liver, kidney and brain were
 in the 60-ppm cadmium group. The foetal body weight and length were                                                comparable as well. Plasma urea nitrogen levels in rats exposed to
 decreased in both groups though litter size was not affected.                                                      cadmium postweaning were significantly higher than in the control group,
 Female CF1 mice were bred for 6 consecutive generations. (Whelton et al.,                                          whereas exposure during lactation and postweaning did not induce
 1988)93 During rounds of gestation-lactation, both females and males                                               differences. No obvious neuropathology was observed after cadmium
 were exposed via the diet to levels of 0.25, 5.0 and 50 mg cadmium/kg                                              exposure. Exposure to cadmium during lactation as low as 5 mg/L in
 food (equivalent doses of 0.05, 1.0 and 10.4 mg/kg bw/d, and 0.06, 1.1                                             drinking water resulted in neurochemical disturbances of the serotonergic
 and 11.4 mg/kg bw/d, respectivelyb). No control group was included.                                                system in offspring.
 The highest dose had no effect on fertility or pup survival during lactation,
 but caused a 15% decrease in litter size at birth and a 25% decrease in                                            Three consecutive generations of Wistar rats were orally (gavage) treated
 pup growth.                                                                                                        with 0, 3.5, 7.0 and 14.0 mg cadmium/kg bw over the period of gestation,
                                                                                                                    lactation and 8 weeks after weaning. (Nagymajtenyi et al., 1997)96
 In a study by Sorell and Graziano (1990)94, rats were exposed to 0, 5, 50,                                         Behavioural tests were performed in male rats from each generation at the
 or 100 ppm cadmium in the drinking water (equivalent to 0, 0.4, 4 or 8 mg/                                         age of 12 weeks. Main results of the behavioural tests were changed in
 kg bw/dc) on days 6 through 20 of pregnancy. In comparison to controls,                                            vertical exploration activity (rearing) and increased exploration of an open
                                                                                                                    field centre. The spontaneous and evoked electrophysiological variables
 a
    Based on a starting body weight of 195 g, and a calculated 26.9 mL water intake/day.
 b
   Calculated based on starting weights (F0) of 25 g (females) and 29 g (males), and calculated feed intakes of 5.2
   g (females) and 5.7 g (males).                                                                                   d
                                                                                                                       Equivalent to 0.70, 0.97, and 1.06 mg cadmium/kg body weight during the first, second, and third weeks of the
 c
   Assuming a body weight of 175 g and a water intake of 24.8 mL                                                      lactation period for dams, and 0.8-1.2 mg/kg bw in pups, according to the authors.
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 showed dose-and generation dependent changes. In most tests, the         weeks. (Desi et al., 1998)98 Behavioural tests were performed in F1-males
 3.5 mg/kg bw group was not affected. Treatment with the mid- and high-   at the age of 12 weeks. The number of pups/litter was slightly lower and
 dose resulted in significantly lower body weights. Pup body weights were the pup weights were slightly (not significantly) decreased in the high dose
 comparable to those in the control groups and there were no visible      group. Body weight gain of the male offspring was comparable to the
 malformations. In the F3-generation reduced relative kidney and spleen   control group. At necropsy kidney weights of all treatment regimes were
 weights were observed in the high-dose group.                            decreased. Behavioural changes were observed in the 7 and 14 mg/kg
                                                                          group in the groups exposed during gestation and lactation. Dose-
 Corpas and Antonio (1998)97 exposed Wistar rats to cadmium (10 mg/L;     dependent changes in electrocorticogram were seen in pups from all
 equivalent to 1.13 mg/kg bw/d, according to the authors) via drinking    treatment groups, but were only statistically significant at the highest dose
 water during gestation, or during early lactation (from delivery until   in the treatment group which included the postweaning period.
 postnatal day 5). Pups exposed in utero were sacrificed on day 0.
 Pups exposed during early lactation were sacrificed on postnatal day 5.  Salvatori et al. (2004)99 administered 0 and 20 mg/kg bw to pregnant rats
 Pup weight, testicular and ovary weight were recorded at necropsy.       from GD 6 to GD14. One subgroup was sacrificed after treatment and
 Furthermore, seminiferous tubule diameter and number of prospermatogonia analysed for effects on the foetuses. Another treatment subgroup and
 in the testis of the pups were measured. On postnatal day 5, ovary and   control group were allowed to give birth and pups were assessed for
 testis weights were reduced in the cadmium-treated pups. In addition,    physical and reflex development at PND 21. Cadmium-treatment
 seminiferous tubule diameter and number of prospermatogonia were         decreased food consumption, however no effect on body weight was
 reduced and a reduced DNA/RNA ratio was observed in ovary and testis     measured. Treatment had no effect on number of implantation sites,
 of the cadmium-treated pups on day 0 and postnatal day 5.                number of resorptions, number of live foetuses/litter, number of corpora
                                                                          lutea, foetal weight, and placental weight. However, reduced metacarpus
 Female Wistar rats were given orally (gavage) 0, 3.5, 7.0 or 14 mg       ossification was observed in 2 litters together with a reduced weight of
 cadmium/kg body weight 3 different treatment regimens: (I) GD 5-15, (II) these litters. In addition, an increase in malformations (cleft palate and
 GD 5-15 and 4 weeks postnatally or (III) GD 5-15, 4 weeks postnatally    renal cavitation) was observed.
 followed by the same treatment of male rats of the F1-generation for 8
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 In a study by Kuriwaki et al. (2005)100, female rats were treated with 0, 1 or delivered by caesarean section and analyses were performed.
 10 mg cadmium/kg bw from GD 9-19. Then, animals were sacrificed and            No differences between groups were observed in maternal body weight,
 organs and foetuses were collected. Cadmium exposure had no effect on          offspring number and size, and placenta’s weight. In the highest dose
 the number of foetuses. A reduced foetal liver weight was reported.            group, a decreased offspring body weight at birth was reported. Also
 Ishitobi et al. (2005)101 studied the effects of lower level cadmium           increased levels of corticosterone were measured in both dams (plasma
 exposure on the reproductive organs of female offspring. Mice were             and placenta) and offspring (plasma).
 exposed to 0, 1 and 10 ppm cadmium in the drinking water (0, 0.2 and
 2.0 mg/kg bw/d) from conception to 10 days after birth. Subsequently,          Couto-Moraes et al. (2010)104 administered cadmium (0, 10 and 20 mg/kg
 littermates were separated and housed according to sex until PND 70.           bw) by gavage to rats during pregnancy (at GD18 and 21) and during
 No effects were observed on litter size, sex ratio, birth weight, livebirth,   lactation (daily from PND 1-7). In both treated groups, a reduced body
 and stillbirth. An increase in deaths after birth and a delay in vaginal       weight gain during pregnancy was observed. At the highest dose, body
 opening were also reported (not statistically significant).                    weight gain was also reduced in the lactational period. At 10 and 20 mg/kg
                                                                                bw, pup weight and weight gain were reduced at PND 1 and PND 21.
 Jacquillet et al. (2007)102 administered cadmium (0.5 mg/kg bw/d) to           At 20 mg/kg bw only, mean body length was reduced and physical and
 pregnant rats during the whole gestation period. After birth, pups were        reflex development was affected.
 assessed for renal dysfunction up to PND 60. A reduced pup weight was
 observed up to 6 days whereas an increased arterial pressure was               Samuel et al. (2011)105 exposed female rats to cadmium through drinking
 measured at PND 21, PND 45, and PND 60. A reduced glomerular                   water at concentrations of 0, 50 or 200 mg/L (equivalent to 5.8 and 17.7
 filtration rate, associated with other signs of kidney toxicity, was observed  mg/kg bw/da), from embryonic day 9 to 21. Gravid uterine/body weights
 at PND60.                                                                      were decreased in both treatment groups. The number of foetuses and the
                                                                                number of implantation sites were decreased at the highest exposure level,
 Ronco et al. (2009)103 administered 0, 3, 15, 30, 50 ppm in drinking           and the number of resorption sites was increased at both 50 and 200 mg/L
 water (equivalent to 0, 0.5, 1.8, 3.9 and 5.3 mg/kg bw, as specified by
 the authors) to pregnant rats until gestation day 20. Then, pups were          a
                                                                                  Calculated based on drinking water intake and mean body weight specified by the authors.
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<pre> chapter 05 | Toxicity for reproduction                                                           Cadmium and selected cadmium compounds | page 67 of 103
 exposure groups. Haematological analyses in rat pups showed increased        offspring exposed to 5 or 10 ppm cadmium during pregnancy and lactation
 numbers of red blood cells, and a reduction in haematocrit and mean          were significantly lower than in the control group until postnatal week 12.
 corpuscular volume at both doses of cadmium studied, while a reduced         Also the absolute weights of some organs were decreased in males and
 haemoglobin level and an increased mean corpuscular haemoglobin              females at the highest dose group. The only relative reduction in organ
 concentration was observed only in the 200 ppm cadmium treatment             weight was reported for kidney and liver, in females exposed to 10 ppm
 group. A disrupted ovarian histoarchitecture, an extended oestrous cycle,    cadmium. Tests on various physical developmental parameters did not
 and delayed pubertal onset was reported in both treatment groups.            show differences between the exposed groups and the control group.
 Zhao et al. (2015)27 exposed male rats to cadmium (13.6 mg/kg) by            Also sperm counts, motility, and incidence of abnormal sperm observed
 gavage, every two days for 9 weeks in total. Animals were allowed to mate    in males, nor the oestrous cycle in females differed between cadmium
 and subsequently, the nervous system development of the offspring was        exposed animals and control animals.
 studied on different days after partus. The cliff-avoidance reflex,
 surface‑righting reflex and negative geotaxis results showed differences     Mikolic et al. (2014)107 administered cadmium via drinking water (50 ppm,
 between the cadmium-exposed and control groups.                              equivalent to 7.5 mg/kg bw/da) to pregnant rats during 20 days of
                                                                              gestation. On GD 20, animals were killed and analysed. Cadmium
 Luo et al. (2015) studied the effects of low doses administered orally in    treatment had no effect on maternal body weight. Foetal weight, the
 offspring during pregnancy and lactation in rats.106 Females rats were       number of corpora lutea and the numbers of live or dead foetuses did not
 allowed to mate, pregnant rats were divided in groups receiving either 0,    differ between the cadmium-exposed group and the control group.
 1, 5 or 10 mg/L (0, 0.09, 0.44 or 0.96 mg/kg bw/d, respectively (doses
 calculated by the authors)). From PND 21, pups of all groups received        Tian et al. (2018)108 administered either 0, 1, or 5 mg/kg bw by gavage,
 distilled water. The body weight gains of the rats were not different        from GD 0 to PND 21. At PND 21, 35 or 56, F1 male rats were sacrificed
 between the treatment groups, nor did the reproductive parameters differ     and testes were removed and blood samples were collected. The authors
 (including gestation length, number of pups and sex ratios). There was no    noted that there were no differences in body weights of rats with different
 maternal mortality, and there were no apparent clinical signs of toxicity in
 either male or female offspring after birth. The body weights of the         a
                                                                                As specified by the authors
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 treatments at PND 21, 35, and 56. The ratio of testis to body weight was    differences in total follicle numbers were observed for F1 and F2 at any
 reduced at the middle dose (at PND 21) and the highest dose (at PND 21,     time point.
 25 and 56). In addition, serum steroid hormone levels were reduced and
 the development of Leydig cells appeared delayed.                           Subcutaneous, intraperitoneal and intravenous exposure
                                                                             Parízek (1964)110 studied the effects in rats of cadmium on the placenta after
 Li et al. (2018)109 studied the effect of cadmium exposure on the           injection of 4.5 mg/kg bw/d between GD 17 and 21. Subcutaneous injection
 reproductive development in rats for two generations. Cadmium was           of cadmium resulted in all cases in rapidly progressive placental changes,
 administered to the F0 from GD 0 to PND 21 at doses of 0, 1 or 5 mg/kg      chiefly in the pars foetalis, which was completely transformed within
 bw/d. According to the authors, survival was unaffected and no mortality    24 hours into an extensive blood clot with little remaining necrotic tissue.
 or deformity was observed (no data provided). F1 female rats were           In most cases the placental changes were accompanied by haemorrhages
 allowed to mate with to obtain the F2 generation. There was no difference   into the uterine cavity and were found within 6 hour after cadmium
 in body weight of offspring with different treatments at PND 21, 35 and 56. injection. Complete destruction of the pars foetalis resulted in interruption
 The days of vaginal opening and first oestrus were advanced in F1 female    of pregnancy, with either delivery of the dead conceptus or resorption.
 offspring with maternal exposure (to 5 mg/kg bw/d), not in F2 female
 offspring. The ratio of uterus to body weight was increased, both in        Ferm et al. (1968)111 studied the effects of intravenous injection of
 offspring of the 1 mg/kg group (at PND 35 and PND 56) and the 5 mg/kg       cadmium (2 and 4 mg/kg bw) to pregnant golden hamsters on GD 8.
 group (at PND 21, 35 and 56). The ratio of ovary to body weight was only    Animals were killed on GD 12. The number of embryonic resorptions
 increased in offspring of the highest dose group, and only at PND 56. In    and malformed foetuses was increased in the cadmium-treated groups.
 the F1 generation, the number of primordial follicles was reduced and the   The observed malformations concerned various degrees of facial
 number of secondary and antral follicles was increased at PND 21, 35 and    malformations, including cleft lip and complete palate clefts). Data on
 56. The increased number of antral follicles eventually caused a big litter higher doses were not specified, but the authors noted that maternal
 size. In the F2 females, the number of primordial follicles was reduced and animals injected with >10 mg cadmium/kg bw all died shortly after
 the number of antral follicles was increased, only at PND 21. No            injection. Furthermore, cadmium levels from 5-10 mg induced foetal
                                                                             resorption rates of almost 100% without noticeable effect on the mothers.
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 Groups of 15 pregnant Wistar-Porton rats received a single intravenous     Pelletier and Satinder (1991)114 studied the effects of daily subcutaneous
 injection of 1.1 or 1.25 mg cadmium/kg body weight between GD 9-15.        injection of 0.075 or 0.225 mg cadmium/kg bw during gestation in
 (Samarawickrama and Webb, 1979)112 Animals were sacrificed on GD 20.       3 genetic lines of rats: Roman High Avoidance (RHA), Roman Low
 No effects were observed after administration of the low dose; the effects Avoidance (RLA) and Satinder’s Heterogeneous stock (SHS). Maternal
 of the higher dose depended on, amongst others, the moment of injection:   body weight gain, food consumption, length of gestation, litter size at birth
 the later exposed, the stronger the increase of resorptions and the larger and weaning, foetal mortality and physical development were not affected
 the decrease in number of abnormal foetuses (no results of a control group by cadmium treatment. Cadmium-exposed progeny from the RHA line
 were specified). The observed malformations included hydrocephalus,        weighed significantly less than control RHA progeny (PND 41-44);
 an- and microphthalmia, gastroschisis and umbilical hernia.                however, SHS progeny of the low-dose group weighed significantly more
                                                                            than progeny from any other group (PND 14-44). Unconditioned response
 Groups of 4 to 8 mated female Wistar rats [Crl:(WI)BR] received a          level (UER) was determined on PND 39 and acquisition of conditioned
 subcutaneous injection of ~ 4.5 or 5.6 mg cadmium/kg bw on GD 12 or        avoidance responses was tested from PND 41-44. Effects on behaviour
 GD 18.(Saltzman et al. 1989)113 Blood flow was determined 16-43 h later    were observed in the high dose group.
 in placenta and uterus. Other groups were treated at PND18. Animals
 were subsequently sacrificed on GD 19 or 20. A reduced blood flow in the   Soukupova and Dostal (1991a)115 administered a single subcutaneous
 chorionallantoic placenta was measured 16-18h after administration of      dose of 0, 2, 4 or 6 mg cadmium/kg bw to random bred ICR mice (number
 4.5 mg/kg at GD 12. No foetal changes were inflicted in the lowest dose    not specified) on GD 8, 9, 10, 11, 12, 13 or 14. The embryolethal effect
 group on GD 12. Administration on GD 18, this dose resulted in             was highest after treatment with 6 mg/kg on GD 12 and 13 (50.0 and
 resorptions; the highest dose group resulted on GD 12 in foetal lethality, 61.3%, respectively), mortality of a control group was not specified.
 and on GD18 both foetal lethality and a decreased foetal body weight.      Among surviving animals, foetuses with haemorrhagic bullae, limb
 Malformations were not observed, apart from 1 case of cleft palate in the  malformations, exencephaly, cleft palate, open eyelids and tail deformities
 5.6 mg/kg on GD 12 group.                                                  occurred. Mainly right-sided limbs were malformed. Foetal weight was
                                                                            only reduced in the 6 mg group dosed on GD 12. Reduction of the foetal
                                                                            thymus weight was observed in the 6 mg group dosed from GD 9-14.
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 Soukupova et al. (1991b)116 exposed mated random bred ICR mice,              observed at GD 5 and GD 8 (total absence of mice with implantation sites
 subcutaneously, to 0, 1.5 or 3.1 mg cadmium/kg body weight on GD 16          was noted at the highest dose). Furthermore, blastocyst degeneration
 and tested the immune response of the offspring at an age of 4 weeks.        assessed at GD 5 amounted to 30 and 80% of blastocysts at doses of
 At 3.1 mg/kg bw, the lymphoproliferation response of spleen lymphocytes      2.8 and 4.3 mg kg/bw, respectively.
 was increased in male offspring 4 weeks after birth. The titre of
 haemogglutination antibodies to sheep red blood cells in the offspring (both Piasek and Lasky (1994)38 injected female Sprague-Dawley rats
 sexes) was increased in the 1.5 mg/kg-group, at 4 and 8 weeks after birth.   subcutaneously on the day of dioestrus, or on day 7 or 16 of gestation
                                                                              with a single dose of 0, 3, or 5 mg cadmium/kg bw and evaluated 24h
 Hartsfield et al. (1992)117 injected pregnant Syrian golden hamsters         later. No general toxic effects, no disruption of oestrous cyclicity, and no
 intravenously with 0, 1.2 or 1.9 mg cadmium on GD 7. Animals were            change in foetal viability were seen. Histologic evaluation revealed
 sacrificed on GD 14 and foetuses were weighed and examined for viability     moderate cadmium-related thecal congestion in the ovaries at GD 8
 and external malformations. Maternal body weight of the 1.9 mg/kg bw         (ovaries were not evaluated at GD 17).
 treatment group was reduced. In both dose groups, an increased number
 of non-viable foetuses, an increased proportion of malformations (mainly     Paksy et al. (1996)41 treated female CFY rats, having regular ovarian
 neural tube defects and oral-facial clefts), a decreased foetal weight, and  cycles, with 0, 1.5, 3.1 or 6.1 mg/kg cadmium on the day of the oestrus
 a decreased foetal crown-rump length were observed.                          or dioestrus. After 32, 80 or 128 h post-treatment animals were mated.
                                                                              Foetal outcome was assessed at GD 10, or postnatally up to day 21.
 De et al. (1993)118 studied the effects of cadmium exposure during the       At the highest dose, a reduced maternal body weight was observed in the
 preimplantation period of pregnancy on the development and implantation      80 and 128 h-post treatment groups at GD 10. The percentage of rats
 of mouse embryos. CD-1 mice were injected with 0, 25 or 38 μmol              mated was reduced at doses of 3.1 mg/kg bw (80 h post-treatment) and
 cadmium/kg body weight (~0, 2.8 or 4.3 mg cadmium/kg bw) on GD 2             6.1 mg/kg (80 and 128 h post-treatment). No treatment-related effect was
 resulted in a reduction of mice with implantation sites at GD 5, but had     observed on the number of litters, litter weight, or the rate of males and
 little effect on the number of implantation sites at GD 8. At examination of females up to GD 21.
 groups treated on GD 4, a reduction of animals with implantation sites was
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 Piasek et al. (2004)119 studied the effect of iron deficiency combined with GD 11-19, and sacrificed on GD 20. A decrease in placental and foetal
 cadmium exposure on development of offspring in Sprague-Dawley rats.        weights and a decrease in the number of live foetuses were observed, while
 Rats were fed diets with either high iron (240 mg/kg food) or low iron      the numbers of resorptions, dead foetuses, and post-implantation losses
 (10 mg/kg). Animals were exposed to cadmium (0, 3 and 5 mg/kg bw from       were increased in the cadmium-treated groups compared to the control
 GD 1-15 by a subcutaneously implanted mini pump (subchronic study) or       group. Furthermore, the authors reported transcriptional and cellular
 a single subcutaneous injection at GD 15 (acute study). Animals were        abnormalities in the placental junctional zone of cadmium treated animals.
 killed at GD 19 and foetuses, selected organs and blood were analysed.
 Maternal body weight, maternal and foetal liver weights, and placental      Wang et al. (2012)122 injected pregnant ICR mice intraperitoneally with
 weights were reduced in the low iron group. Acute cadmium exposure          cadmium (4.5 mg/kg) on GD 9 and sacrificed the animals on GD 18.
 caused lower maternal body weight and organs weights, decreased foetal      No effect on maternal body weight gain was noted, and the number of
 weights and high foetal mortality in both high and low iron groups.         implantation sites, resorptions per litter, live foetuses per litter and dead
                                                                             foetuses per litter did not differ between treated animals and controls.
 Nampoothiri and Gupta (2008)120 treated female Charles Foster rats          Experiments involving biochemical analyses of the placenta revealed a
 subcutaneously with 0 or 0.024 mg cadmium/kg bw during the gestational      reduced placental weight, histological placental alterations and increased
 period (GD 11-19), with a pretreatment of 5 days prior to mating. Animals   markers of oxidative stress.
 were sacrificed on GD 20 and developmental parameters were assessed
 and placentas analysed. No maternal toxicity was noted. Differences in      Del Díaz et al. (2014)123 studied analyse the effect of a single cadmium
 implantation and steroidogenic enzymes were measured, however no            dose (10 mg/kg bw, intraperitoneally) administered at GD 4, 7, 10 or 15 on
 differences in reproductive performance (litter size, number of dead/       the offspring of pregnant Wistar rats. Animals were sacrificed on GD 20.
 resorbed foetuses, litter weight, ovarian weight and placental weight)      Maternal uteri, livers, kidneys and lungs, and foetuses were examined at
 were observed.                                                              necropsy. In all treatment groups, similar results were found. In the dams,
                                                                             circulatory disturbances were observed in all organs (mainly congestion
 In a study by Lee et al. (2009)121, pregnant F344 rats were injected        and haemorrhage). Histopathological examination of liver, kidneys and
 subcutaneously with 0, 0.2, and 2.0 mg/kg bw/day of cadmium from days       lungs revealed mild inflammatory infiltration, degenerative changes and
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 necrosis. Cadmium exposure did not affect the gestational sac weight,         PND 6. For histopathological analysis, a group of dams were sacrificed at
 and the size and weight of the foetuses. However, an increase in the          GD 21. In the dams, increased systemic blood pressure, kidney damage
 number of resorptions and a decrease in total implantations (except for       and proteinuria were observed. Damage to placenta and decidua was noted
 the group treated at GD 7) were noted. Also malformations in skull bones,     and the weight of the pups of the cadmium-exposed group was reduced.
 vertebrae and thoracic, and pelvian limbs were reported.
                                                                               To investigate the effect of cadmium on neural tube formation, Zhang et al.
 Wang et al. (2014) 124 exposed pregnant Sprague-Dawley rats to cadmium        (2016b)126 administered a single intraperitoneal dose of 0, 1.5 and 3.1 mg
 intraperitoneally at doses of 0, 0.25, and 0.5 mg/kg bw/day from GD 5-19.     cadmium/kg bw to Wistar rats at GD 8. On GD 18, the dams were
 On GD 20, animals were sacrificed and maternal-placental-foetal               sacrificed and live, dead and resorbed foetuses were counted and
 parameters linked to preeclampsia were evaluated. Statistically significant   placentas were collected for histological examination. No maternal
 effects were almost exclusively observed in the 0.5 mg/kg bw-dose group.      mortality and no effect on maternal body weight gain were observed
 In the dams, maternal body weight was decreased and systolic blood            (no details provided). Cadmium exposure had no effect on litter size, live
 pressure and urine protein excretion were increased. Pup weight was           foetuses, and resorptions. At 3.1 mg/kg bw, the number of dead foetuses
 significantly reduced and prenatal losses (due either to resorption and/or    per litter was increased. At both doses, the number of neural tube defects
 stillbirth) were increased. A reduction in the number of viable foetuses (not was increased and the foetal weight was reduced. Also placental
 statistically significant) was observed. Also the foetal weight/placental     development was impaired, illustrated by reduced placental weight,
 weight ratio and crown rump length were decreased. These developmental        diameter, and blood sinusoids area. In embryos of cadmium-treated dams,
 effects were associated with increases in placental corticosterone            reduced folate levels were measured (dose group was not specified).
 production, maternal and foetal plasma corticosterone levels and changes
 in expression of placental enzymes involved in corticosteroid synthesis.      In a study by Zhang et al. (2016c)127, pregnant Sprague-Dawley rats were
                                                                               injected intraperitoneally with a dose of 0, 0.25, or 0.5 mg cadmium/kg bw
 As a preeclampsia model, Zhang et al. (2016a)125 administered pregnant        from GD 4 to 19. Systolic blood pressure was monitored on GD 3, 11, and
 rats 0.125 mg/kg bw cadmium intraperitoneally from GD 9-14. Urine             18. On GD 20, rats were sacrificed and tissues were collected. At 0.25
 protein was measured on GD 3-19, systolic blood pressure from GD 0 to         mg/kg, morphological change were observed in the kidney and placenta
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 (the 0.5 mg/kg was not evaluated). Urine protein levels were increased       the animals were sacrificed for assessment of foetal toxicity. Remaining
 in both treatment groups. At the highest dose, maternal body weight was      animals were allowed to deliver and feeding. Functional behaviour tests
 decreased and systolic blood pressure increased. The number of live          were performed on 3-months old female offspring. Analysis of postnatal
 foetuses was reduced in both the 0.25 and 0.5 mg/kg group, whereas           development was only undertaken in the offspring of females exposed to
 foetal weight was reduced and the number of dead foetuses was                cadmium at concentrations of 0.02 and 0.16 mg/m3 due to the high death
 increased only at the highest dose.                                          rate (55.1%) of females exposed to 1.0 mg/m3.
                                                                              No foetal mortality or malformations were observed at 0.02 and 0.16 mg
 Li et al. (2018)128 injected pregnant Sprague-Dawley rats with a single      cadmium/m3. At 0.16 mg/m3, a slight decrease in body weight gain was
 intraperitoneal dose of 0, 0.25, 0.5, or 1.0 mg cadmium/kg on GD 12. On      reported for male and female offspring. Viability was also reduced at this
 GD 20, animals were sacrificed and the testes of the male foetuses were      concentration. A reduction of exploratory motor activity was observed in
 weighed and analysed. Cadmium caused a decrease of body weights of           3-month-old pups from the 0.16 mg/m3 group, and male offspring also
 foetal male rats in the 0.25 and 0.5 mg/kg groups (but not the 1.0 mg/kg     from the 0.02 mg/m3 group. A dose-related reduction of avoidance
 group). A dose-dependent reduction was observed for the testosterone         acquisition was observed in offspring from cadmium exposed mothers at
 production of foetal testis Leydig cell numbers. Downregulation of gene      both exposure groups. In the open-field test, the ambulation of 5-month-old
 and protein expression in Leydig cells and Sertoli cells was also reported.  males from the 0.16 mg/m3 was lowered, whereas in females from the
                                                                              0.02 mg/m3 group it was enhanced when compared to controls.
 Inhalation
 The developmental effects of cadmium in rats after exposure by inhalation    In an prenatal developmental inhalation toxicity study by the NTP (1995)7,
 were studied by Baranski (1983, 1984, 1985).45,46,129 Female rats were       pregnant rats were exposed to 0, 0.044, 0,44 and 1.75 mg cadmium/m3
 exposed to 0, 0.02, 0.16, or 1 mg cadmium/m3 for 5 h/d, 5 days/w             (0, 0.008, 0,08 and 0.34 mg cadmium/kg bw/d b) on gestation day 4-19,
 (equivalent to 0, 6, 48, and 300 µg Cd/kg bw bw/da) for 6 months before      for 6 hours a day, 7 days per week. On gestation day 20, animals were
 fertilisation by untreated males, and from day 1 to 20 of gestation. Half of sacrificed and maternal and foetal examinations were performed.
 a
   Assuming an inhalation volume of 200 mL/min and a body weight of 200 g.    b
                                                                                Assuming an inhalation volume of 175 mL/min and a body weight of 175 g.
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 Maternal toxicity was observed in Sprague-Dawley rats exposed to            Jacobo-Estrada et al. (2016)130 exposed pregnant rats to cadmium by
 1.75 mg cadmium/m3 and included body weights lower than those of the        inhalation (delivered dose of 1.48 mg Cd/kg bw/d) during GD 8–20.
 controls and clinical signs of toxicity (dyspnoea and hypoactivity).        On GD 21, dams were euthanized, markers for kidney toxicity were
 There was no evidence of embryo-lethality in rats at any exposure level.    quantified in amniotic fluid samples and foetal kidneys were examined.
 However, in rats exposed to 1.75 mg/m3, developmental toxicity was          No effect on maternal weight gain, or liver and kidney weights were
 evidenced by lower foetal weights and a significant increase in the         observed. Cadmium exposure had no effect on the number of foetuses
 incidence of reduced skeletal ossifications.                                per litter, and no increased incidence of malformation was reported.
                                                                             However, foetal body weight was reduced and increased levels of kidney
 By the NTP (1995)7, also a prenatal developmental study was performed       injury biomarkers were measured. Also, histological findings showed
 in mice exposed to 00, 0.044, 0,44 and 1.75 mg cadmium/m3 (0, 0.014,        tubular damage and precipitations in the renal pelvis.
 0,14 and 0.54 mg cadmium/kg bw/da), performed according to the study
 design noted above. Maternal toxicity was observed in mice exposed to       5.4.2 Human data
 1.75 mg/m3. Clinical signs were dyspnoea, hypoactivity, lower body          Huel et al. (1984)131 investigated the associations between occupational
 weight, and a lower pregnancy rate (30% vs. 97% in the control group).      exposure to heavy metals and levels of cadmium and lead in hair of
 One female rat in the highest exposure group died on gestation Day          exposed mothers and in hair of newborns. The exposed group mainly
 17.The total number of resorptions per litter, and the percentage live male involved solders, who were generally enrolled in the study during the third
 foetuses per litter were increased at the 1.75 mg/m3 level. Developmental   month of pregnancy. A total of 26 exposed women were matched with
 toxicity was evidenced by lower foetal weights in the 0,44 and 1.75 mg/m3   26 controls (mostly housewives) for age, parity, smoking history, and,
 groups and an increase in the incidence of reduced sternebral ossification  when possible, similar paternal socioeconomic status. The geometric
 in the 1.75 mg/m3 group.                                                    means of cadmium values in in hair of the exposed group were higher
                                                                             than the values in the control group, both for mothers (1.45 ppm and
                                                                             0.59 ppm respectively; P < 0.01) and newborns (1.27 ppm and 0.53 ppm
                                                                             respectively; P < 0.05). For lead, a similar difference was observed for the
                                                                             exposed mothers, but not for the exposed newborns. Both unadjusted and
 a
   Assuming an inhalatory volume of 30 mL/min and a body weight of 35 g.
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 sex- and gestational age-adjusted birthweights of exposed newborns were       Loiacono et al. (1992)134 studied the effects of cadmium on birth weight of
 approximately 250 g less than those in controls. Due to small numbers of      children of non-smoking mothers who lived in the vicinity of a lead smelter
 cases and controls, these differences were not statistically significant.     in Titova Mitrovica, Yugoslavia. Emissions from this lead smelter contained
 No further adverse effects were documented.                                   approximately 0.02% cadmium. Control subjects were studied in Pristina,
 Six years later, the cognitive function (with subscales verbal, perceptual,   a non-exposed town located 25 miles to the south. A higher mean
 and quantitative), memory, and motor abilities were tested in each of the     placental cadmium concentration (p<0.0007) was found in the exposed
 26 children of the exposed group by Bonithon-Kopp et al. (1986)132 using      women (N=106) compared with those not exposed (N=55). Birth weights
 the McCarthy Scales. All scores for children in the highest quartile of       and gestational age of the children did not differ between women from
 cadmium levels measured in mothers and newborns were lower than               Titova Mitrovica and women from Pristina. In multivariable regression
 those for children in the lowest quartile. Inverse correlations (p<0.05) were analyses with adjustment for multiple confounders and mid-pregnancy
 found between the general cognitive, perceptual, quantitative, and motor      blood lead levels, no associations were observed between placental
 abilities of the child and the cadmium levels in mothers, as well as          cadmium concentrations and birth weight or gestational age.
 between perceptual and motor abilities and cadmium levels in newborns.
 After adjustment for birthweight, the latter correlations were no longer      Kippler et al (2012)135 studied the associations of prenatal cadmium and
 statistically significant, which may be due to overadjustment. Similar but    arsenic exposure with five foetal growth parameters measured by
 slightly weaker correlations with cognition were reported for lead.           ultrasound in gestational weeks 14 and 30 in a population-based mother-
                                                                               child cohort in rural Bangladesh. Cadmium levels were measured in 1616
 Kuhnert et al. (1987)133 studied the effects of smoking during pregnancy      pregnant women in gestational week 8. Smoking during pregnancy was
 on decreased infant weight. In smokers (N=77), maternal whole blood           not reported, but it was noted that less than 1% of rural Bangladeshi
 cadmium, placental cadmium, and placental zinc levels were inversely          women smoked. Bivariable and multivariable spline linear regression
 related to birth weight. In multivariable regression analysis on smokers      analyses showed that all foetal growth parameters in both GW 14 and
 and non-smokers combined (N=202) with adjustment for clinical factors         GW 30 were associated positively with urinary cadmium levels in GW 8
 and smoking status, maternal whole blood cadmium and cord blood red           up to 1.5 µg cadmium/L and inversely with cadmium levels of 1.5-7.0 µg
 cell zinc levels were associated with birth weight independently.             cadmium/L (P-values ranging from <0.001 to 0.02 in GW 14 and from
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 <0.001 to 0.27 in GW 30). The multivariable analyses were adjusted for       order, weight, and height, home stimulation, socioeconomic status,
 maternal BMI in early pregnancy, socioeconomic status, birth order, and      maternal BMI in early pregnancy, and maternal IQ. Maternal and
 foetal sex. Similar results were found in longitudinal analyses using linear concurrent urinary cadmium levels (separately and combined) were
 mixed models which were also adjusted for urinary arsenic levels, but the    inversely associated with verbal IQ, performance IQ, and full-scale IQ
 associations between urinary cadmium levels and foetal growth from           (p<0.05), but not with behavioural parameters. These results were
 GW 14 to GW 30 were much stronger for girls than for boys, for whom the      stronger for girls than for boys and for high versus low socioeconomic
 associations were no longer statistically significant. In the same cohort,   status. Further adjustment for maternal and childhood exposure to
 the association between maternal cadmium exposure in pregnancy and           arsenic (through drinking water) and lead did not markedly change the
 size at birth was studied.136 Multivariable linear regression analyses       associations between cadmium and child IQ.
 adjusted for sex and other potential confounders, including urinary arsenic
 levels in GW 8 showed that maternal urinary cadmium was negatively           Vidal et al. (2015)138 studied the associations between maternal cadmium,
 associated with birth weight and head circumference (p<0.05). Notably,       iron, and zinc levels in early pregnancy and DNA methylation and
 these associations appeared to be limited to girls, with little evidence of  birthweight in offspring in a prospective cohort study with women recruited
 effects in boys.                                                             from five prenatal clinics and obstetric care facilities. Cadmium levels
 In addition, Kippler et al. (2012)137 assessed the associations between      were measured in maternal blood of 319 women ≤12 weeks of gestation.
 cadmium exposure during early pregnancy and the neurodevelopmental           In multivariable regression analysis, adjusted for sex, race/ethnicity,
 outcome of children at 5 years of age. From a larger micronutrient           prepregnancy BMI, preconceptional antibiotic use, maternal smoking, and
 supplementation trial, children were selected with assessment of cadmium     gestational age, but not for iron and zinc levels, elevated maternal blood
 levels in maternal urine (generally measured at GW 8) and concurrent         cadmium levels were associated with lower birth weight (p=0.03). As
 children’s urine (at 5 years of age), and data on basic demographic          prenatal growth is partly under control of paternal and maternal imprinted
 factors, maternal IQ, assessment of home environment, and developmental      genes, effects of cadmium on several differentially methylated regions
 measures (N=1,305). Data on the various developmental outcomes at 5          (DMRs) were also studied. Association were observed between maternal
 years and the two (log2-transformed) exposure measures were analysed         cadmium levels and lower offspring methylation. However, the association
 using multivariable linear regression analysis, adjusted for age, sex, birth between birth weight and methylation status was not analysed.
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 In a prospective cohort study, Buck Louis et al. (2017)139 assessed levels Pi et al. (2018)141 examined whether concentrations of heavy metals
 of cadmium, mercury, lead, and arsenic in 501 couples and followed them    (cadmium, lead, mercury, and arsenic) in placental tissues were
 throughout pregnancy to estimate the risk of pregnancy loss. During the    associated with risks of orofacial clefts in offspring. This population-based
 enrolment home visit, whole blood and urine samples were taken and         case-control study included 103 newborns affected by orofacial clefts with
 analysed. Of the 501 couples, 344 (68%) got pregnant. The incidence of     available placental tissues and 206 controls randomly selected from
 pregnancy loss was 28%. Time-to-pregnancy loss was defined as the          509 non-malformed newborns with available placenta samples.
 number of days from observed ovulation as measured by the peak LH day      For cadmium, lead, and mercury, the median concentrations were
 to the date of reported loss. Hazard ratios for pregnancy loss were        statistically significantly higher in orofacial cleft cases than in controls.
 estimated using Cox proportional hazard models, with adjustment for        In logistic regression analysis, adjusted for sex, gestational age, previous
 multiple covariates, for each partner individually and combined. The blood history of birth defects, maternal occupation, maternal flu or fever, and
 and urine cadmium levels were neither associated with pregnancy loss       passive smoking (only 3 mothers in the control group and 1 mother in the
 in the individual partner models (highest hazard ratios 1.08 (95% CI 0.81- case group smoked actively), placental cadmium concentrations above
 1.44) and 1.09 (95% CI 0.84-1.41) for women and men, respectively),        the median were associated with an increased risk of orofacial clefts
 nor in the couple-based models (hazard ratios 1.01 (95% CI 0.75-1.37)      (odds ratio 2.33; 95% CI 1.33-4.09). An increased risk was observed in
 and 0.92 (95% CI 0.68, 1.25), respectively).                               the second and third cadmium concentration tertiles compared to the first
                                                                            tertile (odds ratios of 1.00, 3.06 (95% CI 1.36-6.88), and 8.18 (95% CI
 Karaer et al. (2017)140 investigated the association between blood         6.64-18.37 in consecutive tertiles), respectively; P for trend < 0.001).
 cadmium level and the occurrence of ectopic pregnancy in a case-control    Similar results were observed for placental lead concentrations, but not for
 study with 41 patients with an ectopic pregnancy and 41 uncomplicated      mercury and arsenic.
 intrauterine pregnant patients as controls. Using a logistic regression
 model adjusted for age, parity, spontaneous abortions, and smoking,        Zhang et al. (2018)142 investigated whether urinary cadmium levels during
 no association was observed between blood cadmium concentrations and       pregnancy were associated with adverse birth outcomes in a sex-dependent
 ectopic pregnancies (odds ratio 0.88; 95% CI 0.26-2.97).                   manner. Cadmium levels in maternal urine samples were measured in
                                                                            237 subjects from Guiyu (electronic waste recycling area) and 212 subjects
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 from Haojiang (reference area). The maternal urinary cadmium levels in       5.4.3   Other relevant information
 Guiyu residents were higher than in Haojiang (p<0.001). Both male and        No other relevant information was available to the Committee.
 female neonates from Guiyu had a lower mean birth weight, neonatal BMI,
 head circumference, and 1 min Apgar score compared to the Haojiang           5.5     Short summary and overall relevance of the provided
 neonates (all p<0.001), whereas birth length was higher. Using                       information on adverse effects on development
 multivariable linear regression analysis, adjusted for maternal age, weight, Several human studies concern the associations between cadmium
 height, BMI, and education, inverse associations were found between          exposure and effects on growth and body weight in offspring, and report
 urinary cadmium concentrations and birth weight, birth length, head          an inverse association. Huel et al. (1984)131 reported a non-statistically
 circumference, and Apgar scores at 1 min and 5 mins for female neonates      significant reduction in birth weight (of approximately 250 gram) in
 (p≤0.036). For male neonates, only the 1 min Apgar score was negatively      newborns of occupationally exposed mothers compared to newborns of
 associated with maternal urinary cadmium levels (p=0.004).                   a control group. Kuhnert et al. (1987)133 found an association between
                                                                              increased blood/placental cadmium levels in smokers and a reduction in
 Suhl et al. (2018)143 used data from a large, population-based case-control  infant weight. Multivariable regression analysis among smokers and
 study in the USA to compare maternal occupational cadmium exposure           non-smokers showed that blood cadmium levels were associated with
 from 1 month before through 3 months after conception between orofacial      birth weight, adjusted for smoking and blood zinc levels. Loiacono et al.
 cleft cases (N=1,185) and unaffected controls (N=2,832). Exposure was        (1992)134 found no association between higher placental cadmium levels
 assessed by expert raters based on self-reported occupational histories      in non-smoking mothers living near a lead smelter and birth weight,
 taken in telephone interviews until 2 years after birth. Only 45 mothers     when compared to mothers from a non-exposed control population.
 (cases = 13, controls = 32) were rated as having had occupational            Multivariable linear regression analyses performed by Kippler et al
 cadmium exposure. Multivariable logistic regression analyses, adjusted for   (2012)135 showed that maternal urinary cadmium levels ≥ 1.5 µg/L were
 multiple confounders, did not result in increased odds ratios for any        inversely associated with foetal growth parameters. Mixed model analyses
 occupational cadmium exposure, or for high versus low levels of              adjusted for arsenic exposure showed similar results, but with stronger
 cumulative cadmium exposure and orofacial clefts (either all combined,       associations for girls compared to boys. Maternal urinary cadmium levels
 cleft lip with or without cleft palate and cleft palate only).               were also inversely associated with birth weight and head circumference,
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 but only in girls. Vidal et al. (2015)138 found an association between       blood level of cadmium and the occurrence of ectopic pregnancy in a
 increased maternal blood cadmium levels during early pregnancy and           case-control study and found no association. In two recent studies,
 lower birth weight in offspring. Zhang et al. (2018)142 investigated whether associations between cadmium exposure and the risk of orofacial clefts
 urinary cadmium levels during pregnancy were associated with adverse         were assessed. Pi et al. (2018)141 reported that placental cadmium
 birth outcomes. In multivariable analyses, associations were found           concentrations were associated with an increased risk of orofacial clefts in
 between urinary cadmium concentrations and birth weight, birth length,       a dose-dependent manner. Suhl et al. (2018)143 compared expert rater
 head circumference, and Apgar scores, primarily in female neonates.          assessed maternal occupational cadmium exposure from self-reported
                                                                              occupational histories around conception between orofacial cleft cases
 Studies on maternal cadmium exposure and other effects in offspring are      and unaffected controls. No differences were found.
 also available. Two studies addressed neurodevelopmental parameters.
 In the occupationally exposed cohort of Huel et al. (1984)131 studied by     In multiple animal studies, mainly with rats, adverse effects on
 Bonithon-Kopp et al. (1986)132, an association was found between             development have been observed after oral administration in a dose
 increased cadmium levels in either mothers or newborns and decreased         range of 0-40 mg cadmium/kg bw. In general, effects on development are
 cognitive and motor abilities. Kippler et al. (2012)137 assessed the         either observed in combination with effects on body or organ weights, or
 associations between cadmium exposure during early pregnancy and             data on general toxicity is lacking.
 the neurodevelopmental outcome of children at 5 years of age.                Most notably, exposure to cadmium during gestation consistently resulted
 Maternal urinary cadmium levels were inversely associated with verbal IQ,    in a decrease of growth (in weight or length) in foetuses or pups (Sutou et
 performance IQ and full-scale IQ, independent of childhood cadmium           al. (1980)13; Baranski et al. (1982, 1985, 1987)46,90,91; Sorell and Graziano
 exposure and maternal and childhood arsenic and lead exposure.               (1990)94; Corpas and Antonio (1998)97; Jacquillet et al. (2007)102; Ronco et
 Buck Louis et al. (2017)139 assessed levels of cadmium in couples and        al. (2009)103; Couto-Moraes et al. (2010)104; Luo et al. (2015)106 and a
 followed them throughout pregnancy to estimate the risk of pregnancy         decrease in organ weights (in some cases involving testis and ovary)
 loss. No increased risks for females and males with high blood cadmium       (Nagymajitenyi et al (1997), Corpas and Antonia (1998) Sutou et al.
 levels were observed in individual partner models or in couple-based         (1980), Desi et al. (1998), Kuriwaki et al (2005), Luo et al. (2015), Tian et
 models. Karaer et al. (2018)140 investigated the association between the     al. (2017)108, Li et a. (2018)109).
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 Severe developmental effects have also been observed in rats.                  Saltzman et al. (1989)113; Lee et al. (2009)121; Del Diaz et al. (2014)123;
 These effects include a decrease in number of (live) foetuses (Sutou et al.    Wang et al. (2014)124) a reduced foetal viability and increased mortality
 (1980a,b)13,14, Baranski et al. (1982)91, Baranski (1985)46; an increase in    (Parizek (1964)110; Saltzman et al. (1989)113; Soukupova and Dostal
 resorptions (Sutou et al. (1980a,b)13,14, Baranski et al. (1982)91, Baranski   (1991a)115; Hartsfield et al. (1992)117; Lee et al. (2009)121; Wang et al.
 (1985)46; and Samuel et al. (2011)105), and malformations (lack of forelimbs   (2014)124; Zhang et al. (2016b,c) 126,127, an increase in malformations
 or sirenomelia, (Baranski et al. (1982)91, cleft palate and renal cavitation   including cleft palate, cleft lip, neural tube defects, malformations of limbs
 (Salvatori et al. (2004)99).                                                   and skeletal malformations (Ferm et al. (1968)111; Samarawickrama and
 Further, delayed ossification (Baranski et al. (1982)91, Salvatori et al.      Webb (1979)112, Soukupova and Dostal (1991a)115; Hartsfield et al.
 (2004)99 and disturbances in various behavioural parameters were               (1992)117, Del Diaz et al. (2014)123, Zhang et al. (2016b)126. Also damage to
 reported (Baranski (1986)92; Nagymajitenyi et al (1997)96; Salvatori et al.    maternal organs relevant for development (placenta, ovaries and uterus)
 (2004)99; Couto-Moraes et al. (2010)104; Zhao et al. (2015)27.                 has been noted (Kar et al. (1959)31; Parizek (1964)110, Piasek et al.
 In mice, increased pup mortality (Schroeder and Mitchener, 1971)8 and          (2004)119, Lee et al. (2009)121, Del Diaz et al. (2014)123, Wang et al.
 reduced pup growth and litter size (Whelton et al (1988)93 has been            (2014)124, Zhang et al. (2016a,b,c)125-127.
 reported.
                                                                                Only in few studies, absence of severe developmental toxicity was
 In animal studies (mainly with rats, but also mice and hamsters) in which      reported after parenteral administration of cadmium. In three of these
 cadmium was administered parenterally, similar effect on development           studies, in rats, this could be related to either the use of relatively low
 were observed. As noted previously, these include a consistent decrease        doses (≤ 0.2 mg/kg bw) (Pelletier and Satinder (1991)114; Nampoothiri and
 in foetal body weight or growth (Saltzman et al. (1989)113; Soukupova and      Gupta (2008)120 or a short exposure duration (Piasek and Laskey (1994)38.
 Dostal (1991a)115; Hartsfield et al. (1992)117; Wang et al. (2014)124; Zhang   In one study with mice (Wang et al. (2012)122, a single injection of 2.8 mg/
 et al. (2016a,b,c)125-127, Li et al. (2018)128). Severe developmental effects  kg bw did not affect foetal viability.
 consist of a reduction in implantation sites/post implantation loss (De et al. Inhalation studies performed with rats and mice at equivalent doses up to
 (1993)118, Lee et al. (2009)121), an increase in resorptions (Parizek          1.48 mg/kg bw/d also revealed reductions in foetal body weight in rats and
 (1964)110, Ferm et al. (1968)111; Samarawickrama and Webb (1979)112;           mice (NTP (1995)7; Jacobo-Estrada et al.(2016)130). In inhalation studies in
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 rats by Baranski (Baranski (1983, 1984, 1985)45,46,129, with equivalent                      reduced post-natal survival (only at the highest concentration) was
 doses up to 0.3 mg/kg bw, abnormal findings in behavioural tests and a                       observed. Also in the inhalation studies, maternal toxicity was observed.
 The adverse effects on development observed in animal studies are summarised in the following table:
  Ref.                Species Exposure window                           Exposure route Effects on development                                 General toxicity
  Sutou et al. (1980) Rat     From 6 weeks pre-mating (males and        Oral (gavage)  Decreased number of implantation sites and live        Decreased food intake and body weight; clinical
                              females) to GD 20                                        foetuses; decreased foetal weight; increased placental signs of toxicity
                                                                                       weight                                                 NOAEL=1.0 mg/kg
                                                                                       NOAEL=1.0 mg/kg
  Zenick et al.       Rat     Male rats were exposed for 70-80          Oral (drinking No effect on development observed                      Reduced water intake
  (1982)                      pre-mating                                water)         NOAEL=2.6 mg/kg                                        LOAEL=0.7 mg/kg
  Baranski et al.     Rat     From GD 7-16, sacrifice at GD 21          Oral (gavage)  Decreased foetal weight                                Decreased body weight gain
  (1982)                                                                                                                                      LOAEL=2 mg/kg
                                                                                       NOAEL=4 mg/kg
  Baranski et al.     Rat     For 5 w (5 d/w) and during mating and     Oral (gavage)  Foetuses with oedema                                   Mortality
  (1983)                      gestation                                                NOAEL=0.04 mg/kg                                       NOAEL=0.4 mg/kg
                                                                                       Decreased locomotor activity
                                                                                       LOAEL=0.04 mg/kg
  Baranski (1985)     Rat     From GD 7-16; sacrifice at GD 21          Oral (gavage)  Reduced foetal weight                                  Reduced maternal body weight gain
                                                                                       NOAEL=2 mg/kg                                          LOAEL=2 mg/kg
  Baranski (1986)     Rat     From GD 1-20, pups analysed at weaning    Oral (drinking Reduced brain weight; effects on behaviour             No information provided
                                                                        water)         LOAEL=8.5 mg/kg
  Baranski (1987)     Rat     From GD 1-20                              Oral (drinking Reduced foetal length and body weight                  Reduced body weight gain and food/water intake
                                                                        water)         LOAEL=9.2 mg/kg                                        LOAEL=9.2 mg/kg
  Sorell and          Rat     From GD 1-20                              Oral (drinking Reduced foetal body weight                             Reduced maternal body weight
  Graziano (1990)                                                       water)         NOAEL=0.4 mg/kg                                        NOAEL=0.4 mg/kg
  Andersson et al.    Rat     From partus to PND 17 and/or PND 42       Oral (drinking Reduction in cortical serotonin levels                 No effect on food/water intake and body weight
  (1997)                                                                water)         LOAEL=1.0 mg/kg                                        NOAEL=1.0 mg/kg
  Nagymajtenyi et al. Rat     5 d/w during pregnancy, lactation and 8 w Oral (gavage)  Open field exploration affected                        No information provided
  (1997)                      after weaning. Measurements at 12 w                      LOAEL=3.5 mg/kg
  Corpas and          Rat     Through gestation until PND 5             Oral (drinking Reduced pup, testis and ovary weights                  No information provided
  Antonio (1998)                                                        water)         LOAEL=1.13 mg/kg
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  Ref.                Species Exposure window                             Exposure route Effects on development                                    General toxicity
  Desi et al. (1998)  Rat     During GD 5-15, and/or 4 w of lactation     Oral (gavage)  Reduced kidney weight and changes in                      No visible signs of toxicity
                                                                                         electrocorticogram
                                                                                         Affected behaviour (when exposed during lactation)
                                                                                         LOAEL=3.5 mg/kg
  Salvatori et al.    Rat     From GD 6-14. Foetal effects assessed at    Oral (gavage)  Malformation (cleft palate and renal cavitation);         Decreased food intake; no effect on body weight
  (2004)                      GD20, pup behaviour at PND 21                              abnormal sexual behaviour
                                                                                         LOAEL=20 mg/kg                                            NOAEL=20 mg/kg
  Kuriwake et al.     Rat     From GD 9-19                                Oral (gavage)  Reduced foetal liver weight                               No information provided
  (2005)                                                                                 LOAEL=1 mg/kg
  Jacquillet et al.   Rat     During gestation. Assessment up to PND 60 Oral (gavage)    Reduced pup weight, kidney toxicity                       No information provided
  (2007)                                                                                 LOAEL=0.5 mg/kg
  Ronco et al. (2009) Rat     During gestation until GD 20                Oral (drinking Decreased foetal body weight; increased                   No effect on body weight
                                                                          water)         corticosterone levels                                     NOAEL=5.3 mg/kg
                                                                                         NOAEL=3.9 mg/kg
  Couto-Moraes et     Rat     At GD 18 and 21, and from PND 1-7           Oral (gavage)  Reduced pup weight                                        Reduced body weight gain
  al. (2010)                                                                             LOAEL=10 mg/kg                                            LOAEL=10 mg/kg
  Samuel et al.       Rat     From GD 9-21, assessed at PND 10 and        Oral (drinking Increased number of resorption sites; disruption          Reduced water intake and body weight
  (2011)                      21. Only female offspring was assessed      water)         oestrous cycle and histologically, in ovaries
                                                                                         LOAEL=5.8 mg/kg                                           LOAEL=5.8 mg/kg
  Zhao et al. (2015)  Rat     Male rats, every 2 days for 9 w, females    Oral (gavage)  Abnormal behaviour                                        No information provided
                              were not treated. Offspring was assessed at                LOAEL=13.6 mg/kg
                              various time point after birth
  Luo et al. (2015)   Rat     From GD 0-21. Offspring was followed for    Oral (drinking Reduced body weight                                       No effect on body weight
                              12 w                                        water)         NOAEL=0.089 mg/kg                                         NOAEL=0.955 mg/kg
  Mikolic et al.      Rat     From GD 0-20                                Oral (drinking No effect on development observed                         No effect on body weight
  (2014)                                                                  water)         NOAEL=7.5 mg/kg                                           NOAEL=7.5 mg/kg
  Tian et al. (2017)  Rat     From GD 0-PND 21. Male offspring was        Oral (gavage)  Reduced testis/bw ratio; reduction steroid hormone        No information provided
                              assessed up to PND 56.                                     levels
                                                                                         LOAEL=1 mg/kg
  Li et al. (2018)    Rat     From GD 0-21. Female offspring were         Oral (gavage)  Increased ration uterus/bw                                No reduction in survival
                              allowed to mate to obtain F2                               LOAEL=1 mg/kg                                             NOAEL=5 mg/kg
                                                                                         Effects on ovary, oestrous cycle and litter size at 5 mg/
                                                                                         kg
  Schroeder and       Mouse   Continuous, multiple generations            Oral (drinking Pup mortality                                             2 maternal deaths; no information provided.
  Mitchener (1971)                                                        water)         Runts
                                                                                         LOAEL=2.1 mg/kg                                           LOAEL=2.1 mg/kg
  Whelton et al.      Mouse   During 6 consecutive rounds of gestation-   Oral (diet)    Decreased litter size and pup growth                      No information provided
  (1988)                      lactation                                                  NOAEL=? (No control group included)
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  Ref.                Species Exposure window                               Exposure route  Effects on development                                   General toxicity
  Ishitobi et al.     Mouse   From GD 0-PND 10. Pups were assessed          Oral (drinking  No statistically significant effects                     No effect on bodyweight gain
  (2005)                      at PND 70                                     water)          NOAEL=2 mg/kg                                            NOAEL=2 mg/kg
  Parizek (1964)      Rat     From GD 17-21                                 Subcutaneous    Abnormalities in placenta and uterus, interruption of    No information provided
                                                                                            pregnancy
                                                                                            LOAEL=4.5 mg/kg
  Ferm et al. (1968)  Rat     Single injection at GD 8, sacrifice on GD 12  Intravenous     Resorptions and malformations                            Not observed
                                                                                            LOAEL=2 mg/kg                                            NOAEL=4 mg/kg
  Samarawick and      Rat     From GD 8-15, sacrifice at GD 20              Intravenous     Increased resorptions, abnormal foetuses,                No information provided
  Webb (1979)                                                                               malformations
                                                                                            NOAEL=1.1 mg/kg (LOAEL=1.25 mg/kg)
  Saltzman et al.     Rat     Single injection at GD 12 or 18; sacrifice at Subcutaneous    Foetal mortality and case of cleft palate                No information provided
  (1989)                      GD 19/20                                                      LOAEL=4.5 mg/kg
  Pelletier and       Rat     From GD 0-20, behaviour studied after         Subcutaneous    No effect on length of gestation, litter size, foetal    No effect on food consumption and body weight
  Satinder (1991)             weaning                                                       mortality, physical behaviour                            NOAEL=0.225 mg/kg
                                                                                            NOAEL=0.225 mg/kg
  Piasek and Laskey Rat       Single injection on day of diestrous, or on   Subcutaneous    No effect on oestrous cycle, live implants, resorptions, No effect on maternal body weight
  (1994)                      GD 7 or 16. Analyses were done 24 h later.                    foetal weight
                                                                                            NOAEL=5 mg/kg                                            NOAEL=5 mg/kg
  Paksy et al. (1996) Rat     Single injection on day of oestrus, GD 7 or   Subcutaneous    No effect on litter number/weight                        Reduced maternal body weight
                              GD 8. Foetal outcome was assessed at GD                       NOAEL=6.1 mg/kg                                          NOAEL=1.5 mg/kg
                              10, or PND 21.
  Piasek et al.       Rat     Sub-chronic (on GD 1-15) or acute (on GD      Subcutaneous    Only in acute study: Foetal mortality; placental         Only in acute study: Reduced maternal body and
  (2004)                      15) exposure, analyses on GD 19.                              destruction                                              organ weights
                                                                                            LOAEL=3 mg/kg                                            LOAEL=3 mg/kg
  Nampoothiri and     Rat     Treated during gestation, with 5 days         Subcutaneous    No effect on litter size and weight, number of dead/     No effect on maternal body weight
  Gupta (2008)                pretreatment. Analyses on GD 19.                              resorbed foetuses, and ovarian/placental weight
                                                                                            NOAEL=0.024 mg/kg                                        NOAEL=0.024 mg/kg
  Lee et al. (2009)   Rat     From GD 11-19; analyses on GD 20              Subcutaneous    Increased post-implantation loss, reduced foetal         No information provided
                                                                                            weight, increased resorptions and dead foetuses
                                                                                            LOAEL=0.2 mg/kg
  Del Diaz            Rat     Single injection on GD 4, 7, 10 or 15.        Intraperitoneal Reduced number of implantations, increased number        Severe lesions in liver, kidney and lung
                              Analyses on GD 20.                                            of resorptions and malformations                         LOAEL=10 mg/kg
                                                                                            LOAEL=10 mg/kg
  Wang et al. (2014)  Rat     From GD 5-19; analyses on GD 20               Intraperitoneal Increased prenatal loss, reduced body weight, reduced Decreased maternal body weight, increased systolic
                                                                                            litter size/viable foetuses                              blood pressure, increase urine protein excretion
                                                                                            NOAEL=0.25 mg/kg                                         NOAEL=0.25 mg/kg
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  Ref.               Species  Exposure window                              Exposure route  Effects on development                                       General toxicity
  Zhang et al.       Rat      From GD 5-14; developmental parameters       Intraperitoneal Reduced foetal weight, decreased crown-rump length,          Increased systemic blood pressure, kidney damage
  (2016a)                     analysed on GD 21.                                           damage to the placenta                                       LOAEL=0.125 mg/kg
                                                                                           LOAEL=0.125 mg/kg
  Zhang et al.       Rat      From GD 4-19; developmental parameters       Intraperitoneal Reduced number of live foetuses, morphological               Kidney damage
  (2016c)                     analysed on GD 20.                                           changes placenta                                             LOAEL=0.25 mg/kg
                                                                                           LOAEL=0.25 mg/kg
  Li et al. (2018)   Rat      Single injection at GD 12. Sacrifice and     Intraperitoneal Decreased foetal body weight                                 No effect on maternal body weight
                              analysis at GD 20.                                           LOAEL=0.25 mg/kg                                             NOAEL=1 mg/kg
  Soukupova and      Mouse    Once, during GD 8-14. Analyses on GD 18.     Subcutaneous    Increased mortality and malformations                        No information provided
  Dostal (1991a)                                                                           NOAEL=? (no details control group provided)
  Soukupova and      Mouse    Once, on GD 16. Analyses at 4 w after birth. Subcutaneous    Affected immune response                                     No information provided
  Dostal (1991a)                                                                           LOAEL=1.5 mg/kg
  De et al. (1993)   Mouse    Once, either on GD 2 or 4. Analyses at GD    Subcutaneous    Reduced number of implantation sites                         No information provided
                              5 or 8.                                                      LOAEL=2.8 mg/kg
  Wang et al. (2012) Mouse    Once, on GD 9. Analyses at GD 18.            Intraperitoneal Reduced placenta weight; histological alterations (no        No effect on body weight gain
                                                                                           effect on implantation sites, resorptions, live/dead litter) NOAEL=2.8 mg/kg
                                                                                           LOAEL=2.8 mg/kg
  Zhang et al.       Mouse    Once, on GD 8. Analyses on GD 18.            Intraperitoneal Reduced foetal weight and crown-rump length,                 No effect on maternal body weight gain
  (2016b)                                                                                  increased number of neural tube defects                      NOAEL=3.1 mg/kg
                                                                                           LOAEL=1.5 mg/kg
  Hartsfield et al.  Hamster  Once, on GD 8. Analyses were done on GD      Intravenous     Increase non-viable foetuses and, malformations,             Reduced body weight
  (1992)                      15.                                                          decrease foetal weights and crown-rump length                NOAEL=2 mg/kg
                                                                                           LOAEL=2 mg/kg
  Baranski (1983;    Rat      For 5 h/d, 5 months, during mating and from Inhalation       Abnormal behaviour                                           Mortality
  1984; 1985)                 GD 1-20                                                      LOAEL=0.02 mg/m3 ((~6 µg/kg)                                 NOAEL=1 mg/m3 (~48 µg/kg)
                                                                                           (Reduced pup survival at 0.16 mg/m3)
  NTP (1995)         Rat      For 6 h/d, 7 d/w, from GD 4-19               Inhalation      Reduced foetal bw                                            Clinical signs; decreased bw, reduced fertility
                                                                                           NOAEL=0.44 mg/m3 ((~80 µg/kg)                                NOAEL=0.44 mg/m3 (~80 µg/kg)
  Jacobo-Estrada et  Rat      From GD 8-20                                 Inhalation      Reduced foetal weight; kidney toxicity                       No effect on bw and kidney weight
  al. (2016)                                                                               LOAEL=17.4 mg/m3 (~1.5 mg/kg)                                NOAEL=17.4 mg/m3 (~1.5 mg/kg)
  NTP (1995)         Mouse    For 6 h/d, 7 d/w, from GD 4-17               Inhalation      Reduced foetal bw                                            Clinical signs; decreased bw, reduced fertility
                                                                                           NOAEL=0.044 mg/m3 (~14 µg/kg)                                NOAEL=0.44 mg/m3 (~140 µg/kg)
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 5.6      Comparison with the CLP criteria                                       neurodevelopment measured in offspring at the age of 6 and 5 years,
 In epidemiological studies, associations between maternal cadmium               respectively. The results of Kippler et al. (2012)137 were adjusted for
 exposure and effects on development were reported. Five studies found           several confounders and co-exposure to lead and arsenic.
 associations between increased cadmium levels in maternal blood, urine
 or placenta, and decreased birth weight in offspring (Huel et al. (1984)131;    Multiple animal studies, mainly with rats, revealed adverse effects on the
 Kuhnert et al. (1987)133; Kippler et al. (2012)136; Vidal et al. (2015)138;     development of offspring. In general, exposure to cadmium during
 Zhang et al. (2018)142). In the small-scale study by Huel et al. (1984)131,     gestation resulted in a decreased body weight of foetuses and pups
 the association was not statistically significant. Huel et al. (1984)131, Vidal (reported after cadmium exposure in a dose range of 0.2 mg/kg bw and
 et al. (2015)138, and Zhang et al. (2018)142 did not adjust the analyses for    higher). Severe developmental toxicity was observed in rats and mice at
 co-exposure to other metals, whereas Kuhnert et al. (1987)133 and Kippler       doses that were generally higher than the doses at which effects on body
 et al. (2012)135 adjusted for zinc and arsenic exposure, respectively, in       weight are observed, and include a decrease in live foetuses, an increase
 addition to adjustment for other relevant factors. Kippler et al. also found    in foetal mortality and resorptions, and an increase in malformations
 associations between maternal cadmium levels and foetal growth                  (including cleft palate/lip and malformations of limbs). These
 parameters and head circumference, especially in girls. The latter              developmental effects were observed after both oral and parenteral
 association was also observed by Zhang et al. (2018)142.                        administration. General toxicity is either observed in these studies or
                                                                                 information on general toxicity is lacking.
 Several epidemiologic studies addressed other developmental
 parameters. In two case-control studies, the association between                Conclusion
 cadmium exposure and orofacial clefts was studied. Pi et al. (2018)141          In epidemiological studies, associations were reported between exposure
 reported a dose-dependent increased risk of orofacial clefts for placental      to cadmium and reduced birth weight, increased risk of orofacial clefts,
 cadmium levels adjusted for confounders, whereas Suhl et al. (2018)143          and impaired neurodevelopment. Due to lack of adjustment for relevant
 did not find an increased risk of orofacial clefts (based on only 13 exposed    co-exposures in most studies, the Committee considers these
 cases) in mothers assumed to be exposed to cadmium. Bonithon-Kopp et            associations insufficient for classification in Category 1A.
 al. (1986)132 and Kippler et al. (2012)137 reported adverse effects on          In animal studies, severe developmental toxicity (increased foetal
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 mortality, reduced foetal viability, increased resorptions and                 5.7         Lactation
 malformations) has been observed in rats and mice, following different         5.7.1       Animal data
 routes of administration. In these studies, general toxicity (indicated by a   Toxicity studies
 reduction in body weight) was observed, or not specifically addressed.         Halder et al. (2016) exposed female lactating mice to cadmium (1.2 mg/
 The Committee considers it likely that effects on development in animals       kg/day intraperitoneally) for seven days just after delivery.144 On postnatal
 occur in the presence of maternal toxicity, which likely involve the kidneys   day 21, the pups were tested for learning and memory function by passive
 (the critical organ in cadmium-induced toxicity). It is unclear whether or not avoidance task and Morris water maze test. Pups from cadmium-exposed
 effects on development are a non-specific secondary effect of the general      dams showed impairment of memory and an increased escape latency
 toxicity. As the mode of action is unknown, the Committee assumes that         compared to pups from unexposed dams. Malondialdehyde levels
 the observed developmental effects are relevant for humans.                    (biomarker for oxidative stress) were increased in brain tissue of pups
 Based on associations observed in epidemiological studies, which are           from the treatment group.
 consistent with developmental toxicity observed in animal studies, the
 Committee recommends to classify for effects on development in category        Andersson et al. (1997)95 administered cadmium in the drinking water
 1B (presumed human reproductive toxicant), and to label with H360D             (5 mg/La) to female Sprague Dawley rats during the lactation period.
 (may damage the unborn child) (CLP paragraph 3.7.2.2.3). This proposal         One week later (45-51 days after birth) offspring was sacrificed and
 for classification relates to cadmium, cadmium carbonate, cadmium              analysed. Mean body weights of the dams and offspring, food and water
 chloride, cadmium fluoride, cadmium hydroxide, cadmium nitrate,                intake were comparable to controls. Relative weights of liver, kidney and
 cadmium oxide, cadmium sulphate, and cadmium sulphide (See section             brain were comparable as well. Exposure during lactation did not induce
 4.2 for an explanation of the selection of substances).                        changes in plasma urea nitrogen levels. No obvious neuropathology was
                                                                                observed after cadmium exposure. Exposure to cadmium during lactation
                                                                                resulted in reduced levels of serotonin and its metabolite
                                                                                5-Hydroxyindoleacetic acid in foetal brain.
                                                                                a
                                                                                  Equivalent to 0.70, 0.97, and 1.06 mg cadmium/kg bw during the first, second, and third weeks of the lactation
                                                                                  period for dams, and 0.8-1.2 mg/kg bw in pups, according to the authors.
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<pre> chapter 05 | Toxicity for reproduction                                                           Cadmium and selected cadmium compounds | page 87 of 103
 Petersson Grawé and Oskarsson (2000)145 infused lactating Sprague            chloride at a 21-day interval in a crossover design. One involved 25 mg/kg
 Dawley rats intravenously with 109CdCl2 (doses of 0, 8.8, 62 and 300 µg      of cadmium orally, the other dose 0.1 mg/kg intravenously. Cadmium
 Cd/kg bw/d) in 0.9% saline via osmotic mini-pumps from day 3 to day 16       levels in milk increased rapidly and could be detected 6 hours after
 after parturition. Plasma and milk were collected at day 10 and 16 after     administration. Levels reached a maximum value on the 2nd or 3rd day
 parturition. Cadmium levels were higher in milk (up to 5.4 µg/mL at day      after administration. These values then decreased, first quickly and later
 16) than in plasma, with milk/ plasma ratios varying from 2 to 6. Only a     slowly. Seventy days after the second administration, 1.1 ± 0.8 mg/day of
 fraction of the cadmium dose given to the dams (< 0.05%) was retained in     cadmium was being excreted in milk.
 the litters on day 16 of lactation. No effects were observed on body weights
 of pups and dams. Histological evaluation of mammary tissue did not reveal   5.7.2      Human data
 any abnormalities at any dose level (pups were not further analysed).        In multiple studies, cadmium levels were quantified in breast milk of
                                                                              women from different regions of the world, who were not occupationally
 Studies on cadmium transfer to milk                                          exposed to cadmium (summarised by the Health Council (2000)1
 Bhattacharyya et al. (1982)146 examined the maternal transfer of cadmium     (including literature up to 1999) and by Rebelo and Caldas (2016)149
 administered in drinking water, to pups during gestation and lactation in    (including literature published from 2000 to June 2016). In a total of
 mice. Approximately 11% (as fraction of the amount of 109Cd present in the   40 publications, a range of cadmium levels of 0-25 µg/La in colostrum and
 dams) was measured in the pups following lactation-only exposure.            mature milk was measured. The Committee is not aware of data available
                                                                              on the amount of cadmium that is transferred to breast milk.
 Lucis and Shaikh (1972)147 injected 109Cd subcutaneously to rats during
 pregnancy or during the lactation period. In both cases, 109Cd was present   Calculation safe level of cadmium in (human) breast milk
 in low concentrations (not further specified) in the milk recovered from the The European Food and Safety Authority (EFSA) established a tolerable
 stomach of the pups.                                                         weekly intake (TWI) of 2.5 μg cadmium/kg bw in 2009, and confirmed this
                                                                              value in 2011.150,151 The TWI was based on urinary β2 microglobulin as
 Houpert et al. (1997)148 studied the amount of cadmium eliminated through
 milk in ewes. The ewes received two successive doses of cadmium              a
                                                                                Excluding a study reporting outlier levels of 94.8–97.8 µg/L measured in Nigeria.
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<pre> chapter 05 | Toxicity for reproduction                                                       Cadmium and selected cadmium compounds | page 88 of 103
 early biomarker of cadmium-induced tubular toxicity, to protect the most    (b) r esults of one or two generation studies in animals provide clear
 sensitive groups of the population. For the calculation of a safe cadmium        evidence of adverse effects in the offspring due to transfer in the milk
 level in breast milk, the Committee applies a default breast milk intake         or adverse effect on the quality of the milk; and/or
 value of 900 mL/d.                                                          (c) a
                                                                                  bsorption, metabolism, distribution and excretion studies indicate the
                                                                                 likelihood that the substance is present in potentially toxic levels in
 Assuming a mean infant body weight during lactation of 4.5 kg, and a daily      breast milk.
 milk intake of 900 mL, a TWI of 2.5 μg cadmium/kg bw corresponds with
 a safe cadmium level in breast milk of: (2.5 x 4.5) / (0.9 x 7) = 1.8 μg/L. Cadmium was detected in breast milk of non-occupationally exposed
                                                                             women in amounts leading to doses that exceed the tolerable weekly
 5.8      Short summary and overall relevance of the provided                intake (TWI) derived by EFSA. Occupational exposure to cadmium will
          information on effects on or via lactation                         most likely lead to additionally increased cadmium levels in breast milk.
 In rats, mice and ewes, excretion of cadmium in breast milk has been        The TWI derived by EFSA is noted to protect also sensitive groups in
 measured. In mice, lactational transfer resulted in reduced learning and    the population. The Committee notes that although no specific data on
 memory function in pups. The transfer appears to be relatively low          cadmium-sensitivity of the infant are available, infants are most likely
 (≤ 11%). The available human data consist of levels of cadmium detected     sensitive to the adverse effects of cadmium. Therefore the Committee
 in breast milk (both colostrum and mature) quantified in breast milk of     considers it likely that cadmium is present in potentially toxic levels in
 women from different regions of the world, who were not occupationally      human milk and is of the opinion that classification for effects on or via
 exposed to cadmium.                                                         lactation is warranted.
 5.9      Comparison with the CLP criteria                                   5.10 Conclusions on classification and labelling
 A substance can be classified if:                                           The Committee recommends classification according to Regulation (EC)
 (a) human evidence indicates a hazard to babies during the lactation       1272/2008 of the European Union. For cadmium, cadmium carbonate,
      period; and/or                                                         cadmium chloride, cadmium fluoride, cadmium hydroxide, cadmium
87       Health Council of the Netherlands | No. 2020/22                                                                2                                  89
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<pre> chapter 05 | Toxicity for reproduction                                                     Cadmium and selected cadmium compounds | page 89 of 103
 nitrate, cadmium oxide, cadmium sulphate, and cadmium sulphide,                Proposed classification for fertility
 the Committee recommends:                                                      Category 1B, H360F.
 • for effects on fertility, to classify these substances in category 1B
    (presumed human reproductive toxicant), and to label them with H360F        Proposed classification for developmental toxicity
    (may damage fertility);                                                     Category 1B, H360D.
 • for effects on development, to classify these substances in category 1B
    (presumed human reproductive toxicant) and to label them with H360D         Proposed classification for effect on or via lactation
    (may damage the unborn child);                                              H362.
 • for effects on or via lactation, to classify these substances for effects on
    or via lactation and label them with H362 (may cause harm to breastfed
    babies).
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<pre> References                                            Cadmium and selected cadmium compounds | page 90 of 103
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<pre>                                                                                                                        Cadmium and selected cadmium compounds | page 102 of 103
  The Committee
  Members of the Subcommittee on the Classification of Reproduction Toxic Substances                   Observer
  • M.B.M. van Duursen, Professor of Environmental Health and Toxicology, VU Amsterdam, chair          •  J.J.A. Muller, Bureau Reach, National Institute of Public Health and the Environment, Bilthoven
  • J.E.H. van Kammen-Bergman, Clinical Geneticist, UMCG, Groningen
  • D. Lindhout, Emeritus professor of Medical Genetics; Paediatrician (not practising),               Scientific secretary
    Clinical Geneticist; UMC Utrecht (until January 1st, 2020)                                         •  S.R. Vink, Health Council of the Netherlands, Den Haag
  • N. Roeleveld, Reproductive epidemiologist; Radboudumc, Nijmegen
  • J.G. Theuns­Van Vliet, Reproductive toxicologist; Erasmus UMC, Rotterdam
  • E.C.M. Tonk, Toxicologist; Charles River Laboratories BV, Den Bosch
  • T. Vrijkotte, Epidemiologist, AMC, Amsterdam (until January 1st, 2020)
  • P.J.J.M. Weterings, Toxicologist; Weterings Consultancy BV, Rosmalen
  • A.H. Piersma, Professor of reproductive and developmental toxicology; National Institute of Public
    Health and the Environment, Bilthoven, structurally consulted expert (until January 1st, 2020)
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<pre>The Health Council of the Netherlands, established in 1902, is an independent scientific ad-visory body. Its remit is “to advise the government and
Parliament on the current level of knowledge with respect to public health issues and health (services) research...” (Section 22, Health Act).
The Health Council receives most requests for advice from the Ministers of Health, Welfare and Sport, Infrastructure and Water Management, Social
Affairs and Employment, and Agriculture, Nature and Food Quality. The Council can publish advisory reports on its own initiative. It usually does this in
order to ask attention for developments or trends that are thought to be relevant to government policy.
Most Health Council reports are prepared by multidisciplinary committees of Dutch or, sometimes, foreign experts, appointed in a personal capacity.
The reports are available to the public.
This publication can be downloaded from www.healthcouncil.nl.
Preferred citation:
Health Council of the Netherlands. Cadmium and selected cadmium compounds.
The Hague: Health Council of the Netherlands, 2020; publication no. 2020/22.
All rights reserved
          Health Council of the Netherlands | No. 2020/22                                                               2
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