<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>Tin and selected inorganic
tin compounds
Evaluation of the effects on reproduction, recommendation for classification
To: the Minister of Social Affairs and Employment
No. 2022/27, The Hague, November 8, 2022
                                                                             2 2
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<pre> Contents                                                                  Tin and selected inorganic tin compounds | page 2 of 97
 contents
      Samenvatting4                                              44  Excretion                                                         23
                                                                  4.5 Grouping                                                          23
      Executive summary                                     6
                                                               05 Adverse effects on sexual function and fertility                     27
 01 Scope8                                                       5.1 Animal data                                                       28
      1.1  Background                                       9    5.2 Human data                                                        38
      1.2  Committee and procedure                          9    5.3 Short summary and overall relevance of the provided information on
      1.3  Labelling for lactation                         10        adverse effects on sexual function and fertility                  43
      1.4  Data                                            11    5.4 Comparison with the CLP criteria                                  44
 02 Identity of the compounds                             12  06 Adverse effects on development                                       46
      2.1  Name and other identifiers of the substances    13    6.1 Animal studies                                                    47
      2.2  Composition of the substances                   15    6.2 Human data                                                        56
      2.3  Physico-chemical properties of the substances   15    6.3 Short summary and overall relevance of the provided information on
                                                                      adverse effects on development                                    76
 03 Manufacture and uses                                  18     6.4 Comparison with the CLP criteria                                  79
 04 Toxicokinetics and grouping                           20
      4.1  Absorption                                      21
      4.2  Distribution                                    21
      4.3  Biotransformation                               23
1       Health Council of the Netherlands | No. 2022/27                                             2                                     3
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<pre> Contents                                                   Tin and selected inorganic tin compounds | page 3 of 97
 07 Adverse effects on or via lactation                81
      7.1  Adverse effects on lactation                 82
      7.2  Adverse effects via lactation                82
      7.3  Comparison with the CLP criteria             83
 08 Conclusions on classification and labelling        84
      References86
      Annex A literature search strategy               91
2       Health Council of the Netherlands | No. 2022/27                          2                                4
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<pre> Samenvatting                                                                                         Tin and selected inorganic tin compounds | page 4 of 97
 samenvatting
 Op verzoek van de minister van Sociale Zaken        (legering). In die hoedanigheid wordt het veel          Werknemers kunnen via de lucht blootgesteld
 en Werkgelegenheid (SZW) heeft de                   gebruikt voor het solderen van elektrische en           worden aan stof en damp van tin en
 Gezondheidsraad voor tin en een aantal              industriële apparaten (soldeertin). Ook wordt tin       anorganische tinverbindingen bij het vullen
 anorganische tinverbindingen beoordeeld of          gebruikt als beschermlaag voor andere metalen,          en legen van verpakkingen van tinhoudende
 beroepsmatige blootstelling invloed kan             in het bijzonder in blik voor voedingsmiddelen.         materialen in poedervorm, het smelten van
 hebben op de voortplanting. Op basis van                                                                    tinhoudend materiaal (bijvoorbeeld tijdens het
 deze beoordeling is een classificatievoorstel       Tin komt ook voor in allerlei verbindingen.             solderen) en bij schoonmaakwerkzaamheden.
 opgesteld.                                          De commissie heeft tin en de volgende
                                                     anorganische tinverbindingen beoordeeld:                Classificeren naar bewijskracht
 Dit advies is tot stand gekomen in de               tinsulfide, tinoxide, ditinpyrofosfaat, tindichloride,  Bij de beoordeling van effecten op de
 Subcommissie Classificatie reproductietoxische      tindifluoride, tinsulfaat, tindifluoroboraat,           voortplanting, kijkt de commissie zowel naar
 stoffen, van de Commissie Gezondheid en             tindisulfide en tindioxide. Tindichloride is in         effecten op de vruchtbaarheid van mannen en
 beroepsmatige blootstelling (GBBS).                 commercieel opzicht de belangrijkste                    vrouwen als naar effecten op de ontwikkeling
 Op www.gezondheidsraad.nl staat informatie          anorganische tinverbinding. Het wordt                   van het nageslacht. Daarnaast worden effecten
 over de taken van deze vaste commissie van          voornamelijk gebruikt als hulpstof bij allerlei         op de lactatie (productie en afgifte van
 de Gezondheidsraad. De samenstelling van de         chemische processen en bij de productie van             moedermelk) beoordeeld en effecten via de
 commissie is te vinden achterin dit advies.         glas, gemetalliseerd glas en pigmenten.                 moedermelk op de zuigeling. Als er
                                                     Tindifluoride wordt gebruikt in de preventieve          aanwijzingen bestaan dat de stof schadelijke
 Gebruik van tin                                     tandheelkunde.                                          effecten heeft, stelt de commissie voor om de
 Een belangrijke eigenschap van tin is dat het                                                               stof in te delen in gevarencategorieën.
 een mengsel kan vormen met andere metalen
3       Health Council of the Netherlands | No. 2022/27                                                                     2                               5
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<pre> Samenvatting                                                                                           Tin and selected inorganic tin compounds | page 5 of 97
 Deze categorieën zijn afgeleid van                    gemeten waarvan de commissie het niet
 EU-verordening (EG) 1272/2008.                        waarschijnlijk acht dat ze tot nadelige gevolgen
                                                       leiden bij de baby na borstvoeding.
 Geraadpleegde onderzoeken
 Er zijn slechts enkele onderzoeken bij mensen         Advies aan de minister
 beschikbaar over effecten van blootstelling aan       Wegens onvoldoende wetenschappelijke
 tin op de vruchtbaarheid. Over effecten op            gegevens adviseert de commissie om tin en alle
 de ontwikkeling zijn meer onderzoeken                 beoordeelde anorganische tinverbindingen,
 beschikbaar, maar zowel voor effecten op de           zowel voor effecten op de vruchtbaarheid, als
 vruchtbaarheid als ontwikkeling tonen deze            voor effecten op de ontwikkeling, niet in te delen
 onderzoeken geen of geen duidelijk verband            in een gevarencategorie. Op basis van de
 aan met blootstelling aan tin. Er zijn ook            beschikbare wetenschappelijke gegevens acht
 dierstudies gedaan met tin en enkele                  de commissie voor effecten op of via lactatie
 geselecteerde anorganische tinverbindingen,           een indeling niet op zijn plaats.
 zowel naar effecten op de vruchtbaarheid als
 naar effecten op de ontwikkeling. Deze laten          Classificatievoorstel commissie:
 ook geen duidelijke nadelige effecten zien, maar      • voor effecten op de fertiliteit: niet classificeren
 de diergevens zijn onvoldoende om conclusies             wegens onvoldoende geschikte gegevens;
 uit te trekken.                                       • voor effecten op de ontwikkeling: niet
                                                          classificeren wegens onvoldoende geschikte
 Voor effecten van blootstelling aan tin op of            gegevens;
 via lactatie baseert de commissie zich op             • voor effecten op of via lactatie: niet
 onderzoeken bij mensen. In die onderzoeken               classificeren.
 zijn concentraties van tin in de moedermelk
4         Health Council of the Netherlands | No. 2022/27                                                                    2                                6
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<pre> Executive summary                                                                                     Tin and selected inorganic tin compounds | page 6 of 97
 executive summary
 At the request of the Minister of Social Affairs    extensive use as a protective coating for other          Classification based on evidence
 and Employment, the Health Council of the           metals, especially for food containers.                  To assess effects on reproduction, the
 Netherlands evaluated the effects of tin and                                                                 Committee evaluates the effects on male and
 selected inorganic tin compounds on                 Various tin compounds exists. The committee              female fertility and on the development of the
 reproduction. This advisory report was drafted      has evaluated tin and the following inorganic tin        offspring. Moreover, the Committee considers
 by the Subcommittee on the Classification of        compounds: tin sulphide, tin oxide, ditin                effects of a substance on lactation and on the
 Reproduction Toxic Substances of the Dutch          pyrophosfate, tin dichloride, tin difluoride, tin        offspring via lactation. If the data indicate
 Expert Committee on Occupational Safety             sulphate, tin difluoroborate, tin disulphide and tin     hazardous properties, the Committee
 (DECOS) of the Health Council, hereafter called     dioxide. Tin dichloride is commercially the most         recommends classification in a hazard category.
 the Committee. The Health Council has a             important inorganic compound and is mainly               The classification is performed according to
 permanent task in assessing the hazard of           used as a reducing agent in organic and                  EU-regulation (EC) 1272/2008.
 substances to which man can be occupationally       inorganic syntheses and in the manufacture
 exposed. More information about this task can       of metallized glazing, glass, and pigments.              Research consulted
 be found at www.gezondheidsraad.nl.                 Tin difluoride is broadly used in preventive             Only a few epidemiological studies are available
                                                     dentistry.                                               both regarding effects of exposure to tin on
 Use of tin and inorganic tin compounds                                                                       fertility. Several studies are available on
 An important property of tin is the ability to form Workers may be exposed to inorganic tin                  developmental effects. However, in both cases
 alloys with other metals. As such, tin is           substances via air (dust and fumes) during               studies indicate no, or no clear association with
 frequently used for electrical/electronic and       bagging, smelting operations and cleaning.               exposure to tin. Also, animal studies have been
 general industrial applications. Tin also finds                                                              performed with tin and some selected inorganic
                                                                                                              tin compounds, on effects on fertility as well as
5       Health Council of the Netherlands | No. 2022/27                                                                       2                                 7
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<pre> Executive summary                                       Tin and selected inorganic tin compounds | page 7 of 97
 on effects on development. These studies do not
 show clear adverse effects, however, the data
 available are insufficient to draw conclusions.
 For effects of exposure to tin on or via lactation,
 the evaluation is based on research with
 humans. The Committee considers it unlikely
 that the concentrations of tin in breastmilk that
 have been measured in those studies will
 result in adverse effects for the infant after
 breastfeeding.
 Recommendations to the Minister
 Based on the scientific data available, the
 Committee recommends to not classify tin, and
 all evaluated inorganic tin compounds for effects
 on fertility, for effects on offspring development
 and for effects on or via lactation.
 The Committee recommends:
 • for effects on fertility: not to classify due to a
     lack of appropriate data;
 • for effects on development: not to classify
     due to a lack of appropriate data;
 • for effects during lactation: not to classify.
6        Health Council of the Netherlands | No. 2022/27                      2                                8
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<pre> chapter 01 | Scope                                    Tin and selected inorganic tin compounds | page 8 of 97
 01
 scope
7      Health Council of the Netherlands | No. 2022/27                      2                                9
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<pre> chapter 01 | Scope                                                                                  Tin and selected inorganic tin compounds | page 9 of 97
                                                                                Classifications and hazard statement codes
 1.1     Background
                                                                                Classification for reproduction (fertility (F) and development (D)):
 As a result of the Dutch regulation on registration of compounds toxic to
                                                                                Category 1       Known or presumed human reproductive toxicant (H360(F/D))
 reproduction that came into force on 1 April 1995, the Minister of Social      Category 1A      Known human reproductive toxicant
 Affairs and Employment requested the Health Council of the Netherlands         Category 1B      Presumed human reproductive toxicant
 to classify compounds toxic to reproduction. This classification is            Category 2       Suspected human reproductive toxicant (H361(f/d))
                                                                                No classification for effects on fertility or development
 performed by the Health Council’s Subcommittee on the Classification
 of reproduction toxic substances of the Dutch Expert Committee on
                                                                                Classification for lactation:
 Occupational Safety (DECOS). The classification is performed according                          Effects on or via lactation (H362)
 to European Union Regulation (EC) 1272/2008 on classification, labelling                        No labeling for lactation
 and packaging (CLP) of substances and mixtures. The CLP regulation is
                                                                                Hazard statement codes:
 based on the Globally Harmonised System of Classification and Labelling
                                                                                H360F            May damage fertility.
 of Chemicals (GHS). The subcommittee’s advice on the classification will
                                                                                H360D            May damage the unborn child.
 be applied by the Ministry of Social Affairs and Employment to extend the      H361f            Suspected of damaging fertility.
 existing list of compounds classified as reproductive toxicant (category 1A    H361d            Suspected of damaging the unborn child.
 and 1B and 2) or compound with effects on or via lactation.                    H360FD           May damage fertility. May damage the unborn child.
                                                                                H361fd           Suspected of damaging fertility. Suspected of damaging the
                                                                                                 unborn child.
 1.2     Committee and procedure
                                                                                H360Fd           May damage fertility. Suspected of damaging the unborn child.
 This document contains the recommendations for classification of tin and       H360Df           May damage the unborn child. Suspected of damaging fertility.
 tin compounds by the Health Council’s Subcommittee on the Classification       H362             May cause harm to breast-fed children.
 of Reproduction Toxic Substances, hereafter called the Committee.
 The members of the Committee are listed on the last page of this report.    The classification and labelling of substances is performed according to
 The classification is based on the evaluation of published human and        the guidelines of the European Union (Regulation (EC) 1272/2008).
 animal studies concerning adverse effects with respect to fertility and     The classification of compounds is the result of an integrated assessment
 offspring development as well as adverse effects on or via lactation.       of the nature of all parental and developmental effects observed, their
8        Health Council of the Netherlands | No. 2022/27                                                                        2                              10
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<pre> chapter 01 | Scope                                                                                         Tin and selected inorganic tin compounds | page 10 of 97
 specificity and adversity, and the dosages at which the various effects               Regarding fertility, the Committee takes into account data on parameters
 occur. The guideline necessarily leaves room for interpretation, dependent            related to fertility, such as seminal fluid volume and spermatozoa
 on the specific data set under consideration. In the process of using the             concentration, that are related to male fertility. The Committee excludes
 regulation, the committee has agreed upon a number of additional                      publications containing only data on sex hormone levels from the
 considerations.                                                                       assessment, because the relationship between these hormone levels
                                                                                       and functional fertility (ability to conceive children) is too uncertain.
   Additional considerations to Regulation (EC) 1272/2008
   If there is sufficient evidence to establish a causal relationship between human    In 2022, the President of the Health Council released a draft of the report
   exposure to the substance and impaired fertility or subsequent developmental        for public review. The Committee has taken the comments received into
   toxic effects in the offspring, the compound will be classified in category 1A,     account in deciding on the final version of the report. These comments,
   irrespective of the general toxic effects (see Regulation (EC) 1272/2008,
                                                                                       and the replies by the Committee, can be found on the website of the
   3.7.2.2.1.).
                                                                                       Health Council.
   Adverse effects in a reproductive study, reported without information on the
   paternal or maternal toxicity, may lead to a classification other than category 1B, 1.3     Labelling for lactation
   when the effects occur at dose levels which cause severe toxicity in general        The recommendation for classifying substances for effects on or via
   toxicity studies.
                                                                                       lactation is also based on Regulation (EC) 1272/2008. The criteria define
                                                                                       that substances that are absorbed by women and have been shown to
   Clear adverse reproductive effects will not be disregarded on the basis of
   reversibility per se.                                                               interfere with lactation or which may be present (including metabolites) in
                                                                                       breast milk in amounts sufficient to cause concern for the health of a
   The committee does not only use guideline studies (studies performed                breastfed child, shall be classified and labelled. Unlike the classification of
   according to OECD standard protocols) for the classification of compounds,
                            a
                                                                                       substances for fertility and developmental effects, which is based on
   but non-guideline studies are taken into consideration as well.
                                                                                       hazard identification only (largely independent of dosage), the labelling for
 a
   Organisation for Economic Cooperation and Development                               effects on or via lactation is based on a risk characterization and
9         Health Council of the Netherlands | No. 2022/27                                                                          2                                 11
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<pre> chapter 01 | Scope                                                           Tin and selected inorganic tin compounds | page 11 of 97
 therefore, it also includes consideration of the level of exposure of the
 breastfed child.
 Consequently, a substance should be labelled for effects on or via
 lactation when it is likely that the substance would be present in breast
 milk at potentially toxic levels. The Committee considers a concentration
 of a compound as potentially toxic to the breastfed child when this
 concentration leads to exceeding the exposure limit for children, or if that
 level is unknown, the exposure limit for the general population, e.g., the
 acceptable daily intake (ADI).
 1.4      Data
 A literature search for publications on reproductive toxicity of tin and
 inorganic tin compounds was performed using various databases up to
 March 2021. Additionally, the search strategy included publications on
 (toxico)kinetics and monitoring. The NIOSH suggested additional literature
 during public consultation which was included in the final version of the
 report.
 Details on the literature search strategy can be found in Annex A.
10       Health Council of the Netherlands | No. 2022/27                                            2                               12
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<pre> chapter 02 | Identity of the compounds                Tin and selected inorganic tin compounds | page 12 of 97
 02
 identity of the
 compounds
11     Health Council of the Netherlands | No. 2022/27                       2                               13
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<pre> chapter 02 | Identity of the compounds                                                              Tin and selected inorganic tin compounds | page 13 of 97
 2.1      Name and other identifiers of the substances                     Table 1 Substance identity and information related to molecular and structural formula
                                                                           of tin (group 1).
 For the selection of tin and inorganic tin compounds, an overall list was
 compiled first based on data from the WHO1, a report of the Health         Category                                                                  Value
                                                                            Name(s) in the IUPAC nomenclature or other international chemical         Tin
 Council of the Netherlands2, and the Handbook of chemistry and physics.3   name(s)
                                                                            Other names (usual name, trade name, abbreviation)                        -
 From this list, a selection of compounds was made, which were divided
                                                                            ISO common name (if available and appropriate)                            N/A
 into five groups based on chemical properties:                             EC/EINECS number (if available and appropriate)                           231-141-8
                                                                            EC name (if available and appropriate)                                    Tin
 • Group 1: Metallic tin;
                                                                            CAS number                                                                7440-31-5
 • Group 2: Inorganic tin compounds; oxidation state 2+, insoluble (tin     Other identity code (if available)                                        [Sn]
                                                                            Molecular formula                                                         Sn
    sulphide, tin oxide, and ditin pyrophosphate);
                                                                            Structural formula                                                        Sn
 • Group 3: Inorganic tin compounds; oxidation state 2+, soluble (tin       Molecular weight or molecular weight range                                118.7
                                                                            Information on optical activity and typical ratio of (stereo) isomers (if N/A
    dichloride, tin difluoride, tin sulphate, and tin(II) difluoroborate);  applicable and appropriate)
 • Group 4: Inorganic tin compounds; oxidation state 4+, insoluble (tin     Description of the manufacturing process and identity of the source (for  N/A
                                                                            UVBC substances only)
    disulphide and tin dioxide).                                            Degree of purity (%) (if relevant for the entry in Annex VI)              N/A
 For an explanation of the selection of compounds, the Committee refers to
 section 4.5 ‘Grouping’.
12       Health Council of the Netherlands | No. 2022/27                                                                               2                        14
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<pre> chapter 02 | Identity of the compounds                                                                                       Tin and selected inorganic tin compounds | page 14 of 97
 Table 2 Substance identity and information related to molecular and structural formula               Table 3 Substance identity and information related to molecular and structural formula
 of tin sulphide, tin oxide, and ditin pyrophosphate (group 2).                                       of tin dichloride, tin difluoride, tin sulphate and tin(II) tetrafluoroborate (group 3).
  Category                              Tin sulphide          Tin oxide      Ditin pyrophosphate       Category                Tin dichloride    Tin difluoride     Tin sulphate      Tetrafluoroborate
  Name(s) in the IUPAC                  Stannanethione        Stannanone     ditin(2+)                 Name(s) in the IUPAC    Tin(2+)           Tin(2+) difluoride Lambda2-tin(2+) tin(2+);
  nomenclature or other international                                        (phosphonooxy)            nomenclature or other   dichloride                           sulphate          ditetrafluoroborate
  chemical name(s)                                                           phosphonate               international chemical
  Other names (usual name, trade        Tin sulphide,         Tin(II) oxide, Tin(II) pyrophosphate,    name(s)
  name, abbreviation)                   tin(2+) sulphide,     stannous oxide stannous                  Other names (usual      Tin dichloride;   Tin difluoride,    Tin(II) sulphate, Tin(II)
                                        tin(II) sulphide, tin                pyrophosphate             name, trade name,       tin(II) chloride; tin(II) fluoride,  stannous          tetrafluoroborate;
                                        sulphide, tin                                                  abbreviation)                             stannous           sulphate          Tin(II) fluoroborate;
                                        monosulphide                                                                                             fluoride                             Tin fluoroborate;
  ISO common name (if available         N/A                   N/A            N/A                                                                                                      tin(2+);
  and appropriate)                                                                                                                                                                    ditetrafluoroborate
  EC/EINECS number (if available        215-248-7             244-499-5      239-635-5                 ISO common name (if     stannous          N/A                N/A               N/A
  and appropriate)                                                                                     available and           chloride
  EC name (if available and             Tin sulphide          Tin monoxide   Ditin pyrophosphate       appropriate)
  appropriate)                                                                                         EC/EINECS number        231-868-0         231-999-3          231-302-2         237-487-6
  CAS number                            1314-95-0             21651-19-4     15578-26-4                (if available and
                                                                                                       appropriate)
  SMILES code (if available)            S=[Sn]                O=[Sn]         [O-]P(=O)([O-])OP(=O)
                                                                             ([O-])[O-].[Sn+2].[Sn+2]  EC name (if available   Tin dichloride    Tin difluoride     Tin sulphate      Tin
                                                                                                       and appropriate)                                                               bis(tetrafluoroborate)
  Molecular formula                     SnS                   SnO            Sn2P2O7
                                                                                                       CAS number              7772-99-8         7783-47-3          7488-55-3         13814-97-6
  Structural formula
                                                                                                       SMILES code (if         Cl[Sn]Cl          F[Sn]F             [O-]S(=O)(=O)     [B-](F)(F)(F)F.[B-](F)
                                                                                                       available)                                                   [O-] .[Sn+2]      (F)(F)F.[Sn+2]
                                                                                                       Molecular formula       SnCl2             SnF2               SnSO4             B2F8Sn
                                                                                                       Structural formula
  Molecular weight or molecular         150.8                 134.7          411.3
  weight range
  Information on optical activity and   N/A                   N/A            N/A
  typical ratio of (stereo) isomers (if
  applicable and appropriate)                                                                          Molecular weight or     189.6             156.7              214.8             292.3
  Description of the manufacturing      N/A                   N/A            N/A                       molecular weight
  process and identity of the source                                                                   range
  (for UVBC substances only)
  Degree of purity (%) (if relevant for N/A                   N/A            N/A
  the entry in Annex VI)
13          Health Council of the Netherlands | No. 2022/27                                                                                                    2                                            15
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<pre> chapter 02 | Identity of the compounds                                                                                      Tin and selected inorganic tin compounds | page 15 of 97
  Category                   Tin dichloride      Tin difluoride     Tin sulphate    Tetrafluoroborate
  Information on optical     N/A                 N/A                N/A             N/A
  activity and typical
                                                                                                         2.2     Composition of the substances
  ratio of (stereo)                                                                                      Not applicable to mono-constituent substances.
  isomers (if applicable
  and appropriate)
  Description of the         N/A                 N/A                N/A             N/A
  manufacturing process
                                                                                                         2.3     Physico-chemical properties of the substances
  and identity of the                                                                                    The physicochemical properties of the selected tin compounds are
  source (for UVBC
  substances only)                                                                                       presented in Tables 5, 6 and 7 below. The ECHA dissemination website
  Degree of purity (%) (if N/A                   N/A                N/A             N/A
  relevant for the entry
                                                                                                         and the Handbook of chemistry and physics were used as the primary
  in Annex VI)                                                                                           sources.
 Table 4 Substance identity and information related to molecular and structural formula                  In many cases, data were waived in the REACH registration dossier,
 of tin disulphide and tin dioxide, (group 4).                                                           because the data are considered scientifically not necessary or technically
  Catgory                                                   Tin disulphide         Tin dioxide           not feasible. This is indicated in the tables (i.e. N/A).
  Name(s) in the IUPAC nomenclature or other                Tin(4+) disulfanediide Tin(4+) dioxidandiide
  international chemical name(s)
  Other names (usual name, trade name,                      Tin disulphide         Tin dioxide, stannic
                                                                                                         The 2+ (stannous) and 4+ (stannic) oxidation states are both reasonably
  abbreviation)                                                                    oxide
  ISO common name (if available and appropriate)            N/A                    N/A                   stable and interconverted by moderately active reagents. In aqueous
  EC/EINECS number (if available and appropriate)           215-252-9              242-159-0
                                                                                                         solutions tin(IV) is more stable than tin(II), which can be oxidized to tin(IV).
  EC name (if available and appropriate)                    Tin disulphide         Tin dioxide
  CAS number                                                1315-01-1; 12738-87-3 18282-10-5             The Sn2+/Sn4+ potential is low (-0.15 V) and tin(II) can act as a mild
  SMILES code (if available)                                S=[Sn]=S               O=[Sn]=O
  Molecular formula                                         SnS2                   SnO2
                                                                                                         reducing agent. Tin reacts with strong acids and strong bases but remains
  Structural formula                                                                                     relatively resistant to neutral solutions. A thin protective oxide film forms
                                                                                                         on tin exposed to oxygen or dry air at room temperature; heat accelerates
  Molecular weight or molecular weight range                182.8                  150.7
  Information on optical activity and typical ratio of      N/A                    N/A                   this reaction.
  (stereo) isomers (if applicable and appropriate)
  Description of the manufacturing process and              N/A                    N/A
  identity of the source (for UVBC substances only)
  Degree of purity (%) (if relevant for the entry in        N/A                    N/A
  Annex VI)
14          Health Council of the Netherlands | No. 2022/27                                                                                         2                                  16
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<pre> chapter 02 | Identity of the compounds                                                                                                    Tin and selected inorganic tin compounds | page 16 of 97
 Table 5 Summary of physicochemical properties: state of the substance, melting/freezing point, boiling point, relative density, water solubility and partition coefficient.
   Substance                   State of the substance at normal temperature Melting/freezing point          Boiling point             Relative density         Water solubility                          Partition coefficient
                               and pressure                                       (at 101325 Pa)            (at 101325 Pa)                                                                               n-octanol/water
   Tin                         Solid, grey metallic powder                        232°C                     2,500-2,600°C             5.8-7.3 (20°C)           Insoluble: <0.1 mg/L at 20°C              N/A
   Tin sulphide                Solid, dark grey powder                            >650°C                    1210°C                    1.6 (20°C) ; 5.08
                                                                                                                                                 a     b
                                                                                                                                                               Insoluble: 0.6 µg/L (20°C)                N/A
   Tin oxide                   Solid                                              1,080°C c,d
                                                                                                            - d
                                                                                                                                      6.3-6.45 (20°C)          Insoluble: <0.1 mg/L (25°C)               N/A
   Ditin pyrophosphate         White inorganic solid                              >400°C d
                                                                                                            -                         4 (25°C)                 Insoluble                                 N/A
   Tin bis(tetrafluoroborate) White powder; registered as aquous solution         -                         -                         -                        Soluble                                   -
   Tin dichloride              Solid, white crystalline substance                 247°C                     623°C                     3.9 (20°C)               Very soluble: 178 g/L (20°C)              Log Kow -2.15 (20°C)
   Tin difluoride              Solid, white, monoclinic, crystalline, hygroscopic 215°C                     850°C                     4.6 (25°C)               Very soluble: 300-390 g/L (20°C)          N/A
   Tin sulphate                Solid, white crystals                              378°Cd                    -d                        4.15 (20°C)              Very solublee                             Log Kow 3.28 (20°C)
   Tin disulphide              Odourless gold yellow powder                       515-600°C   d
                                                                                                            >515°C  d
                                                                                                                                      4.5 (20°C)               Insoluble: 0.67 µg/L (20°C)               N/A
   Tin dioxide                 Solid white powder                                 1,630°C d
                                                                                                            - d
                                                                                                                                      6.9 (20°C)               Insoluble: <0.1 mg/L at 20°C              N/A
 N/A: Not applicable. Data was waived in the REACH registration dossier.                                        d
                                                                                                                  Decomposes before melting.
 a
    Source: ECHA dissemination website                                                                          e
                                                                                                                  The REACH registration dossier mentions a solubility of 10 g/L at 20°C (source not provided) and a solubility of
 b
    Source: Handbook of chemistry and physics, 96th edition.                                                      188 g/L at 20°C (source: CRC Handbook of Chemistry and Physics).
 c
    At ca. 600 mmHg (= 80,000 Pa).
 Table 6 Summary of physicochemical properties: vapour pressure, surface tension, flammability, explosive properties and self-ignition.
   Substance                       Vapour pressure                 Surface tension              Flash point                    Flammability                   Explosive properties                Self-ignition temperature
   Tin                             0 kPa (20°C) a
                                                                   N/A                          N/A                            Not highly flammable           N/A                                 Not below 400°C
   Tin sulphide                    -                               N/A                          -                              Not highly flammable           -                                   -
   Tin oxide                       N/A                             N/A                          N/A                            N/A                            N/A                                 N/A
   Ditin pyrophosphate             N/A                             N/A                          N/A                            Not flammable                  N/A                                 N/A
   Tin bis(tetrafluoroborate)      -                               -                            -                              -                              -                                   -
   Tin dichloride                  0 kPa (20°C) a
                                                                   N/A                          N/A                            N/A                            N/A                                 N/A
   Tin difluoride                  N/A                             N/A                          N/A                            Not flammable                  N/A                                 N/A
   Tin iodide b
                                   -                               -                            -                              -                              -                                   -
   Tin sulphate                    N/A                             73 mN/m                      N/A                            Not flammable                  Not explosive                       No self-ignition
   Tin disulphide                  N/A                             72.8 mN/m                    N/A                            Not flammable                  Not explosive                       348°C
   Tin dioxide                     N/A                             N/A                          N/A                            N/A                            Not explosive                       N/A
 N/A: Not applicable. Data was waived in the REACH registration dossier.
 a
    1 Pa at 1224°C
 b
    No REACH registration dossier available.
15           Health Council of the Netherlands | No. 2022/27                                                                                                                 2                                                    17
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<pre> chapter 02 | Identity of the compounds                                                                                    Tin and selected inorganic tin compounds | page 17 of 97
 Table 7 Summary of physicochemical properties: oxidising properties, granulometry, stability in organic solvents, dissociation constant and viscosity.
   Substance                                Oxidising properties    Granulometry                             Stability in organic solvents and identity  Dissociation constant Viscosity
                                                                                                             of relevant degradation products            (pKa)
   Tin                                      No oxidising properties D25: 2.7 µm                              N/A                                         N/A                   N/A
                                                                    D50: 3.2 µm
                                                                    D75: 3.8 µm
   Tin sulphide                             No oxidising properties D10: 5 µm, D50: 26 µm, D90: 78 µm        N/A                                         N/A                   N/A
   Tin oxide                                N/A                     D50: Approx. 15 µm                       N/A                                         N/A                   N/A
   Ditin pyrophosphate                      N/A                     Mass median aerodynamic diameter:        -                                           -                     -
                                                                    18.2 µm
                                                                    D10: 11 µm
                                                                    D50: 27 µm
                                                                    D99: 47 µma
   Tin dichloride                           No oxidising properties Aerodynamic diameter >32.4 µm. The ratio N/A                                         logK = 7.8            N/A
                                                                    of particle <10 µm is approximate 3.6%.
   Tin difluoride                           N/A                     D10: 36.9 µm                             N/A                                         N/A                   N/A
                                                                    D50: 82.2 µm
                                                                    D90: 144.4 µm
   Tin bis(tetrafluoroborate)               N/A                     -                                        N/A                                         N/A                   N/A
   Tin sulphate                             No oxidising properties D50: 20 µm                               N/A                                         N/A                   N/A
   Tin disulphide                           No oxidising properties D10: 0.59 µm                             N/A                                         N/A                   N/A
                                                                    D50: 1.58 µm
                                                                    D90: 6.22 µm
   Tin dioxide                              N/A                     D10:0.115 µm                             N/A                                         N/A                   N/A
                                                                    D50: 0.691 µm
                                                                    D90: 1.979 µm
 N/A: Not applicable. Data was waived in the registration dossier.
 a
    Data from one of the two REACH registration dossiers.
16           Health Council of the Netherlands | No. 2022/27                                                                                            2                                18
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<pre> chapter 03 | Manufacture and uses                     Tin and selected inorganic tin compounds | page 18 of 97
 03
 manufacture
 and uses
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<pre> chapter 03 | Manufacture and uses                                              Tin and selected inorganic tin compounds | page 19 of 97
 The main use of tin, accounting for approximately a third of the annual
 global production, is for solder alloys for electrical/electronic and general
 industrial applications. Tin also finds extensive use (about 25-30% of
 production) as a protective coating for other metals, especially for food
 containers. Tin dichloride is commercially the most important inorganic
 compound and is mainly used as a reducing agent in organic and
 inorganic syntheses and in the manufacture of metallized glazing, glass,
 and pigments. Tin tetrachloride is used in organic synthesis, in plastics,
 as an intermediate in organotin compound manufacture, and in the
 production of tin tetraoxide films on glass. Tin difluoride is broadly used
 in preventive dentistry.1
 An important property of tin is its ability to form alloys with other metals.
 Tin alloys cover a wide range of compositions and many applications.
 People can be exposed to organic, inorganic and elemental tin through
 food, drinking water, consumer products and environmental media (air,
 soil and dust). Most of this tin exposure is in the form of inorganic tin from
 the consumption of canned food and beverages.1,4
 Workers may be exposed to inorganic tin substances via air (dust and
 fumes) during bagging, smelting operations and cleaning.
18       Health Council of the Netherlands | No. 2022/27                                              2                               20
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<pre> chapter 04 | Toxicokinetics and grouping              Tin and selected inorganic tin compounds | page 20 of 97
 04
 toxicokinetics
 and grouping
19     Health Council of the Netherlands | No. 2022/27                       2                               21
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<pre> chapter 04 | Toxicokinetics and grouping                                                          Tin and selected inorganic tin compounds | page 21 of 97
 In this section, a short summary is provided mainly based on the              and blood samples were taken after 2, 5, and 24 h. The two women had
 evaluation of the WHO1, supplemented with information from ATSDR4,            detectable tin blood levels (3 ng/mL) only in the 5-h samples. The two
 SCOEL5, and a report of the Health Council of the Netherlands.2               men had peak blood tin concentrations of 4.7 ng/mL (40 nmol/L) after 2
 Additional studies are referenced where appropriate. The overview of          hours and 3.9 ng/ml (33 nmol/L) after 24 hours, respectively.
 studies in humans and animals as presented here is not comprehensive.
                                                                               A single administration of 20 mg/kg bw 113Sn(II) or 113Sn(IV) as the
 4.1      Absorption                                                           citrate or fluoride to rats by gavage resulted in an absorption of 2.85%
 Generally, absorption of tin from the gastrointestinal tract is low in humans (2+ oxidation state) and 0.64% (4+ oxidation state). This was based on
 and laboratory animals, including rats, mice, rabbits, cats, and dogs, but it 48-h recovery of radioactivity in the urine and tissues.
 may be influenced by aqueous solubility, dose, anion, and the presence of
 other substances. Absorption seems to occur by passive diffusion.             4.2      Distribution
 Adequate data on uptake following inhalation or dermal exposure appear        Inorganic tin distributes mainly to bone, but also to the lungs, liver,
 to be lacking.                                                                kidneys, spleen, lymph nodes, tongue, and skin. In a survey of tin
                                                                               concentrations in post-mortem human tissues collected from several
 Eight healthy volunteers were given a diet containing 0.11 mg of tin per      hundred subjects, the highest concentrations occurred in the kidney
 day for 20 days. Mean faecal excretion was 55% of the daily dose,             (0.2-0.78 mg/kg tissue), liver (0.35-1.0 mg/kg), lung (0.45-1.20 mg/kg),
 suggesting a mean net absorption of 45% at this low dose (although            and bone (0.5-8.0 mg/kg). Certain data indicate that tin may have a higher
 the range was wide, varying from -4 to 71%). When the diet was                affinity for the thymus than for other organs. Laboratory animal data
 supplemented (with tin dichloride) to provide an additional 50 mg of tin      suggest that inorganic tin does not readily cross the blood-brain barrier.
 per day for 20 days, mean faecal excretion was 97% of the daily dose,
 suggesting a net absorption of 3% (range -7 to 9%) at this higher dose.       With increasing age, tin levels seem to increase in the human lung,
                                                                               possibly because of inhalation of tin from polluted air. The tin content in
 Four volunteers with tin blood levels of <2 ng/mL (<17 nmol/L) each           human tissues was high in the United States and low in Africa, and
 consumed 60 mg of tin in the form of fruit juice from an unlacquered can,     seldom present in newborn babies in the United States. In humans with no
20       Health Council of the Netherlands | No. 2022/27                                                                 2                                 22
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<pre> chapter 04 | Toxicokinetics and grouping                                                            Tin and selected inorganic tin compounds | page 22 of 97
 occupational exposure to tin compounds, blood tin concentrations of 2-9         In another study, pregnant female Sprague-Dawley rats received tin salts
 μg/L are reported. Others reported average tin concentrations in the            (tin difluoride, sodium pentachlorostannite, or sodium pentafluorostannite)
 general population of 11.6 ± 4.4 nmol/L (=1.4 µg/L) in plasma and 21.7 ±        at 125-625 mg/kg in the feed (about 10-50 mg of tin/kg bw/day). Foetal tin
 6.7 nmol/L (=2.6 µg/L) in red blood cells in 12 humans (8 women, 4 men,         values were only slightly elevated (0.8-1.3 mg/kg bw) on day 20 of
 mean age 77.8 years). Background tin concentrations of <1 μg/L in serum         gestation, compared to foetuses of the control group (0.64 mg/kg bw).
 and urine have been reported, and a 95th upper percentile of 20 μg/L in
 urine was calculated for a group of 496 US residents.                           Others have reported that “considerable” tin concentrations were noted
                                                                                 in embryos of rats exposed to tin dichloride, without further specification.
 The concentrations of a variety of heavy metals were measured in 25             Data are very limited but suggest the possibility of a low level of tin
 amniotic fluid samples obtained from amniocentesis between 15 and 18            transfer across the placenta.
 weeks of gestation. The aim of this study was to evaluate the presence of
 heavy metals in human amniotic fluid to investigate whether there is early      Metal concentrations in liver, kidney, brain and testes were measured in
 foetal exposure. Eighteen metals were detected in measurable amounts in         rats exposed to miniature alloy pellets containing bismuth, tin and minor
 the amniotic fluid; the tin concentrations ranged from 0.001 to 1.279 μg/L.     amounts of lead by implantation in muscle tissues of the hind legs. The tin
 The study demonstrates that tin can pass into the foetal compartment            concentrations during a 53-week period decreased in the kidney and liver,
 from a very early stage in gestation, although it is noted that only trace      but increased in time in the testes and brain. The highest concentrations
 amounts were found.6                                                            of tin in whole blood were observed three weeks after implantation, then
                                                                                 declining to background levels 53 weeks after implantation.7
 In pregnant rats fed tin at 20 mg/kg bw/day as radioactive tin difluoride or
 tin tetrafluoride, no tin was found in foetal or placental tissues on day 10 of The profile of prenatal exposure to toxic elements and metals, including
 pregnancy. On day 21, foetuses of dams administered tin difluoride              tin, was assessed using the maternal blood, cord blood and placenta in
 apparently contained approximately 0.2% of the cumulative dose.                 the Tohoku Study of Child Development of Japan of n=594-650 pregnant
                                                                                 women. Tin was detected in 44% of the maternal blood samples (LOD =
21       Health Council of the Netherlands | No. 2022/27                                                                   2                                  23
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<pre> chapter 04 | Toxicokinetics and grouping                                                         Tin and selected inorganic tin compounds | page 23 of 97
 0.20 ng/ml) and in 36% of the cord blood samples, with a maximum              tin was cleared with a halftime of 4 days, a further 20% with a half-time of
 concentration measured of 8 ng/mL.8                                           25 days, and the remaining 60% with a longer half-time of 400 days.
                                                                               No further details were given. When nine healthy adults were given diets
 4.3      Biotransformation                                                    consisting of fresh foods (10 mg of tin per day), cold-stored canned foods
 Few data on biotransformation are available. The difference in the relative   (26 mg of tin per day), or warm-stored canned foods (163 mg of tin per
 affinity of the kidneys and liver for tin(II) and tin(IV) indicates a valence day) for 24 days, faecal excretion accounted for the whole dose, and none
 stability of the administered tin.9 Similarly, the difference observed        was detected in the urine.
 between tin dichloride and tin tetrachloride in their effects on the immune
 response in C57BL/6J mice also suggests that these two oxidation states       In laboratory animals, the small proportion of tin that is absorbed following
 are not readily interconverted in vivo.10 Together, the available data        ingestion is mainly excreted via the kidneys.
 suggest that tin cations are not rapidly oxidized or reduced during
 absorption and systemic transportation in mammals.                            For rat liver and kidney, the biological half-life of tin(II) has been
                                                                               estimated to be 10-20 days. For bone, the half-life of tin(II) and tin(IV) is
 44       Excretion                                                            approximately 20-100 days. A biological half-life of approximately 30 days
 Both faeces and urine are major routes of excretion of ingested tin in        was estimated for inorganic tin in mice, using a whole-body counting
 humans. Ingested tin is largely unabsorbed and excreted mainly in the         method.
 faeces. Absorbed tin is mainly excreted via the kidneys.
                                                                               4.5     Grouping
 In a mineral balance study, eight adult men ate food providing 0.11 mg or     The list of inorganic tin compounds is long and for most of the compounds
 50 mg of tin per day (as tin dichloride) for 20-day periods. Their urinary    specific toxicity data are lacking. Therefore, the Committee applies a
 excretion was 29 ± 13 μg/day (mean ± SD) and 122 ± 52 μg/day,                 grouping-approach.
 respectively, representing 36% and 2.4% of the dose, respectively.
 Mean faecal excretion accounted for 55% and 97% at the low and high           For each compound, information on reproduction toxicity, water solubility
 daily dose, respectively. A review stated that, in humans, 20% of absorbed    and the existence of a REACH registration dossier was collected.11
22        Health Council of the Netherlands | No. 2022/27                                                                2                                   24
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<pre> chapter 04 | Toxicokinetics and grouping                                                           Tin and selected inorganic tin compounds | page 24 of 97
 Reproduction toxicity data were collected based on the literature search           determines the bioavailability of the compounds, and thus also the
 and from the REACH registration dossiers when available.                           potential of inducing toxicity;
                                                                                 4. Reproductive toxicity data. For at least one of the grouped compounds,
 Second, criteria were set to be used for grouping of inorganic tin                 reproductive toxicity data are available for evaluation.
 compounds. For grouping of metals, solubility and ionic state have been
 identified as the main parameters (Guidances such as ECHA’s Read-               Applying the four criteria resulted in the selection of tin and 9 tin
 Across Assessment Framework (RAAF)).12                                          compounds and the following four groups:
                                                                                 1. Metallic tin;
 A selection of tin compounds was made based on the following criteria:          2. Tin sulphide, tin oxide, and ditin pyrophosphate (oxidation state 2+,
 1. Registration status. Only substances that are registered under REACH,           insoluble);
    implicating use of the substance within the EU, are included;                3. Tin dichloride, tin difluoride, tin sulphate, and tin(II) difluoroborate
 2. Oxidation state. Some studies suggest that effects of tin and inorganic         (oxidation state 2+, soluble);
    tin compounds can differ depending on the oxidation state. In mice, tin      4. Tin disulphide and tin dioxide (oxidation state 4+, insoluble).
    tetrachloride caused suppression of both IgM and IgG antibody
    production in a plaque forming test with spleen cells, whereas tin           The above grouping of tin compounds is only relevant for the evaluation of
    dichloride caused suppression of IgM and stimulation of IgG antibody         animal data. In the epidemiological studies, only elemental tin was meas-
    production.10 Also, a differential toxicity between dichloride tin           ured and the oxidation status was not determined.
    tetrachloride in fish has been observed.1 Further, a difference in the
    relative affinity of the kidneys and liver for tin dichloride and tin        An overview of all inorganic tin compounds considered is presented in
    tetrachloride is seen in rats.9 These observations suggest a valence         Table 8.
    stability and that tin cations are not rapidly oxidized or reduced during
    absorption and distribution in mammals;
 3. Water solubility. Inorganic tin compounds have low toxicity in general,
    partly due to their low solubility. The solubility of tin compounds (partly)
23       Health Council of the Netherlands | No. 2022/27                                                                     2                               25
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<pre> chapter 04 | Toxicokinetics and grouping                                                                         Tin and selected inorganic tin compounds | page 25 of 97
 Table 8a List of all inorganic tin compounds considered for this overview: selected inorganic tin compounds
  Chemical name                 Synonyms                                       Chemical formula CAS number  REACH registration Reproduction    Oxidation state Solubility in water
                                                                                                            dossier            toxicity data
  Tin                                                                          Sn               7440-31-5   +                  +                               Insoluble
  Tin sulphide                  Tin(II) sulphide, stannous sulphide; tin       SnS              1314-95-0   +                  +               2+              Insoluble
                                monosulphide
  Tin monoxide                  Tin(II) oxide, tin oxide; stannous oxide       SnO              21651-19-4  +                  -               2+              Insoluble
  Ditin pyrophosphate           Tin(II) pyrophosphate, stannous pyrophosphate  Sn2P2O7          15578-26-4  +                  -               2+              Insoluble
  Tin dichloride                Tin(II) chloride, stannous chloride, stannous  SnCl2            7772-99-8   +                  +               2+              Soluble
                                chloride dihydrate
  Tin difluoride                Tin(II) fluoride, stannous fluoride            SnF2             7783-47-3   +                  -               2+              Soluble
  Tin sulphate                  Tin(II) sulphate, stannous sulphate            SnSO4            7488-55-3   +                  -               2+              Soluble
  Tin(II) difluoroborate        Stannous fluoroborate                          Sn(BF4)2         13814-97-6  +                  -               2+              Soluble
  Tin disulphide                Tin(IV) sulphide, stannic sulphide             SnS2             1315-01-1;  +                  +               4+              Insoluble
                                                                                                12738-87-3
  Tin dioxide                   Tin(IV) oxide; stannic oxide                   SnO2             18282-10-5  +                  -               4+              Insoluble
 Table 8b List of all inorganic tin compounds considered for this overview: compounds considered but not selected for grouping
  Chemical name                 Synonyms                                       Chemical formula CAS number  REACH registration Reproduction    Oxidation state Solubility in water
                                                                                                            dossier            toxicity data
  Stannane                                                                     SnH4             2406-52-2    -                 -                               Soluble / very soluble
  Disodium tin trioxide         Sodium stannate                                Na2SnO3          12058-66-1;  +                 -               4+              Soluble
  Disodium tin hexahydroxide    Sodium stannate trihydrate                     Na2Sn(OH)6       12027-70-2;  +                 -               4+              Soluble
  Potassium stannate            Dipotassium tin trioxide                       K2SnO3           12142-33-5   -                 -               4+              Very soluble
  Potassium stannate trihydrate Potassium stannate trihydrate; dipotassium tin K2Sn(OH)6        12125-03-0   -                 -               4+              Soluble/miscible
                                trioxide trihydrate
  Sodium pentachlorostannite    Sodium chlorostannite                          NaSn2Cl5         102696-35-5  -                 -               2+              -
  Sodium hexachlorostannate     Sodium chlorostannate                          Na2SnCl6         Not found    -                 -               4+              -
  Sodium pentafluorostannite    Sodium fluorostannite                          NaSn2F5          22578-17-2   -                 -               2+              -
  Sodium tin citrate            Sodium stannous citrate                        C12H10Na2O14Sn   Not found    -                 -               4+              -
  Tin(II) bromide               Tin dibromide; stannous bromide                SnBr2            10031-24-0   -                 -               2+              -
  Tin(IV) bromide               Tin tetrabromide; stannic bromide              SnBr4            7789-67-5    -                 -               4+              Soluble
  Tin(IV) chloride              Tin tetrachloride; stannic chloride            SnCl4            7646-78-8    -                 -               4+              Soluble
24           Health Council of the Netherlands | No. 2022/27                                                                                 2                                      26
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<pre> chapter 04 | Toxicokinetics and grouping                                                                        Tin and selected inorganic tin compounds | page 26 of 97
  Chemical name                 Synonyms                                       Chemical formula CAS number REACH registration Reproduction    Oxidation state Solubility in water
                                                                                                           dossier            toxicity data
  Tin(IV) chloride iodide       Tin dichloride diiodide; stannic dichloride    SnCl2I2          13940-16-4 -                  -               4+              Soluble
                                diiodide
  Tin(IV) chloride pentahydrate Stannic chloride pentahydrate                  SnCl4∙5H2O       10026-06-9 -                  -               4+              Very soluble
  Tin(IV) chromate              Stannic chromate                               Sn(CrO4)2        38455-77-5 -                  -               4+              Soluble
  Tin(II) citrate               Stannous citrate; tritin dicitrate             Sn3((HO)C(COO)-  59178-29-9 -                  -               2+              -
                                                                               (CH2COO))2
  Tin(IV) citrate               Stannic citrate                                H2N4O12Sn        Not found  -                  -               4+              -
  Tin(IV) fluoride              Stannic fluoride, tin tetrafluoride            SnF4             7783-62-2  -                  -               4+              Soluble
  Tin(II) hydroxide             Stannous hydroxide; tin dihydroxide            Sn(OH)2          12026-24-3 -                  -               2+              -
  Tin(IV) hydroxide             Stannic hydroxide; tin tetrahydroxide          Sn(OH)4          12054-72-7 -                  -               4+              -
  Tin(IV) iodide                Tin tetraiodide; stannic iodide                SnI4             7790-47-8  -                  -               4+              Soluble
  Tin(II) nitrate               Stannous nitrate                               Sn(NO3)2         Not found  -                  -               2+              -
  Tin(IV) nitrate               Stannic nitrate                                Sn(NO3)4         13826-70-5 -                  -               4+              -
  Tin(II) orthophosphate        Tritin bis(orthophosphate); stannous phosphate Sn3(PO4)2        15578-32-2 -                  -               2+              -
  Tin(IV) orthophosphate        Stannic phosphate                              Sn3(PO4)4        Not found  -                  -               4+              -
  Tin monophosphide             Tin(IV) phosphide; stannic phosphide           SnP              25324-56-5 -                  -               2+              -
  Tin triphosphide              Tetratin triphosphide                          Sn4P3            12286-33-8 -                  -                               -
  Tin(II) phytate               Stannous phytate                               Not found        Not found  -                  -               2+              -
  Tin(IV) sulphate              Stannic sulphate                               Sn(SO4)2         19307-28-9 -                  -               4+              -
  Tin(II) telluride             Tin(II) telluride, stannous telluride          SnTe             12040-02-7 -                  -               2+              -
25           Health Council of the Netherlands | No. 2022/27                                                                                2                                     27
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<pre> chapter 05 | Adverse effects on sexual function and fertility Tin and selected inorganic tin compounds | page 27 of 97
 05
 adverse effects on
 sexual function and fertility
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<pre> chapter 05 | Adverse effects on sexual function and fertility                                                                   Tin and selected inorganic tin compounds | page 28 of 97
 Adverse effects reported in animal studies are statistically significant (p<0.05), unless specified otherwise.
 5.1        Animal data
 Table 9a Summary table of animal studies on adverse effects on sexual function and fertility. Group 1: Metallic tin
  Reference     Species             Experimental period and design                                      Dose and route                    General toxicity       Effects on reproductive     Remark
                                                                                                                                                                 organs or reproduction
  ECHA          Wistar rats, males  Reproduction / developmental toxicity screening test according to   Test material: tin metal powder   No treatment-related   No effects on mating        Study is
  Registration  and females, 10/    OECD Guideline 421                                                  (2-11 µm)                         adverse effects on     performance, conception     reported to
  dossier13     sex/group                                                                                                                 parental animals       rates, gestation length or  comply with
                                    Daily treatment:                                                    Purity: not reported                                     parturition                 GLP
                Control group:      Females: 14 days pre-mating, mating (days not specified),                                             Males treated with
                ten males and ten   gestation and 5 days postpartum                                     Route of exposure: oral, gavage   1,000 mg/kg/day        Group mean corpora          Only a study
                females, dosed      Males: 43 days (starting at pre-mating)                                                               showed a statistically lutea, implantation counts, summary is
                with vehicle alone                                                                      Exposure levels: 0 (vehicle),     significant increase   and implantation losses     available for
                (1% (w/v) aqueous   Duration of exposure: 56 days                                       100, 300 and 1,000 mg/kg bw/      in bodyweight gain     all indicated no effect of  evaluation
                carboxy                                                                                 day                               during Week 3          maternal exposure
                methylcellulose     Effect parameters: maternal examinations, ovarine and uterine
                (sodium salt))      content including gravid uterus weight, number of corpora lutea,
                                    number of implantations and pre- and post-implantation loss indices
                                    Statistical analysis: not reported
  Naser et al., Wistar rats, males, 30-day exposure of rats to nanoparticles of silver, copper, zinc    Test material: tin nanoparticles. No data reported       Increased concentrations    No guideline
  202014        6 animals/group     oxide, cadmium oxide or tin                                         Average diameter is 67.34 nm                             of LH, FSH and              study. No
                                                                                                                                                                 testosterone compared to    information on
                Control: deionized  Parameters: luteinizing hormone (LH), follicle stimulating hormone  Route of exposure: oral gavage                           control levels              GLP. No
                water only          (FSH) and testosterone, measured in blood                                                                                                                method
                                                                                                        Exposure level: 0.3 mL per day                                                       described on
                                    Statistical analysis: ANOVA one-way                                 for 30 days, concentration is                                                        hormone
                                                                                                        53.45 ppm (corresponding to                                                          analysis in the
                                                                                                        53-64 µg/kg bw/day)                                                                  blood.
                                                                                                        Total experiment includes 6                                                          Limited
                                                                                                        groups: 1 control group and 5                                                        number of
                                                                                                        groups for each of the metals                                                        animals
                                                                                                        tested
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<pre> chapter 05 | Adverse effects on sexual function and fertility                                                                      Tin and selected inorganic tin compounds | page 29 of 97
 Table 9b Summary table of animal studies on adverse effects on sexual function and fertility. Group 2: Inorganic tin compounds; oxidation state 2+, insoluble
  Reference       Species             Experimental period and design               Dose and route                   General toxicity              Effects on reproductive organs or             Remark
                                                                                                                                                  reproduction
  Study           Wistar rats, males  Reproduction / Developmental Toxicity        Test material: tin sulphide      Parental males: increased     Parental males: microscopical changes in Study in
  report15, 26    and females, 12     Screening Test (OECD 421)                                                     absolute weight of pituitary  structure of the testes (sporadic             compliance with
                  animals/sex/dose                                                 Analytical purity: ca. 97.6%     gland in males at the dose    degeneration and/or atrophy of germ           GLP.
                                      Daily administration for the following       (77.5% Sn, 20.1% S)              level of 1,000 mg/kg bw/day   epithelium, residual bodies in germ
                  Control: concurrent periods:                                                                                                    epithelium and vacuolation of cytoplasm
                  vehicle (0.5%       • males and females: 2 weeks prior to        Route of exposure: oral gavage   No changes of microscopic     of spermiogonia) at 1,000 mg/kg bw/day
                  methylcellulose in    the mating period and during the           Exposure levels: 0, 100, 300 and structure of the pituitary
                  water)                mating period                              1,000 mg/kg bw/day               gland                         No effect on sperm parameters were
                                      • pregnant females: during pregnancy                                                                        observed.
                                        and till the 3rd day of lactation                                           Parental females: no
                                      • males: after mating period; totally for 42                                  significant treatment-related Parental females: no significant
                                        days                                                                        effects                       treatment-related effects
                                      • non-pregnant females (mated females
                                        without parturition): for 25 days after                                                                   Reproductive performance: no effect on
                                        the confirmed mating                                                                                      the ability of male and female animals to
                                                                                                                                                  successfully mate and produce viable
                                      Parameters: observations and                                                                                offspring
                                      examinations parental animals, phases of
                                      the oestrous cycle (recorded during                                                                         No effect on sex ratio and development
                                      histopathological examination), sperm                                                                       of pups
                                      motility and sperm morphology, litter
                                      observations (behaviour, number and sex                                                                     F1 generation: decreased number of
                                      of pups, stillbirths, live births and                                                                       corpora lutea, implantations and number
                                      presence of gross anomalies), post-                                                                         of pups (not statistically significant), most
                                      mortem examinations parental animals                                                                        notably at dose levels 300 and 1,000 mg/
                                      and offspring                                                                                               kg/day).
                                      Statistical analysis: the ANOVA test                                                                        No effect on sex ratio
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<pre> chapter 05 | Adverse effects on sexual function and fertility                                                                                      Tin and selected inorganic tin compounds | page 30 of 97
 Table 9c Summary table of animal studies on adverse effects on sexual function and fertility. Group 3: Inorganic tin compounds; oxidation state 2+, soluble
   Reference         Species                Experimental period and design                  Dose and route                              General toxicity                          Effects on reproductive      Remark
                                                                                                                                                                                  organs or reproduction
   EFSA, 201816;     CPB:WU rats, 10        Multigeneration study                           Test material: tin dichloride, reacting     No maternal effects were noted            No effect on mating (14-16   Not according to
   WHO, 20051;       males/group 20                                                         in aqueous medium with the casein                                                     of 20 females in each group  current guidelines.
   ECHA              females/group          Daily administration via diet                   content of the diet to simulate                                                       successful) and pregnancy    Based on abstracts
   Registration                             Mating after 12 and 20 weeks (1 male/2          exposure through canned food                                                          (14-15/20 in all groups)     only; original study
   dossier17                                females) leading to F1A and F1B                                                                                                                                    by Sinkeldam et al.
                                            generation                                      Exposure levels: 0, 200, 400, or 800                                                  Increased mortality in F2    (1979) not
                                                                                            ppm in diet, equivalent to 0, 10, 20,                                                 generation during lactation  available
                                            F1B generation was used to produce F2A or 40 mg tin/kg                                                                                (iron deficiency of maternal
                                            and F2B generation                                                                                                                    animals)
   NTP, 198218       F344/N rats, males     13-week toxicity study                          Test material: tin dichloride, CAS          No treatment related mortality            No effects on reproductive   Dose range finding
                     and females, 10/                                                       7772-99-8                                   Mean body weight gain >10% lower          organs                       study
                     sex/group              Duration of exposure: 13 weeks                                                              in the rats receiving the highest
                                            Parameters: mortality, clinical                 Purity: not specified                       dose, compared to controls
                     Control group:         examination, body weight, feed
                     diet only              consumption, necropsy, histopathology           Route of exposure: oral, feed               Gross distention of the cecum and
                                                                                                                                        reddened gastric mucosa in
                                            Microscopy included mammary gland,              Exposure levelsa: 0, 500, 1000,             70%-100% of all rats receiving 3800
                                            seminal vesicles, prostate, testes, ovaries 1,900, 3,800 and 7,500 ppm,                     or 7500 ppm, but no compound-
                                            and uterus                                      equivalent to 0, 20, 40, 76, 152 and        related histopathologic effects in the
                                                                                            316 mg/kg bw/day for males and 0,           cecum or stomach or in any other
                                                                                            25, 50, 95, 190 and 395 mg/kg bw/           tissues examined
                                                                                            day for females
   NTP, 198218       F344/N rats, males     Carcinogenesis bioassay                         Test material: tin dichloride, CAS          Survival of high-dose male rats was       No effects on reproductive   Study aimed at
                     and females, 50/                                                       7772-99-8                                   somewhat lower than that of the           organs were observed         determining
                     sex/group              Duration of exposure: 105 weeks                                                             control and low-dose groups                                            carcinogenicity
                                                                                            Purity: not specified
                     Control group:         Parameters: mortality, clinical                                                             (37/50, control; 39/50, low-dose;
                     diet only              examination, body weight, feed                  Route of exposure: oral, feed               30/50, high-dose)
                                            consumption, necropsy, histopathology.          Exposure levels: 0, 1,000 and 2,000
                                            Microscopy included mammary gland,              ppm, equivalent to 0, 40 and 80 mg/
                                            seminal vesicles, prostate, testes, ovaries     kg bw/day for males and 0, 50 and
                                            and uterus                                      100 mg/kg bw/day for females
 a
    1 ppm is equivalent to 0.04 mg/kg bw/day for male rats and 0.05 mg/kg bw/day for female rats, based on the default values as reported in ECHA guidance R.8, version 2.1, Table 8-17.
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<pre> chapter 05 | Adverse effects on sexual function and fertility                                                                                     Tin and selected inorganic tin compounds | page 31 of 97
   Reference         Species                Experimental period and design                  Dose and route                              General toxicity                          Effects on reproductive    Remark
                                                                                                                                                                                  organs or reproduction
   NTP, 198218       B6C3F1/N mice,         13-week toxicity study                          Test material: tin dichloride, CAS          No mortality observed                     No effects on reproductive Dose range finding
                     males and females,                                                     7772-99-8                                                                             organs                     study
                     10/sex/group.          Duration of exposure: 13 weeks                                                              A pronounced reduced relative
                                                                                            Purity: not specified                       weight gain in the highest dose
                     Control group:         Parameters: mortality, clinical                                                             group (56% in males; 32% in
                     diet only              examination, body weight, feed                  Route of exposure: oral, feed               females)
                                            consumption, necropsy, histopathology.
                                            Microscopy included mammary gland,              Exposure levelsa: 0, 1,900, 3,800,          A dose-dependent increase in
                                            seminal vesicles, prostate, testes, ovaries     7,500, 15,000 and 30,000 ppm,               incidence of mice with distended
                                            and uterus                                      equivalent to 0, 228, 456, 900, 1,800       cecum from 3,800 ppm and higher
                                                                                            and 3,600 mg/kg bw/day for males
                                                                                            and 0, 247, 494, 975, 1,950 and             No compound-related
                                                                                            3,900 mg/kg bw/day for females              histopathological effects detected in
                                                                                                                                        the cecum
   NTP, 198218       B6C3F1/N mice,         Carcinogenesis bioassay                         Test material: tin dichloride, CAS          No effects on body weight                 No effects on reproductive Study aimed at
                     males and females,                                                     7772-99-8                                                                             organs                     determining
                     50/sex/group.          Duration of exposure: 105 weeks                                                             Survival of the control group was                                    carcinogenicity
                                                                                            Purity: not specified                       lower compared to the treatment
                     Control group:         Parameters: mortality, clinical                                                             groups in males
                     diet only              examination, body weight, feed                  Route of exposure: oral, feed
                                            consumption, necropsy, histopathology.
                                            Microscopy included mammary gland,              Exposure levels: 0, 1,000 and 2,000
                                            seminal vesicles, prostate, testes, ovaries     ppm, equivalent to 0, 120 and 240
                                            and uterus                                      mg/kg bw/day for males and 0, 130
                                                                                            and 260 mg/kg bw/day for females
 a
    1 ppm is equivalent to 0.04 mg/kg bw/day for male rats and 0.05 mg/kg bw/day for female rats, based on the default values as reported in ECHA guidance R.8, version 2.1, Table 8-17.
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<pre> chapter 05 | Adverse effects on sexual function and fertility                                                                     Tin and selected inorganic tin compounds | page 32 of 97
  Reference      Species              Experimental period and design             Dose and route                         General toxicity                Effects on reproductive       Remark
                                                                                                                                                        organs or reproduction
  Yousef, 200519 New Zealand White Treatment: every other day for 12 weeks       Test material: tin dichloride (SnCl2). No effect on body weight        Decreased relative testes     No measurement
                 rabbits, males, 7                                               Purity: 97.0%                                                          weight (control 0.187 g/100g  of tissues other
                 months old, 6/       Parameters: volume of ejaculate, sperm                                                                            bw; treated 0.149 g/100g      than testes and
                 group                concentration, fructose concentration in   Animals treated with or without                                        bw) and relative epididymis   epididymis
                                      seminal plasma. Assessment of live and     ascorbic acid (Vitamin C)                                              weight (control 0.069 g/100g
                 Control group: 6     normal spermatozoa and weight of testes                                                                           bw; treated 0.055 g/100g      No clinical
                 animals, not further and epididymis.                            Exposure route: oral, inserted                                         bw)                           observations,
                 specified                                                       directly into the oesopharyngeal                                                                     clinical
                                      Statistical analysis: General Linear Model region                                                                 Decrease in the overall       biochemistry or
                                      (GLM) procedure using SAS statistical                                                                             means of sperm parameters     (histo)pathology
                                      package. Variations between means          Exposure level: 20 mg/kg bw                                            (ejaculate volume (EV),
                                      were compared by Duncan’s Multiple                                                                                sperm concentration, total    Only one dose
                                      Range Test                                                                                                        sperm output (TSO), sperm     tested
                                                                                                                                                        motility (%), total motile
                                                                                                                                                        sperm per ejaculate (TMS),    No data on
                                                                                                                                                        packed sperm volume           reproductive
                                                                                                                                                        (PSV), total functional sperm outcome
                                                                                                                                                        fraction (TFSF), normal
                                                                                                                                                        sperm, initial fructose), and Not according to
                                                                                                                                                        a decrease in the reaction    GLP; limited
                                                                                                                                                        time during mating            number of animals
                                                                                                                                                        Increase in dead sperm and
                                                                                                                                                        initial hydrogen ion
                                                                                                                                                        concentration (pH)
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<pre> chapter 05 | Adverse effects on sexual function and fertility                                                                   Tin and selected inorganic tin compounds | page 33 of 97
 Table 9d Summary table of animal studies on adverse effects on sexual function and fertility. Group 4: Inorganic tin compounds; oxidation state 4+, insoluble
  Reference      Species            Experimental period and            Dose and route                   General toxicity            Effects on reproductive organs or reproduction                    Remark
                                    design
  Bai et al,     ICR mice, males,   Treatment: 4 weeks                 Test material: Three different   No apparent changes in      Morphology testes: no changes in the 200 nm group but a
  201820         10/group                                              sizes of tin disulphide (SnS2)   growth, activity, or        moderate intertubular oedema and a mild interstitial infiltration
                                    Animals were exposed by            nanoflowers (diameters of 50,    performance of the mice     of inflammatory cells in testes of mice treated with 50 and
                 Total: 70 males (7 gavage 6 times a week, for 4       80, and 200 nm) with high purity                             80nm tin disulphide nanoflowers
                 groups)            weeks                              (not specified)                  Gradual increase in body
                                                                                                        weight in the 4 groups      A dose-dependent increase in tin levels were observed in all
                 Control group:     The content of tin was             Route of exposure:               with varying sizes          examined tissues
                 de-ionized water   determined in liver, kidney,       intraperitoneal injection        (control, 50 nm, 80 nm,
                 without tin        spleen, heart, brain, testicle and                                  200 nm), but without        Sperm count and sperm survival mildly decreased in mice in
                 disulphide flowers whole blood                        Exposure levels: variations in   statistical significance    the 50 and 80 nm groups
                                                                       size and in dose level:
                                    The sperm count and survival       • 38 mg/kg, 50 nm                                            Sperm count and sperm survival percentages mildly
                                    rate were measured                 • 38 mg/kg, 80 nm                                            decreased in the 38 mg/kg group (50 nm), but not in the 0.38
                                                                       • 38 mg/kg, 200 nm                                           and 3.8 mg/kg groups
                                    Analysis of the testes:            • 0.38 mg/kg, 50 nm
                                    morphological analysis, TUNEL      • 3.8 mg/kg, 50 nm                                           Blood testes barrier (BTB) relevant gene expression: changes
                                    assay and Caspase-3 staining       • 38 mg/kg, 50 nm                                            in expression of several genes and expression of TGF-β3
                                    for determining apoptotic rates,   • control group                                              protein in the 38 mg/kg group with 50 and 80 nm tin
                                    ultrastructure observation by                                                                   disulphide nanoflowers, but not in the other groups
                                    transmission electron
                                    microscopy (TEM),                                                                               TEM analysis: vacuolation of the seminiferous epithelium in
                                    measurement of                                                                                  affected tubules, especially near the rete, revealing a
                                    malondialdehyde level and                                                                       breakdown in Sertoli-germ cell junctions in the 50 nm and 80
                                    superoxide dismutase activity to                                                                nm groups (dose: 38 mg/kg)
                                    evaluate oxidative stress,
                                    immunohistochemistry, Q-PCR                                                                     Oxidative stress: elevated malondialdehyde level and
                                    and Western blotting                                                                            decreased superoxide dismutase activity in the tin disulphide
                                                                                                                                    NFs (dose: 38 mg/kg; size: 50 and 80nm) treated groups
                                    Statistical analysis:
                                    The chi-squared test for sperm                                                                  Apoptosis: apoptosis was induced in the 50 and 80 nm
                                    survival rates data, and one-way                                                                groups (dose: 38 mg/kg)
                                    analysis of variance (ANOVA)
                                    test for other data                                                                             Testicular inflammation: signs of inflammation in the 50 and
                                                                                                                                    80 nm groups (dose: 38 mg/kg) by immunohistochemistry and
                                                                                                                                    expression of key inflammatory cytokine and enzymes
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<pre> chapter 05 | Adverse effects on sexual function and fertility                                 Tin and selected inorganic tin compounds | page 34 of 97
 OECD 421 study with tin powder (only abstract available)                   no effects on food consumption. No effects of tin metal powder exposure
 Tin metal powder (2-11 µm) was administered by gavage to male and          on mating performance, conception rates, gestational length, or parturition
 female Wistar rats (10 animals/group) in compliance with OECD guideline    were observed.
 421 (Reproduction/developmental toxicity screening test).13 Rats were
 exposed for up to 56 consecutive days (including a two-week maturation     30-day study with tin nanoparticles (Naser et al., 2020)
 phase, pairing, gestation and early lactation for females) to 100, 300 and The effect of nanoparticles of tin on sexual hormones was investigated in
 1,000 mg/kg bw/day tin metal powder. A control group was dosed with        rats (6 animals/group).14 Male Wistar rats were exposed for 30 days to low
 vehicle alone (1% (w/v) aqueous carboxy methylcellulose (sodium salt)).    levels of tin nanoparticles (average diameter: 67.34 nm) at 0.3 mL per day,
 Clinical signs, bodyweight development, dietary intake and water           with a concentration of 53.45 ppm (corresponding to 53-64 µg/kg bw/day).
 consumption were monitored during the study. The parental rats were        At the end of the experimental period, blood was collected and the
 paired one to one from day 15 of treatment and females were allowed to     concentrations of luteinizing hormone (LH), follicle-stimulating hormone
 litter and rear young to day 5 post-partum. During the lactation phase,    (FSH) and testosterone were measured. The concentrations of LH, FSH
 daily clinical observations were performed on all surviving offspring,     and testosterone were significantly increased compared to levels (P<0.05)
 together with litter size and offspring weights and assessment of surface  in the control group. Results were given in figures; no absolute number
 righting reflex. Adult males were euthanised on Day 43, and all females    were presented.
 and surviving offspring on Day 5 post-partum. All animals were subjected
 to a gross necropsy examination and histopathological evaluation of        OECD 421 study with tin sulphide
 reproductive tissues was performed.                                        A reproduction/developmental toxicity screening test, according to OECD
                                                                            421, was performed with male and female Wistar rats (12 animals/
 There were no deaths and no significant clinical signs of toxicity.        group).15,26 The animals were treated with 0, 100, 300 and 1,000 mg/kg
                                                                            bw/day tin sulphide via oral gavage at daily basis.
 Males treated with 1,000 mg/kg bw/day showed a statistically significant
 increase in bodyweight gain during Week 3 (results not presented           No relevant clinical changes were observed in males at all dose
 quantitatively). Female body weight (gain) was unaffected. There were      levels. A slight reduction of weight (one male at the dose level of
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<pre> chapter 05 | Adverse effects on sexual function and fertility                                     Tin and selected inorganic tin compounds | page 35 of 97
 100 mg/kg bw/day in the 6th week) and thinner excrements (one male at          higher than the control groups. Duration of mating and pregnancy
 the dose of 1,000 mg/kg bw/day in the first week) were observed                were similar in the control and treated females. Pre-implantation,
 sporadically in treated males. Slight decreases in body weights were           post-implantation and postnatal losses were relatively well balanced
 sporadically (in 1 or 2 females from the group) recorded in the 3rd week       at the treated groups and control group.
 at all groups including control. In treated females at all dose levels, no
 signs of disease were found during the check-in, acclimatization and           Average numbers of pups per litter were well-balanced at the control and
 application period. Treatment-related effects were not detected during         the dose level 100 mg/kg bw/day. At the dose levels 300 and 1,000 mg/kg
 health condition control and clinical observation of females (except of        bw/day, the average number of pups per litter was decreased compared to
 vocalization in one female at the dose level of 1,000 mg/kg/day in the         the control, however they fell within the normal range of historical control
 5th week). There were no unscheduled deaths during the study and no            data.
 treatment-related effects on body weight and food consumption.
                                                                                Multigeneration study with tin dichloride (only abstracts available)
 Effects were observed in the pituitary gland of males and in the testes.       In a multigeneration reproduction study including 3 generations, rats
 A statistically significant increase in absolute pituitary weight was detected (20 females and 10 males/group/generation) were exposed to levels of
 in males at 1,000 mg/kg bw/day. No changes of microscopic structure of         0 (control), 200, 400 or 800 ppm (0, 10, 20 or 40 mg/kg bw/day) tin in the
 the pituitary gland were found. Histopathological examination of testes of     diet (WHO, 20051; EFSA 201816; ECHA 202217). To simulate tin exposure
 parental males showed increased incidence of degenerations and/or              from canned food, tin chloride was allowed to react in aqueous medium.
 atrophies of germ epithelium and vacuolations of cytoplasm of                  The iron content in the diet was increased for the F2 generation onwards
 spermatogonia in males of the dose level 1,000 mg/kg bw/day.                   (from initially 70 mg Fe/kg diet to 140 mg Fe/kg diet). In this study, no
 No effect on sperm parameters were observed.                                   maternal effects were noted and no differences in the percentages of
                                                                                mated males and females and subsequent pregnancies were observed
 Reproduction parameters – number of females achieving pregnancy,               between the groups.
 number of females bearing live pups and number of females with live pups
 at day 4 after parturition – in treated groups were similar to the control or
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<pre> chapter 05 | Adverse effects on sexual function and fertility                                 Tin and selected inorganic tin compounds | page 36 of 97
 13-week study and carcinogenesis bioassay with tin dichloride              for females. In both the 13-week study and the carcinogenicity bioassay,
 (NTP, 1982)                                                                no adverse effects were observed in the reproductive organs upon
 The carcinogenicity of tin dichloride was examined in an NTP               treatment with tin dichloride.
 carcinogenesis bioassay, preceded by a 13-week toxicity study.18
 Both studies were performed with male and female F344/N rats and male      12-week study with tin dichloride (Yousef, 2005)
 and female B6C3F1/N mice (10 animals/group in the 13-week studies,         The protective role of ascorbic acid on reproductive performance of male
 50 animals/group in the carcinogenicity bioassays).                        New Zealand White rabbits treated with tin dichloride was studied by
                                                                            Yousef (2005).19 Rabbits (6 animals/group) were treated with 20 mg/kg bw
 Rats were exposed to 0, 20/25, 40/50, 76/95, 152/190 and 300/375 mg/kg     tin dichloride, 40 mg/kg bw ascorbic acid or a combination of both
 bw/day (males/females) tin dichloride for 13 weeks via diet.               treatments. A control group (6 animals) was included but not specified.
 Mortality, clinical signs, body weight, feed consumption, necropsy and     Treatment was performed every other day for 12 weeks, by gavage.
 histopathology were examined. Microscopy included examination of the       Daily feed intake and body weight were recorded weekly. Sperm collection
 mammary gland, seminal vesicles, prostate, testes, ovaries and uterus.     occurred weekly over the 12 weeks of the study and was used to measure
 No treatment-related adverse effects were reported on the reproductive     the volume of each ejaculate, the sperm concentration, fructose
 organs. In the chronic study, the rats were exposed to 0, 40/50 and 80/100 concentration in seminal plasma, and assessment of live and normal
 mg/kg bw/day (males/females) tin dichloride for 105 weeks. Examination     spermatozoa. The weight of the testes and epididymis was recorded.
 of organs included the mammary gland, seminal vesicles, prostate, testes,  Only results from the control group and the tin dichloride exposure group
 ovaries and uterus. No neoplastic or non-neoplastic adverse effects were   are described here.
 found in these organs upon treatment with tin dichloride.
                                                                            Exposure to tin dichloride did not change the body weight or feed intake.
 Mice were treated with tin dichloride for 13 weeks at a dose level of 0,   The relative weight of testes and epididymis was statistically significantly
 228/247, 456/494, 900/975, 1,800/1,950 and 3,600/3,900 mg/kg bw/day        decreased in rabbits treated with tin dichloride compared to control
 (males/females), via diet. In the chronic study, the dose levels were 0,   animals. Most sperm parameters (volume, concentration, output, motility,
 120 and 240 mg/kg bw/day for males and 0, 130 and 260 mg/kg bw/day         functional fraction) were decreased compared to the control group.
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<pre> chapter 05 | Adverse effects on sexual function and fertility                                   Tin and selected inorganic tin compounds | page 37 of 97
 The percentage of dead sperm was increased in the treated group.             inflammation responses were seen in the same treatment groups.
 Overall, effects were observed on testes and epididymis weight and on        Also ultrastructural abnormalities were more severe than those formed by
 sperm parameters. It is noted that only the testes and epididymis were       the large-sized tin disulphide particles in testes. It is noted that results
 assessed (no other organs) and that no other clinical observations, clinical were presented in figures; no quantitative data were available.
 biochemistry or (histo)pathology was performed. Only one dose was
 tested in this study.
 4-week study with tin disulphide (Bai et al., 2018)
 In a 4-week study, ICR mice (10 animals/group) were exposed via
 intraperitoneal injection to three different sized tin disulphide (SnS2)
 nanoflowers and to different dose levels to investigate the effect on the
 testes.20 Three groups were exposed to 38 mg/kg bw of 50, 80, or 200 nm
 tin disulphide nanoflowers, and three groups were exposed to 0.38, 3.8, or
 38 mg/kg bw tin disulphide nanoflowers (50 nm). The animals were
 exposed by injection 6 times a week, continued for 4 weeks. Nanoflowers
 are a newly developed class of nanoparticles showing a structure similar
 to flower.
 No apparent changes in growth, activity, or performance of the mice were
 seen upon treatment. The results of sperm count and survival analysis,
 histopathological evaluation, and qRT-PCR analysis showed that
 apparently size-dependent, moderate toxicity was induced in the group
 of 50 and 80 nm tin disulphide nanoflowers (dose: 38 mg/kg bw) in testicle
 tissues. Furthermore, signs of oxidative stress, apoptosis and
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<pre> chapter 05 | Adverse effects on sexual function and fertility                                                                        Tin and selected inorganic tin compounds | page 38 of 97
 5.2       Human data
 An overview of the human studies on adverse effects on sexual function and fertility is provided in Table 10. These studies include cross-sectional
 studies only.
 Table 10 Summary table of human data on adverse effects on sexual function and fertility.
  Reference     Population and study        Exposure assessment and statistical analyses Health assessment                         Results on sexual function     Bias and confounding              Remarks
                design                                                                                                             and fertility
  Wang, et al   Design:                     Exposure assessment:                                 Semen quality tested in fresh     Group with at least one sperm  For tin concentration in          The study
  (2017)21      cross-sectional study       • Tin and 17 other metals in seminal plasma;         semen (using computer-aided       quality abnormality versus     semen, approximately one          population is
                                            • Semen specimen produced at clinic visit, after     semen analyser):                  group without abnormalities:   third of samples below LOQ        the same as in
                Study location:               2-7 days abstinence;                               • Volume, progressive sperm       • No difference in tin         (risk of exposure                 Wang, et al
                subjects recruited at       • Measured by ICP-MS, reported in micrograms           motility, non-progressive         geometric mean               misclassification)                (2016), but a
                reproductive medicine         per litre semen, μg/L;                               sperm motility, total motility,   concentration in seminal                                       lower number of
                centre in Wuhan, China      • Limit of quantification (LOQ) for tin: 0.020 μg/L;   total sperm count, sperm          plasma                       Number of days of abstinence      participants was
                                              % > LOQ: 57%.                                        concentration, sperm                                           in 3 categories: <3; 3-5; >5,     included due to
                Study period: 2013                                                                 morphology ;                    Association between tin level  but might be too crude            extra exclusion
                                            Statistical analysis:                                • Quality measures were           in semen (<60 (<LOQ), 60-80,                                     criteria (semen
                Population: 1247 men,       • Multivariable: linear and logistic regression to     dichotomized based on           >80 percentiles, and %         Smoking included both as          volume)
                aged 18-55 yrs, from          estimate associations between metals and             WHO reference values;           necrotic spermatozoa; p-trend  continuous variable (cigarette
                subfertile couples visiting   outcomes; Tin in three equally-sized categories: • Sperm apoptosis reported          = 0.03, adjusted for FDR and   consumption) and categorical
                fertility centre              <LOQ, middle, and high exposure;                     as % necrotic, % apoptotic      adjustment for multiple metals (current or former/never).
                                            • Logistic regression to estimate associations         and % viable spermatozoa;       and covariables.
                Exclusion criteria:           between metal levels and dichotomized              • Sperm DNA-damage,                                              Sperm quality measurement
                azoospermia (n=58),           outcomes (sperm quality using WHO reference          reported as tail DNA %, tail    Chosen percentiles (<60,       in same sample as tin
                occupational exposure to      values as cut-off);                                  length, and tail distributed    60-80, >80) were different     measurement: an ex vivo
                metals (n=16), self-        • Covariables (obtained by questionnaire during        moment.                         than for the other metals,     direct effect of tin on sperm (in
                reported disease with         centre visit): age, BMI, abstinence duration,                                        indicating that cut-offs were  contrast to the effect on
                possible adverse effect on    time between semen ejaculation and analysis,       Not all measurements done in      data-based.                    spermatogenesis due to
                the reproductive system or    daily number of cigarettes smoked, smoking         all subjects: for spermatozoa                                    chronic exposure) cannot be
                urinary excretion of          (current, former, never), having ever fathered a apoptosis n=331, for DNA                                           excluded
                chemicals (n=121).            pregnancy, education category, and alcohol         integrity n=404.
                Among the remaining           consumption;
                1052 subjects, semen        • Models with multiple metals were constructed
                volumes were inadequate       on the basis of statistical significance in single
                in n=306.                     metal models;
                                            • Benjamini-Hochberg method (with false
                Final population: n=746       discovery Rate (FDR)) used to account for
                                              multiple testing.
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<pre> chapter 05 | Adverse effects on sexual function and fertility                                                                  Tin and selected inorganic tin compounds | page 39 of 97
  Reference    Population and study       Exposure assessment and statistical analyses Health assessment                     Results on sexual function    Bias and confounding             Remarks
               design                                                                                                        and fertility
  Wang et al.  Design:                    Exposure assessment:                                 Sperm quality characteristics No associations between       The two urine samples taken      The study
  (2016a)22    cross-sectional study      • Tin and 17 other metals in two spot-urine          in semen sample, after 2-7    semen quality parameters and  within a few hours, so           population
                                            samples collected a few hours apart (mean          days abstination:             a 10-fold increase in average variability of exposure over     overlaps partly
               Study location:              interval 4.4 h (SD 3.7 h; range 2.0-11 h),         • Progressive motility;       urine metal levels            longer period not known          with Wang et al.
               Subjects recruited at        measured by ICP-MS, reported in μg/L;              • Total motility;             (ln-transformed).                                              (2017), see
               reproductive medicine      • Lower limit of quantification (LOQ) 0.020 μg/L.    • Sperm concentration;                                      Selected population (male        above.
               centre in Wuhan, China       Percentages below LOQ: first urine sample          • Total sperm count;                                        partners from infertile couples)
                                            17%, second urine sample 24%.                      • Morphology.
               Study period: 2013
                                          Statistical analysis:
               Population:                • Multivariable linear regression to estimate
               1247 men, aged 18-55         associations between tin and outcomes, with
               yrs, from subfertile         ln-transformed tin concentrations in quartiles
               couples visiting fertility   (as ordinal variable);
               centre                     • Covariables (obtained by questionnaires during
                                            centre visit): age, BMI, abstinence duration,
               Exclusion criteria:          daily number of cigarettes smoked, smoking
               Azoospermia (n=58),          status (current, formed, never), education,
               occupational exposure to     alcohol consumption, income, and creatinine
               metals (n=16), self-         levels (average over the two samples);
               reported disease with      • Models with multiple metals were constructed
               possible adverse effect on   on the basis of statistical significance in single
               the reproductive system or   metal models ;
               urinary excretion of       • Dose-response relations were modeled using
               chemicals/ (n=121).          cubic splines, with reference values set to
                                            median;
               Final population: n=1052   • Benjamini-Hochberg method used to account
                                            for multiple testing.
38        Health Council of the Netherlands | No. 2022/27                                                                                                   2                                               40
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<pre> chapter 05 | Adverse effects on sexual function and fertility                                                       Tin and selected inorganic tin compounds | page 40 of 97
  Reference    Population and study Exposure assessment and statistical analyses Health assessment                Results on sexual function        Bias and confounding             Remarks
               design                                                                                             and fertility
  Wang, et al  See Wang, 2016a      See Wang, 2016a                              Sperm characteristics in         No associations were found        The two urine samples taken      The study
  (2016b)23                                                                      semen sample, after 2-7 days     for tin with any of the sperm     within a few hours, so           population
                                                                                 abstination                      characteristics tested            variability of exposure over     overlaps partly
                                                                                 • Spermatozoa apoptosis,                                           longer period not known          with Wang et al.
                                                                                   reported as % necrotic, %      Median, interquartile range       Not all outcomes were            (2017), see
                                                                                   apoptotic, % viable;           (IQR) tin concentrations 0.38     measured in all subjects         above.
                                                                                 • Sperm DNA-damage,              (0.26-0.54) μg/L in first urine   because of limitations due to
                                                                                   reported as tail DNA %, tail   sample, 0.35 (0.24-0.53) μg/L     need to analyse sperm within     Intraclass
                                                                                   length, and tail distributed   in second urine sample            1 hr                             correlation
                                                                                   moment.                                                                                           coefficients
                                                                                                                  Urinary tin quartiles negatively Selected population (male         (ICC) between
                                                                                 Serum hormones, in blood         associated with total             partners from infertile couples) tin
                                                                                 samples collected in the         testosterone (T)                                                   concentrations
                                                                                 morning, same day as semen                                                                          in the two
                                                                                 sample: total testosterone (T),  4th quartile versus 1st quartile,                                  samples was
                                                                                 luteinizing hormone (LH),        mean (95%CI): -20% (-32%,                                          0.66, i.e. fair to
                                                                                 oestradiol, follicle-stimulating -7.3%)                                                             good (i.e 0.40
                                                                                 hormone, sex-hormone-                                                                               <ICC <0.75)
                                                                                 binding globulin; and derived    Median value of T for whole
                                                                                 measures: total T/LH ratio,      study population: 389 ng/dL
                                                                                 free androgen index, free T
                                                                                                                  Urinary tin quartiles
                                                                                 Not all measurements done in     associated with Total T/LH
                                                                                 all subjects: for hormones       ratio
                                                                                 n=511, for spermatozoa
                                                                                 apoptosis n=460, for DNA         4th quartile versus 1st
                                                                                 integrity n=516. N=171           quartile: -25% (-43%, -8.3%)
                                                                                 measured for all three
                                                                                                                  Median value of Total T/LH
                                                                                                                  ratio for whole study
                                                                                                                  population: 3.5
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<pre> chapter 05 | Adverse effects on sexual function and fertility                                                             Tin and selected inorganic tin compounds | page 41 of 97
  Reference      Population and study       Exposure assessment and statistical analyses Health assessment              Results on sexual function      Bias and confounding           Remarks
                 design                                                                                                 and fertility
  Guzikowski,    Design:                    Exposure assessment:                            Semen quality according to  Pearson correlation between     No results of measurements     Statistical
  et al (2015)24 cross-sectional study      • Tin and 8 other metals in seminal plasma;     WHO criteria:               tin level and sperm count:      provided                       analysis and
                                            • Semen specimen produced by masturbation       • Semen volume              0.34 (p-value not reported, but                                reporting are
                 Study location:              after 5 days of abstinence measured by ICP-MS • Semen pH (not reported)   flagged as significant)         No information on potential    poor;
                 hospital in Opole, Poland    with time-of-flight analyser (ICP-ToF-MS);    • Sperm count (per ml)                                      exposure to metals or          description
                                            • Units not reported, nor other details of      • Sperm motility (% motile) Difference in tin levels        potential confounders          results section
                 Study period:                measurement results.                          • Sperm morphology (%       between group with abnormal                                    does not match
                 first half of 2009                                                           abnormal)                 sperm quality parameters        Being men from subfertile      tables; some
                                            Statistical analysis:                                                       (n=23) and reference group      couples for which no fertility conclusions are
                 Population:                • Group comparisons: at least one of the sperm  Quality measures were       (n=11): p=0.04 (group           abnormalities were found in    not supported
                 34 men, aged 26-42           quality criteria not meeting WHO reference    dichotomized based on WHO   concentrations and difference the women, sperm                 by data.
                 (mean 28.9) yrs, from        values (abnormal group: n=23) versus the      reference values: count     between groups not reported) parameters of reference
                 primary infertile couples    reference group (meeting all three criteria:  >20×106 sperm/ml, >50% of                                   group may be suboptimal.
                 visiting fertility centre    n=11);                                        sperm motile, <15% abnormal                                 This might have resulted in a
                                            • Correlations (Pearson) between metal          forms                                                       lower power to detect
                 Exclusion criteria:          concentrations and sperm quality parameters.                                                              associations.
                 all other potential causes
                 of subfertility, such as
                 previous pelvic surgery,
                 alcohol consumption,
                 thyroid disturbances
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<pre> chapter 05 | Adverse effects on sexual function and fertility                                  Tin and selected inorganic tin compounds | page 42 of 97
 Associations between environmental exposure to metals and semen            analyses. No associations were observed for urinary tin levels and any of
 quality were investigated by Wang et al. (2017).21 They analysed 18        the semen quality parameters.
 metals, including tin, in seminal plasma of 764 men (subgroup of 1052
 men from a previous investigation using metal concentrations in spot urine In an earlier investigation within the same setting, Wang et al (2016b)
 samples, see Wang et al (2016) below), recruited from a reproductive       analysed 18 metals (including tin) in two spot urine samples (collected a
 medicine centre in Wuhan, China. Semen quality parameters, including       few hours apart) of 1052 men from subfertile couples.23 Measurements
 volume, sperm count, sperm concentration, sperm motility and sperm         were related to spermatozoa apoptosis (n=460) and sperm DNA-damage
 morphology, were dichotomized according to WHO reference values.           (n=516) and to sex hormones in serum (n=511). No associations were
 Also, sperm apoptosis and sperm DNA-damage were analysed in                found for tin with any of the sperm characteristics under study. Urinary tin
 subgroups (n=331 and n=404, respectively). Tin geometric mean              quartile concentrations were found to be associated with total testosterone
 concentrations (SDs not reported) did not differ between the group with    (median 389 ng/dL), with adjusted mean percentage difference (95% CI)
 sperm abnormalities (n=264) and the reference group (n=482): 0.17 μg/L     of -20% (-32%, -7.3%) of 4th quartile versus 1st quartile, and with total
 versus 0.16 μg/L, p=0.15. However, an association was found between tin    testosterone/luteinising hormone ratio (median 3.5), with a corresponding
 levels across percentiles (<60, 60-80, >80 percentiles, cut-off choice     difference of -25% (-43%, -8.3%). These associations were maintained
 data-driven) and the percentage of necrotic spermatozoa, with a ptrend of  when tin was modelled as continuous variable in a cubic spline analysis
 0.03, after adjustment for multiple metals and a range of other            (p<0.01), allowing for possibly non-linear associations.
 covariables.
                                                                            Guzikowski et al. (2015) studied associations between exposure to 9
 Wang et al. (2016a) analysed 18 metals (including tin) in two spot urine   metals, including tin, and semen quality in a cross-sectional study
 samples (collected a few hours apart) of 1052 men from subfertile          conducted in 2009 in Poland.24 Metals were measured in semen samples
 couples.22 Semen quality parameters (motility, sperm concentration and     from 34 primary infertile couples, in which the women had no fertility
 count, and morphology) were determined and associated with urinary         abnormalities. A Pearson’s correlation coefficient of 0.34 was found
 levels of tin using confounder adjusted linear and logistic regression     between tin level and sperm count, but no p-value was provided.
                                                                            In addition, a difference in tin levels was observed between men with at
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<pre> chapter 05 | Adverse effects on sexual function and fertility                                    Tin and selected inorganic tin compounds | page 43 of 97
 least one abnormal sperm quality parameter (n=23) and the remaining          Group 2: Inorganic tin compounds; oxidation state 2+, insoluble
 men (p=0.04), but group concentrations and difference between the            In a reproduction/developmental toxicity screening test in rats, oral
 groups were not reported. These results were not adjusted for other          administration of tin sulphide (0, 100, 300 and 1,000 mg/kg bw/day)
 covariables.                                                                 resulted in microscopical changes in structure of the testes.26 No effects
                                                                              on sperm parameters were noted. The ability of male and female animals
 5.3     Short summary and overall relevance of the provided                  to successfully mate and produce viable offspring was unaffected.
         information on adverse effects on sexual function and
         fertility                                                            Group 3: Inorganic tin compounds; oxidation state 2+, soluble
                                                                              No effects were observed on mating and pregnancy in a multigeneration
 Animal studies                                                               study of rats exposed up to 40 mg/kg bw/day.1,16,17
 Several animal studies are available that provide information on the
 potential effects on fertility or reproductive organs of tin and selected    As part of an assessment for carcinogenicity, the NTP evaluated the
 inorganic tin compounds.                                                     effects of tin dichloride (administered via the diet, up to 395 mg/kg bw/day)
                                                                              on the organs of both rats and mice (males and females).18 Both in a 13-w
 Group 1: Metallic tin                                                        toxicity study and a chronic carcinogenicity assay, no effects were
 Tin metal powder was tested in a reproduction/developmental toxicity         observed on mammary gland, seminal vesicles, prostate, testes, ovaries,
 screening test in rats (only a study summary was available for               and uterus.
 evaluation).13 After oral exposure to 0, 100, 300 and 1,000 mg/kg bw/day,
 no effects on fertility and developmental parameters were observed.          Yousef (2005) administered 20 mg/kg bw/day tin dichloride to male rabbits
                                                                              for 12 weeks and studied the effects on testes and several sperm quality
 Naser et al. (2020) studied the effect of nanoparticles of tin, administered parameters.19 A decreased relative testes weight was observed, and
 to male rats by gavage at a dose of 60 µg/kg bw/day for 30 days.14           several sperm quality parameters were affected.
 Concentrations of LH, FSH and testosterone were increased compared to
 levels in the control group.
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<pre> chapter 05 | Adverse effects on sexual function and fertility                                     Tin and selected inorganic tin compounds | page 44 of 97
 Group 4: Inorganic tin compounds; oxidation state 4+, insoluble               Group 1: For metallic tin, a reproduction/developmental toxicity screen
 Bai et al. (2018) administered tin disulphide nanoparticles (0, 0.38, 3.8, or showed no effects on fertility or reproductive organs. Naser et al. (2020)
 38 mg/kg bw/day; 50, 80, or 200 nm) to male mice intraperitoneally.20         reported increases in hormone levels in male rats treated with nanoparti-
 Moderate effects in testicular tissue (reduced sperm count and sperm          cles of tin.14 This study, however, included only 6 animals per group and
 survival) were induced in the groups with 50 and 80 nm tin disulphide         showed limitations in reporting. The Committee also notes that is it is not
 nanoflowers (dose: 38 mg/kg bw/day).                                          clear whether these effects can be attributed to intrinsic properties of tin or
                                                                               to nano-specific properties. Moreover, effects on hormone levels are not
 Epidemiological studies                                                       considered a basis for classification by the Committee.
 A few epidemiological studies investigated the effects on sexual function
 and fertility. Wang et al (2016a/b and 2017) wrote three publications on a    Group 2: In a reproduction/developmental toxicity screening test in rats
 cross-sectional study within the same study setting (fertility centre in      with tin sulphide, microscopical changes in structure of the testes were
 Wuhan, China) and largely the same study population (subfertile               observed, but no effects on spermatogenesis were noted and the ability to
 couples).21-23 They found an association between quartiles of tin concen-     produce viable offspring was unaffected.25 Therefore, the results of this
 trations in urine and total testosterone levels (Wang, 2016b) and an asso-    screening study do not provide sufficient indication for classification.
 ciation between tin levels in semen and percentage of necrotic sperma-
 tozoa (Wang, 2017). The analyses were adjusted for multiple testing,          Group 3: In a multigeneration study with rats, no maternal toxicity after
 other metals, and a range of covariables, but an effect of co-exposure        exposure to tin dichloride was noted and no differences with the control
 could not be excluded. As the small cross-sectional study by Guzikowski       group were observed in the percentages of mated females and subse-
 et al (2015) had several limitations and issues in presentation, the results  quent pregnancies. However, only limited summaries of this study are
 are considered questionable.24                                                available for evaluation.1,16,17 In repeated dose studies and carcinogenicity
                                                                               studies of the NTP with tin dichloride (oxidation state 2+, insoluble) in rats
 5.4      Comparison with the CLP criteria                                     and mice (males and females), no histopathological changes in the repro-
 Animal data on the effects of tin and inorganic tin compounds are very        ductive organs were observed.18 In a study with male rabbits, Youssef
 limited.                                                                      (2005) reported effects on testes and several sperm quality parameters.19
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<pre> chapter 05 | Adverse effects on sexual function and fertility                  Tin and selected inorganic tin compounds | page 45 of 97
 However, this study has several limitations in study design (e.g. only 6
 animals/group) and reporting, and provides no information on functional
 effects.
 Group 4: Bai et al. (2018) treated mice with different sizes of tin disulphide
 nanoflowers and observed effects on sperm count and survival and
 morphological changes in the testis.20 As only one dose was tested,
 particle-specific effects cannot be excluded.
 Four epidemiological studies were available on exposure to tin and effects
 on fertility. One study had substantial limitations24, whereas the other three
 were performed well and used appropriate statistical analyses.21-23 One of
 these studies showed an association between percentage necrotic sper-
 matozoa and exposure to tin, but a role of co-exposure could not be
 excluded.21
 As a result, no conclusions can be drawn regarding an association
 between exposure to tin and adverse effects on fertility in humans.
 Conclusion
 The Committee concludes that a lack of appropriate data precludes the
 assessment of tin and inorganic tin compounds for effects on fertility.
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<pre> chapter 06 | Adverse effects on development           Tin and selected inorganic tin compounds | page 46 of 97
 06
 adverse effects on
 development
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<pre> chapter 06 | Adverse effects on development                                                                                       Tin and selected inorganic tin compounds | page 47 of 97
 6.1        Animal studies
 Table 11a Summary table of animal studies on adverse effects on development. Group 1: Metallic tin
  Reference    Species           Experimental period and design                                            Dose and route       General toxicity      Developmental toxicity                   Remark
  ECHA         Wistar rats,      Reproduction / developmental toxicity screening test according to OECD Test material: tin      No treatment-related  Non-statistically significant effects in Only study
  Registration males and         Guideline 421                                                             metal powder (2-11   adverse effects on    high dose group:                         summary available
  dossier13    females, 10/sex/                                                                            µm)                  parental animals
               group             Daily treatment:                                                          Purity: not reported                       Decreased offspring weight at day 4 Study is reported
                                 Females: 14 days pre-mating, mating (days not specified), gestation and                        Increase in           post-partum (14-15%)                     to be in compliance
               Control group:    5 days postpartum                                                         Route of exposure:   bodyweight gain in                                             with GLP
               ten males and     Males: 43 days (starting at pre-mating)                                   oral, gavage         males treated with    Increased number of implants per
               ten females,                                                                                                     1,000 mg/kg bw/day    dam and live offspring per dam
               dosed with        Duration of exposure: 56 days                                             Exposure levels: 0   during Week 3
               vehicle alone                                                                               (vehicle), 100, 300                        Decreased sex ratio (i.e. % male
               (1% (w/v)         Effect parameters: maternal examinations, external examinations (all per and 1,000 mg/kg                             offspring) in the high dose group at
               aqueous carboxy   litter), soft tissue examinations (all per litter)                        bw/day                                     day 4 post-partum as compared
               methylcellulose                                                                                                                        with the control group, from 54% to
               (sodium salt))    Statistics: not reported                                                                                             44%
  ECHA         Crl:WI(Han) rats, Prenatal developmental toxicity study according to OECD Guideline 414     Test material: tin   No maternal toxicity  No effects on development                Only study
  Registration females, 20/                                                                                powder (2-11 µm)                           observed; foetal external, skeletal      summary available
  dossier13    group             Duration of exposure: daily from day 6 to 20 of gestation                                      Clinical observations and visceral parameters consistent
                                                                                                           Purity: not reported consistent across     across all groups                        Fifteen females
               Control group:    Effect parameters:                                                                             groups and                                                     with implantations
               carboxymethyl     • Maternal examinations (clinical observations, body weight, food         Route of exposure: unaffected by                                                    in the control
               cellulose            consumption, post-mortem examinations);                                oral, gavage         treatment                                                      group, while
                                 • Ovaries and uterine content -(gravid uterus weight, number of corpora                                                                                       sixteen females
                                    lutea, implantations, early resorptions and late resorptions);         Exposure levels:     No mortality and no                                            with implantations
                                 • Foetal examinations (external, soft tissue and skeletal examinations.   0 (vehicle), 30, 300 treatment-related                                              per group
                                                                                                           and 1,000 mg/kg      effects on body                                                considered optimal
                                 Statistics:                                                               bw/day               weight or food                                                 for statistical
                                 • ANOVA (body weight, body weight gains, food consumption, gravid                              consumption                                                    analysis of data
                                    uterine weights and corrected body weights) ;                                                                                                              according to OECD
                                 • ANCOVA (mean foetal weight, litter size as covariate);                                       No macroscopic                                                 414
                                 • Kruskal-Wallis and Wilcoxon rank sum test (number of corpora lutea,                          observations
                                    implantation sites, early and late resorptions, dead foetuses, live                         associated with                                                Study reported to
                                    foetuses and percent pre- and post-implantation loss, percent male                          treatment                                                      be in compliance
                                    foetuses and percentage of foetuses affected);                                                                                                             with GLP
                                 • 1–sided upper tail Fishers exact test (proportion of litters affected).
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<pre> chapter 06 | Adverse effects on development                                                                                       Tin and selected inorganic tin compounds | page 48 of 97
 Table 11b Summary table of animal studies on adverse effects on development. Group 2: Inorganic tin compounds; oxidation state 2+, insoluble
  Reference       Species             Experimental period and design                                      Dose and route        General toxicity        Developmental toxicity              Remark
  Study           Wistar rats, males  Reproduction / Developmental Toxicity Screening Test (OECD          Test material:        Parental males:         F1 generation                       Study in
  report15, 26    and females, 12     421)                                                                tin sulphide          Absolute weight of      No statistically significant effect compliance with
                  animals/sex/dose                                                                                              pituitary gland         on number of pups and               GLP
                                      Daily administration for the following periods:                     Analytical purity:    increased in males at   accompanied weight of litter
                  Control: concurrent • males and females: 2 weeks prior to the mating period and         ca. 97.6% (77.5% Sn,  the dose level of 1,000 (decrease noted most notably at
                  vehicle (0.5%          during the mating period;                                        20.1% S)              mg/kg bw/day            dose levels 300 and 1,000 mg/kg
                  methylcellulose in  • pregnant females: during pregnancy and till the 3rd day of                                                      bw/day, within historical controls)
                  water)                 lactation;                                                       Route of exposure:    No changes of
                                      • males: after mating period; totally for 42 days;                  oral gavage           microscopic structure   Average weight of pups and
                                      • non-pregnant females (mated females without parturition): for                           of the pituitary gland  postnatal development of pups
                                         25 days after the confirmed mating.                              Exposure levels:                              unaffected. Macroscopic
                                                                                                          0 (vehicle), 100, 300 Parental females:       abnormalities described
                                      Parameters: observations and examinations parental animals,         and 1,000 mg/kg bw/   slight non-significant  sporadically in pups of all treated
                                      litter observations (behaviour, number and sex of pups,             day                   decrease in body        and the control groups
                                      stillbirths, live births and presence of gross anomalies), post-                          weights at 300 and
                                      mortem examinations parental animals and offspring                                        1000 mg/kg bw/day;
                                                                                                                                no other significant
                                      Offspring viability: pre-implantation loss, post-implantation loss,                       treatment-related
                                      postnatal loss, mating index, fertility index, conception index,                          effects
                                      gestation index, percentage of postnatal loss days 0-4 post-
                                      partum and viability index were calculated.
                                      Statistics: The ANOVA test
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<pre> chapter 06 | Adverse effects on development                                                                                                Tin and selected inorganic tin compounds | page 49 of 97
 Table 11c Summary table of animal studies on adverse effects on development. Group 3: Inorganic tin compounds; oxidation state 2+, soluble
   Reference        Species              Experimental period and design                                 Dose and route                   General toxicity   Developmental toxicity                   Remark
   Theuer et al.,   Sprague-Dawley Rats were fed a diet containing tin fluoride from day 0 of           Test material: tin difluoride    No data            No effects on the numbers of litters,    Verly low number of
   197127           rats, females        pregnancy until gestation day 20                               (SnF2), sodium                                      live foetuses per litter, mean placental pregnant females
                    9-10 pregnant                                                                       pentafluorostannite                                 and foetal weights
                    females              Body weight of dams, food/water intake, number of              (NaSn2F5), sodium                                                                            Gravid uterus weight
                                         implantation sites, number of resorptions, number of live      pentachlorostannite                                 Increased number of resorptions in the (including cervix),
                                         foetuses, number of litters, placental weight, foetal weight   (NaSn2Cl5) and a mixture of                         125 ppm and 500 ppm sodium               number of corpora
                                         as well as tin levels in foetuses and placentas were           sodium fluoride and tin                             pentafluorostannite group                lutea, number of
                                         recorded                                                       fluoride                                                                                     dead foetuses, foetal
                                                                                                                                                                                                     sex as well as on
                                         Note: significant methodological deficiencies                  Route of exposure: oral, feed                                                                external, skeletal and
                                                                                                                                                                                                     soft alterations of
                                         Statistics: two-way analysis of variance; Duncan’s multiple    Exposure levels:                                                                             foetuses not
                                         range test                                                     • tin fluoride: 156, 312 and                                                                 measured
                                                                                                           625 ppm (as tin),
                                                                                                           equivalent to 7.8, 15.6 and                                                               Clinical observation
                                                                                                           31.3 mg/kg bw/daya.                                                                       and macroscopic
                                                                                                        • sodium                                                                                     examination of dams
                                                                                                           pentafluorostannite,                                                                      not measured;
                                                                                                           sodium                                                                                    intervals of recording
                                                                                                           pentachlorostannite,                                                                      body weight and food
                                                                                                           sodium fluoride + tin                                                                     consumption not
                                                                                                           fluoride: 125, 250 and 500                                                                stated; individual
                                                                                                           ppm (as tin), equivalent to                                                               animal data not given
                                                                                                           6.3, 12.5 and 25 mg/kg bw/
                                                                                                           day
 a
    1 ppm is equivalent to 0.05 mg/kg bw/day, based on an assumed body weight of 350 g and assumed food consumption of 17.5 g per day. See ECHA guidance R.8, version 2.1, Table 8-17.
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<pre> chapter 06 | Adverse effects on development                                                                                    Tin and selected inorganic tin compounds | page 50 of 97
  Reference     Species          Experimental period and design                              Dose and route                 General toxicity  Developmental toxicity                  Remark
  ECHA          Wistar rats, 24  Prenatal developmental toxicity study equivalent or similar Test material: tin dichloride. No maternal       No clearly discernible effect on        Only abstract
  Registration  mated females    to OECD 414, with several deviations, including:                                           toxicity was      nidation or on maternal or foetal       available
  dossier17     (22-24 pregnant) • Purity of the test substance not stated                   Purity: not reported           observed          survival. No differences were observed
                                 • Body weight and food consumption was not recorded                                                          between the number of abnormalities
                Control group:     according to guidelines                                   Route of exposure: oral,                         seen in either soft or skeletal tissues
                24 mated         • Gross pathological examination of the females consisted   gavage                                           of the exposed groups and the control
                females (20        only of the examination of the urogenital tract                                                            group.
                pregnant         • Deviations of guidelines for organ and litter analyses    Exposure levels: 0.5, 2.3,
                females)         • Data on clinical signs not provided                       11.0, and 50.0 mg/kg bw/day
                                 • Age and individual weight of the animals not reported
                                 • Data on number and percent of pre- and post-
                                   implantation losses lacking
                                 • Daily treatment, from day 6 through day 15 of gestation
                                 • Test duration: 20 days
                                 Effect parameters: appearance and behaviour, food/water
                                 consumption and intake, post-mortem examinations,
                                 ovaries and uterine content, foetal examination
  ECHA          CD-1 mice,       Prenatal developmental toxicity study equivalent or similar Test material: tin dichloride. No maternal       No clearly discernible effect on        Only abstract
  Registration  22-26 mated      to OECD 414, with several deviations, including:                                           toxicity observed nidation or on maternal or foetal       available
  dossier17     females (20-23   • Purity of the test substance not stated                   Purity: not reported                             survival
                pregnant)        • Body weight and food consumption not recorded
                                   according to guidelines                                   Route of exposure: oral,                         No differences observed between the
                Control group:   • Gross pathological examination of the females consisted   gavage                                           number of abnormalities seen in either
                29 mated           only of the examination of the urogenital tract                                                            soft or skeletal tissues of the exposed
                females (21      • Deviations of guidelines for organ and litter analyses    Exposure levels: 0.5, 2.3,                       groups and the control group
                pregnant         • Data on clinical signs not provided.                      11.0, and 50.0 mg/kg bw/day
                females)         • Age and individual weight of the animals not reported
                                 • Data on number and percent of pre- and post-
                                   implantation losses lacking
                                 • Daily treatment, from day 6 through day 15 of gestation.
                                 • Test duration: 17 days
                                 Effect parameters: appearance and behaviour, food/water
                                 consumption and intake, post-mortem examinations,
                                 ovaries and uterine content, foetal examination
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<pre> chapter 06 | Adverse effects on development                                                                                    Tin and selected inorganic tin compounds | page 51 of 97
  Reference     Species          Experimental period and design                              Dose and route                 General toxicity  Developmental toxicity                  Remark
  ECHA          Golden hamster,  Prenatal developmental toxicity study equivalent or similar Test material: tin dichloride. No maternal       No clearly discernible effect on        Only abstract
  Registration  22 mated         to OECD 414, with several deviations, including:                                           toxicity observed nidation or on maternal or foetal       available
  dossier17     females (20-21   • Purity of the test substance not stated                   Purity: not reported                             survival
                pregnant)        • Body weight and food consumption not recorded
                                   according to guidelines                                   Route of exposure:                               No differences observed between the
                Control group:   • Gross pathological examination of the females consisted   oral, gavage                                     number of abnormalities seen in either
                22 mated           only of the examination of the urogenital tract                                                            soft or skeletal tissues of the exposed
                females (21      • Deviations of guidelines for organ and litter analyses    Exposure levels:                                 groups and the control group
                pregnant         • Data on clinical signs not provided                       0.5, 2.3, 11.0, and 50.0 mg/
                females)         • Age and individual weight of the animals not reported     kg bw/day
                                 • Data on number and percent of pre- and post-
                                   implantation losses lacking
                                 • Daily treatment, from day 6 through day 10 of gestation.
                                   Test duration: 14 days
                                 Effect parameters: appearance and behaviour, food/water
                                 consumption and intake, post-mortem examinations,
                                 ovaries and uterine content, foetal examination
  ECHA          Rabbit, 15-17    Prenatal developmental toxicity study equivalent or similar Test material: tin dichloride. No maternal       No clearly discernible effect on        Only abstract
  Registration  mated females    to OECD 414, with several deviations, including:                                           toxicity was      nidation or on maternal or foetal       available
  dossier17     (11-12 pregnant) • Purity of the test substance not stated.                  Purity: not reported           observed          survival. No differences were observed
                                 • Body weight and food consumption not recorded                                                              between the number of abnormalities
                Control group:     according to guidelines                                   Route of exposure:                               seen in either soft or skeletal tissues
                14 mated         • Gross pathological examination of the females consisted   oral, gavage                                     of the exposed groups and the control
                females (10        only of the examination of the urogenital tract                                                            group.
                pregnant         • Deviations of guidelines for organ and litter analyses    Exposure levels:
                females)         • Data on clinical signs not provided.                      0.42, 1.90, 8.90, and 41.5
                                 • Age and individual weight of the animals not reported     mg/kg bw/day
                                 • Data on number and percent of pre- and post-
                                   implantation losses lacking
                                 • Daily treatment, from day 6 through day 18 of gestation.
                                 • Test duration: 29 days
                                 Effect parameters: appearance and behaviour, food/water
                                 consumption and intake, post-mortem examinations,
                                 ovaries and uterine content, foetal examination
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<pre> chapter 06 | Adverse effects on development                                                                                         Tin and selected inorganic tin compounds | page 52 of 97
  Reference      Species            Experimental period and design                                 Dose and route                 General toxicity    Developmental toxicity                   Remark
  WHO, 2005 ;  1
                 CPB:WU rats,       Multigeneration study                                          Test material:                 No effects          No effects observed on the number of     Only abstracts of this
  EFSA 201816;   10 males/group                                                                    tin dichloride, reacting in    observed on         offspring per litter, or birth weight    study available
  ECHA           20 females/        Daily administration via diet                                  aqueous medium with the        maternal growth
  registration   group              20 mated F2b females included in the developmental             casein content of the diet to                      Decrease in body weight gain during
  dossier17                         toxicity study (including visceral and skeletal examination of simulate exposure through                          lactation
                                    the foetuses).                                                 canned food
                                                                                                                                                      Increased mortality and decreased Hb
                                    Other F2 animals were allowed to mate and litter, and          Exposure levels:                                   at weaning in F1 generation off-spring
                                    clinical and pathological examinations of their offspring (F3) 0, 200, 400, or 800 ppm in                         (Fe-deficiency of maternal animals)
                                    were performed                                                 diet, equivalent to 0, 10, 20,
                                                                                                   or 40 mg/kg bw/day                                 No teratogenic effects in F2B offspring
                                                                                                                                                      Microscopic changes were observed
                                                                                                                                                      in the liver and spleen in the F3 pups
  El-Makawy et   Swiss albino       32-39 days of treatment                                        Test material: tin dichloride. No information      No effect on the number of               No reporting of the
  al., 200828    mice, males and                                                                   Purity: >99.0%                 available on        implantations                            condition of maternal
                 females, 15/       Females paired with males during week 3 of the treatment.                                     general toxicity of                                          animals or
                 group (10          Females sacrificed at GD18                                     Exposure route: oral gavage    maternal animals    Increased post-implantation loss at 10   examination of
                 females and 5                                                                                                                        and 20 mg/kg bw/day                      maternal animals
                 males)             Effect parameters: gravid uterine contents (numbers of         Exposure levels: 0, 2, 10 and
                                    implantation sites, resorptions, late foetal deaths and live   20 mg/kg bw/day                                    Decreased number of live foetuses per Not clear if reported
                 Control group:     foetuses)                                                                                                         litter at 10 mg/kg bw/day                developmental
                 distilled water by                                                                                                                                                            effects are (partially)
                 gavage.            Examination: foetus weight, gross external malformation,                                                          No live foetuses at 20 mg/kg bw/day      caused by maternal
                                    viability of the foetuses, evaluation for weight, external,                                                                                                toxicity or not
                                    visceral, and skeletal abnormalities                                                                              Decreased foetal body weight at 2 and
                                                                                                                                                      10 mg/kg bw/day (no live foetuses at     Not clear if values
                                    Statistics: one-way analysis of variance (ANOVA). Multiple                                                        20 mg/kg bw/day)                         were compared with
                                    comparisons were performed by Duncan’s Test                                                                                                                the control group, or
                                                                                                                                                      Treatment-related reduction in the       with the number of
                                                                                                                                                      ossification of the foetal skeleton at 2 implantations of the
                                                                                                                                                      and 10 mg/kg bw (described as ‘some treatment group itself
                                                                                                                                                      evidence’, no details available)
                                                                                                                                                      Decrease in the size of the skeletons
                                                                                                                                                      at 2 and 10 mg/kg bw/day, due to
                                                                                                                                                      reduced ossification
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<pre> chapter 06 | Adverse effects on development                                                         Tin and selected inorganic tin compounds | page 53 of 97
 Table 11d Summary table of animal studies on adverse effects on development.      to a gross necropsy examination and histopathological evaluation of
 Group 4: Inorganic tin compounds; oxidation state 2+, soluble                     reproductive tissues was performed.
  Reference  Species Experimental       Dose and General      Developmental Remark
                      period and design route      toxicity   toxicity
  N/A        N/A      N/A               N/A        N/A        N/A           N/A    There were no deaths and no clinical signs of toxicity. Males treated with
                                                                                   1,000 mg/kg bw/day showed a statistically significant increase in
 OECD 421 study with tin powder (ECHA registration dossier, only                   bodyweight gain during week 3 (results not presented quantitatively).
 abstract available)                                                               Female body weight (gain) was unaffected. No effects on food
 Tin metal powder (2-11 µm) was administered by gavage to male and                 consumption were observed.
 female Wistar rats in compliance with OECD guideline 421 (Reproduction/
 developmental toxicity screening test).13 Rats were exposed for up to 56          The offspring weight at day 4 post-partum was 14-15% decreased in the
 consecutive days (including a two-week maturation phase, pairing,                 high dose group as compared to the control group. The number of
 gestation and early lactation for females) to 100, 300 and 1,000 mg/kg bw/        implants per dam and live offspring per dam was increased at the high
 day tin metal powder. A control group was dosed with vehicle alone (1%            dose level. The sex ratio (i.e., % male offspring) was decreased in the
 (w/v) aqueous carboxy methylcellulose (sodium salt)). It should be noted          high dose group at day 4 post-partum from 54% to 44%. None of the
 that only a summary of results is available.                                      observations showed a statistically significant effect. There were no
                                                                                   treatment-related effects on loss of offspring reported.
 Clinical signs, bodyweight development, dietary intake and water
 consumption were monitored during the study. The parental rats were               OECD 414 study with tin powder (ECHA registration dossier, only
 paired one to one from day 15 of treatment and females were allowed to            abstract available)
 litter and rear young to day 5 post-partum. During the lactation phase,           In a prenatal developmental toxicity study according to OECD guideline
 daily clinical observations were performed on all surviving offspring,            414, female Crl:WI(Han) rats were exposed to tin powder (2-11 µm) by
 together with litter size and offspring weights and assessment of surface         oral gavage.13 The animals were treated from day 6-20 of gestation with 0,
 righting reflex. Adult males were euthanised on Day 43, and all females           30, 300 or 1,000 mg/kg bw/day tin powder. Control animals were given the
 and surviving offspring on Day 5 post-partum. All animals were subjected          vehicle alone (1% w/v aqueous carboxy methylcellulose).
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<pre> chapter 06 | Adverse effects on development                                                                    Tin and selected inorganic tin compounds | page 54 of 97
 Maternal examinations were performed, ovaries and uterine content were                     No treatment-related effects on the number of live foetuses, foetal weight
 examined and foetal external, soft tissue and skeletal examinations were                   or placental weight were observed. The number of resorptions was higher
 done.                                                                                      in the 50 ppm and 500 ppm sodium pentafluorostannite group, compared
                                                                                            with the other treatment groups and the control group.
 Clinical observations were consistent across the groups. There were no
 treatment-related effects on body weight and food consumption and there                    Foetal tin values were elevated when the maternal diet contained tin salts,
 were no treatment-related macroscopic observations in the dams.                            but without apparent relation to dietary tin level. Placental levels of tin
 Effects on development were consistent across all groups and also no                       showed no correlation with the tin levels in the diet.
 effects of the treatment were observed on external, skeletal and visceral
 malformations in the foetuses.                                                             Multigeneration study with rats (WHO 2005; EFSA 2018, ECHA
                                                                                            registration dossier; only abstracts available)
 Developmental toxicity study with tin fluoride (Theuer et al., 1971)                       In a multigeration study with rats, the third generation was used to study
 Sprague-Dawley pregnant rats (7-10/group) were given a diet containing                     the effect of tin dichloride (0, 10, 20, and 40 mg tin/kg bw) on
 tin fluoride (SnF2) at 156, 312 or 625 ppm as tin (equivalent to 7.8, 15.6                 developmental parameters.1,16,17 Microscopic changes were observed in
 and 31.3 mg/kg bw/day), or with sodium pentafluorostannite (NaSn2F5),                      the liver and spleen in the F3 pups at weaning but were not observed in
 sodium pentachlorostannite (NaSn2Cl5) or a mixture of sodium fluoride +                    young at 4 weeks of age. Visceral and skeletal examination of the F2
 tin fluoride at 125, 250 or 500 ppm as tin (equivalent to 6.3, 12.5 and 25                 generation rats did not show any tin-related teratogenic effects.
 mg/kg bw/day)a.27 Also sodium fluoride and sodium chloride were tested.                    No abortions or litter resorptions were reported, all pregnant animals
 On day 20 of gestation, foetuses and placentas were obtained for                           delivered live foetuses, the number of corpora lutea and implantation sites
 analyses on development and tin levels. Data on clinical and macroscopic                   were higher in the treatment groups, and no gross changes were visible in
 observations of the dams, number of dead foetuses, foetal sex, external                    pregnant animals. The growth of the parent rats was not adversely
 alterations, skeletal alterations or soft alterations are missing.                         affected in any generation. In the abstract of the WHO, it was noted that
                                                                                            increased mortality occurred in the F2 generation litters during the first 10
 a
    Ppm conversion to mg/kg bw/day was based on ECHA guidance R.8, version 2.1, Table 8-17.
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<pre> chapter 06 | Adverse effects on development                                                      Tin and selected inorganic tin compounds | page 55 of 97
 days of lactation, but this effect was negated following an increase in iron No relevant clinical changes were observed in males at all dose levels
 in the diet.                                                                 after application of the test substance. A slight reduction in body weight
                                                                              was observed sporadically in treated males and females in different
 Developmental toxicity study in rats, mice, hamsters and rabbits             treatment groups. There were no unscheduled deaths observed during the
 (ECHA registration dossier, only abstracts available)                        study.
 Two study reports (1972, 1974)17, summarised in the REACH registration
 dossier17, describe prenatal developmental studies with rats, mice           The average weights of the litters and pups at the dose level 100 mg/kg
 hamsters and rabbits. These studies are reported to be equivalent or         bw/day were slightly increased against control. At the dose levels of 300
 similar to OECD 414, with several deviations. For each species, 15-29        and 1,000 mg/kg bw/day, the average weight of the litter was lower
 females were allowed to mate with males and were subsequently exposed        compared to control, but the average body weights of pups were slightly
 to tin dichloride from gestational day (GD)6 through GD15 (rats and mice),   higher compared to pups in the control group. No statistically significant
 GD6 through GD10 (hamsters) or GD6-GD18 (rabbits). It was noted that         changes were found, and all observations were within historical control
 ‘no clearly discernible effect on implantation or on maternal or foetal      values.
 survival’ was observed. Furthermore, no differences were observed
 between the number of abnormalities seen in either soft or skeletal          Statistical evaluation was performed on the number of live pups. The total
 tissues of the exposed groups and the control group.                         numbers of live pups (on the day of parturition/1st day after parturition and
                                                                              the 4th day after parturition) were similar in the controls and at the dose
 OECD 421 study with tin sulphide (Study report, 2010)                        level 1,000 mg/kg bw/day. The number was higher at the dose level 100
 A reproduction/developmental toxicity screening test, according to OECD      mg/kg bw/day, and vice versa at the dose level 300 mg/kg bw/day, at
 421, was performed with male and female Wistar rats.26 The animals were      which the number was slightly lower.
 treated with 0, 100, 300 or 1,000 mg/kg bw/day tin sulphide via oral
 gavage at daily basis.                                                       One pup of the control group and one pup in the 300 mg/kg bw/day group
                                                                              died after birth – in the period 0/1st day-4th day. No treatment related
                                                                              differences in external malformations were observed between the control
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<pre> chapter 06 | Adverse effects on development                                                         Tin and selected inorganic tin compounds | page 56 of 97
 group and at all treated groups. Macroscopical examination was                   suggested in the text above) or by relating results to the number of
 performed in all pups. Sporadic pathologic findings were recorded in pups        implantations of the corresponding treatment group.
 of the treated and control groups. The number of pups with macroscopic
 changes was comparable in the control and 100 and 300 mg/kg bw/day               There was some evidence of treatment-related reduction in the
 dosed groups; an increase in livers with marked structure was noted in           ossification of the foetal skeleton. The weight of foetuses in the 2 and
 two litters in the 1,000 mg/kg bw/day dose group. This finding was               10 mg/kg bw/day group was statistically significantly decreased compared
 attributed to physiological extramedullary haematopoiesis.                       to those in the control group. All bones of the axial (skull and vertebrae)
                                                                                  and appendicular (bones of pelvic girdle, fore and hind limbs, bones of
 Developmental toxicity study with tin dichloride (El-Makawy et al.,              digits) skeletons of foetuses in the treated groups showed less ossification
 2008)                                                                            than the controls. No (quantitative) details were provided on the results on
 A study with male and female Swiss mice treated with tin dichloride during       ossification.
 pairing and gestation was performed by El-Makawy et al.(2008).28
 Males and females were treated with 0, 2, 10 or 20 mg/kg bw/day and              6.2      Human data
 paired during week 3 of treatment. Females were sacrificed at gestational        An overview of the human studies on adverse effects on development is
 day 18, after 32-39 days of treatment in total. Effects were observed on         provided in Table 12. These studies include prospective cohort studies,
 post-implantation loss, number of live foetuses, foetal body weight and          case-control studies, and one cross-sectional study.
 ossification of the foetal skeleton. The high dose (20 mg/kg bw/day)
 induced complete post-implantation loss. Treatment with 10 mg/kg bw/day
 induced a significant decrease in the number of live foetuses and a
 significant increase in the number of post-implantation losses. Further, the
 foetal body weight at 2 and 10 mg/kg bw/day was significantly decreased
 compared with the control group. It is noted that it is not clear if statistical
 analysis was performed by relating results to the control group (as
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<pre> chapter 06 | Adverse effects on development                                                                                          Tin and selected inorganic tin compounds | page 57 of 97
 Table 12a Human studies on adverse effects on development: cohort studies
  Reference   Population and study design           Exposure assessment and statistical                 Health assessment          Results on developmental          Bias and confounding          Remarks
                                                    analyses                                                                       toxicity
  Howe, et al Design: prospective cohort study      Exposure assessment:                                Birth weight for           Posterior inclusion probability   Only subjects with            Study population
  (2020a)29                                         • Spot urine samples collected by participant       gestational age and sex,   for tin in the secondary          complete covariable           was an
              Study location:                         during first study visit (median gestational age  z-scores based on a        exploratory analysis was          information were included     impoverished
              Los Angeles, CA, USA                    13.1 weeks)                                       2017 US reference (Airs,   0.45, which ranked in fourth                                    urban population,
                                                    • Tin and 9 other metals measured by ICP-MS in      et al. 2019)               place of importance. By           Measurement of metals         probably above
              Study period: 2015-2019                 urine, expressed as μg/L                                                     setting all other metals to their only once in urine            average at risk of
                                                      13.7% of samples <LOD                             Birth weight measures      median values, an inverse         (variability) at one point in both exposure to
              Population: participants in the       • Urinary concentrations of tin (urine specific     obtained from medical      linear relationship was shown     pregnancy                     pollution and
              MADRES (Maternal and                    gravity corrected), median (IQR): 0.49 (0.27-     records; if missing (n=22) for tin with birth weight                                       intra-uterine
              Developmental Risks from                0.97) μg/L                                        based on information       z-scores                          The focus of this study was   growth retardation
              Environmental and Social                                                                  from mother                                                  on mixtures of metals
              Stressors) study, i.e., pregnant      Statistical analysis:                                                                                                                          Sample size was
              women recruited at one of four        • Tin was not included in the primary analysis      Gestational age                                                                            quite small (lack of
              prenatal care providers in LA,          with 7 metals, but was added to the secondary     estimates using                                                                            power)
              mainly lower-income Hispanic            explorative analysis with 10 metals               ultrasound or observation
              populations                           • Relation between mixture of metals and            at birth (physician’s
                                                      outcome analysed with Bayesian kernel             estimate)
              Exclusion criteria: pregnancy ≥20       machine regression
              wks of gestation at recruitment,      • Directed acyclic graphs (DAG) were used to
              <18 years of age, HIV positive,         identify potential confounders: recruitment site;
              physical, mental or cognitive           self-reported (questionnaire) variables:
              disability, multiple gestation,         maternal age, pre-pregnancy BMI, race by
              incarceration, no urine sample at       ethnicity and birthplace, smoke exposure;
              first visit                             measured variables: pregnancy anaemia
                                                      (Hb,Ht), urinary arsenobetaine (as marker of
              Urine analysis restricted to 262        fish consumption)
              participants (enrolled prior to urine • Interactions were analysed using a novel
              metals analysis (fall 2019), not        method (NLinteraction method)
              withdrawn from the study and
              complete covariable information
              present
              Other publications in the same
              cohort: Howe et al. (2020b), other
              health outcome
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<pre> chapter 06 | Adverse effects on development                                                                                        Tin and selected inorganic tin compounds | page 58 of 97
  Reference   Population and study design          Exposure assessment and statistical                Health assessment           Results on developmental        Bias and confounding          Remarks
                                                   analyses                                                                       toxicity
  Howe, et al Design: prospective cohort study     Spot urine samples collected by participant        Mid-pregnancy foetal        Posterior inclusion             Only subjects with            Study population
  (2020b)30                                        during first study visit (median gestational age   growth measures,            probabilities for tin were 0.33 complete covariable           was an
              Study location: Los Angeles, CA,     12.4 weeks)                                        evaluated at 18-22 weeks    in the primary analysis and     information were included     impoverished
              USA                                                                                     (median 20.4) of            0.22 in the exploratory                                       urban population
              Study period: 2015-2019              Tin and 9 other metals measured by ICP-MS in       pregnancy and obtained      analysis, the lowest ranking    Measurement of metals         probably above
                                                   urine samples, expressed as μg/L                   from medical records                                        only once in urine            average at risk of
              Population: participants in the                                                                                     No associations were            (variability) at one point in both exposure to
              MADRES (Maternal and                 Urinary concentrations of tin (urine specific      Abdominal circumference     observed between tin            pregnancy                     pollution and
              Developmental Risks from             gravity corrected): median (IQR): 0.47 (0.28-                                  concentration in urine and                                    intra-uterine
              Environmental and Social             0.92) μg/L                                         Head circumference          any of the outcome measures     The focus of this study was   growth retardation
              Stressors) study, i.e., pregnant                                                                                                                    on mixtures of metals.
              women recruited at one of four       Statistical analysis:                              Biparietal diameter                                                                       Sample size was
              prenatal care providers in LA,       • Primary analysis focused on a mixture of 6                                                                                                 quite small (lack of
              mainly lower-income Hispanic           metals, including tin. Secondary analysis        Femur length                                                                              power)
              populations                            included four more metals
                                                   • Association between mixtures of metals and       Estimated foetal weight
              Exclusion: pregnancy ≥20 wks of        outcome analysed with Bayesian kernel            (EFW) was main outcome
              gestation at recruitment, <18          machine regression                               in the statistical analysis
              years of age, HIV positive,
              physical, mental or cognitive        Directed acyclic graphs (DAG) were used to
              disability, multiple gestation,      identify potential confounders: gestational age at
              incarceration, no urine sample at    ultrasound, recruitment site, maternal age,
              first visit                          pre-pregnancy BMI, race by ethnicity and
                                                   birthplace, education, infant sex, maternal
              Analyses restricted to 195           anaemia, prenatal vitamin use, parity, smoke
              participants enrolled prior to urine exposure and urinary arsenobetaine (as marker
              metals analysis (fall 2019) and      of fish consumption).
              prior to routine anatomy
              ultrasound scan, not withdrawn       Metals with high-ranking posterior inclusion
              from the study and complete          probabilities were further analysed with linear
              covariable information present       regression models
              Other publications in the same       Interactions were analysed using a novel method
              cohort:                              (NLinteraction method)
              Howe et al. (2020a), other health
              outcome
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<pre> chapter 06 | Adverse effects on development                                                                                        Tin and selected inorganic tin compounds | page 59 of 97
  Reference    Population and study design           Exposure assessment and statistical               Health assessment          Results on developmental       Bias and confounding         Remarks
                                                     analyses                                                                     toxicity
  Kim, et al   Design: prospective cohort study      Tin and 16 other metals in urine samples,         Parameters of foetal       In single metal models, tin    Ultrasounds at weeks 26      The authors
  (2020)31                                           collected at 26 weeks of pregnancy, measured      growth, measured by        associated with head           and 35 (visits 3 and 4) were labelled the
               Study location: Boston, MA, USA       with ICP-MS                                       ultrasound at weeks 26     circumference z-scores for     taken at participant’s       principal
                                                                                                       (median) and 35            repeated measures:adjusted     request or when              component
               Study period: 2006-2008               Tin LOD: 0.10 ppb (μg/kg); 6.15% below LOD        (median), following        β (95% CI), per IQR increase,  abnormality suspected.       combining tin,
                                                     Tin specific-gravity-corrected concentrations,    guidelines of ACOG:        -0.22 (-0.36, -0.07) and with  Availability of ultrasound   arsenic, and
               Population: participants in           weighted to account for case-control selection,   • Abdominal                femur length z-scores among    measurements was             mercury as “sea
               LIFECODES study, i.e., pregnant       median (IQR): 0.62 (0.35-1.22)                      circumference (mm)       at term deliveries only:       selective (sampling bias)    food-related”.
               women planning hospital delivery,                                                       • Head circumference       adjusted β (95% CI), per IQR
               enrolled before week 15 of            Demographics, lifestyle factors, medical and        (mm)                     increase, -0.21 (-0.40, -0.02) Measurement of metals in     Sensitivity
               pregnancy and participating in up     pregnancy history obtained by questionnaire       • Femur length (mm)                                       urine was done only at one   analyses with
               to four study visits.                                                                   • Estimated foetal weight  In multi metal models, no      timepoint at varying         imputation for
                                                     Statistical analysis:                               (EFW) from these         associations between tin and   pregnancy durations, which   missing data was
               Inclusion criteria: pregnancy         • Linear mixed effect models for associations       measures, following      z-sores for any of the foetal  might impact metal           performed, which
               resulting in preterm birth (<37         between metals and repeated outcome               Hadlock formula          growth parameters              concentrations due to        did not lead to
               weeks) (n=130, almost all               measures (at 26 weeks, 35 weeks, birth)         • Z-scores based on                                       metabolic changes            different
               occurrences) or in at term birth      • Linear regression for associations with birth     gestational age at scan, In multi metal models, tin                                  conclusions.
               (n=352, randomly selected in 3:1        weight, birth length, and placental weight        with all singleton       associated with placental
               ratio) originally selected for nested • Covariables (in all adjusted models): urine       pregnancies in the       weight:
               case-control study                      specific gravity, maternal age, race/ethnicity,   hospital in 2006-2012    Adjusted β (95% CI), per IQR
                                                       education, pre-pregnancy BMI, type of             as reference             increase, 38.9 (2.79, 75.0),
               Exclusion criteria: no urine sample     insurance, self-reported use of alcohol and     • Birth weight (g), birth
               from third study visit (=26 weeks       tobacco, assisted reproduction, gestational       length (cm), and         Principle component
               of pregnancy) available                 age at time of ultrasound, gestational age at     placental weight (g) (in combining tin, arsenic, and
                                                       delivery (when appropriate), and metal            subset)                  mercury associated with
               Final study population: n=390           co-exposure (in multi metal models).                                       decreased head
                                                     • Principal components analysis to identify                                  circumference z-score for
                                                       combinations of covariables                                                repeated measures: adjusted
                                                     • Inverse probability weighting (IPW) to account                             β (95% CI), -0.14 (-0.23,
                                                       for case-control selection                                                 -0.05) and with the
                                                     • Sensitivity analyses (amongst others) on                                   combination of estimated
                                                       missing data (multiple imputation by chained                               foetal weight and birth weight
                                                       equation method)                                                           z-scores: adjusted β (95%
                                                                                                                                  CI), -0.10 (-0.19, -0.01),
                                                                                                                                  Sensitivity analyses showed
                                                                                                                                  the same associations with
                                                                                                                                  similar precision but with
                                                                                                                                  slightly attenuated effect
                                                                                                                                  estimates
58         Health Council of the Netherlands | No. 2022/27                                                                                                        2                                           60
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<pre> chapter 06 | Adverse effects on development                                                                                      Tin and selected inorganic tin compounds | page 60 of 97
  Reference    Population and study design         Exposure assessment and statistical                Health assessment         Results on developmental    Bias and confounding Remarks
                                                   analyses                                                                     toxicity
  Wu, et al    Design: prospective cohort study    Concentrations of tin and 11 other heavy metals    Primary tooth eruption    No associations between tin                      Study reported
  (2020)32                                         in maternal urine in first trimester of pregnancy  until age 1 of child      and tooth eruption                               according to
               Study location: Nanjing, China                                                                                                                                    STROBE
                                                   Measurement by ICP-MS expressed as μg/L            Time of teeth eruption by                                                  guidelines
               Study period: 2014-2015             urine                                              asking mother and
                                                                                                      number of teeth by oral
               Population: n=183 pregnant          LOD: 0.221 μg/L; detection rate tin 78%            examination (by two
               women in first trimester recruited                                                     dentists)
               at hospital maternity ward, and     Concentration tin, median (IQR): 0.68 (0.29-
               the children born from their        1.41) μg/L
               pregnancies.
                                                   Metabolomics of maternal urine sample by
               Exclusion criteria: diabetes, other ultrahigh performance LC coupled MS; 172
               disease requiring medication,       metabolites were identified
               alcohol or substance abuse,
               HIV-positive, <18 years of age,     Statistical analysis:
               assisted reproduction, infants with • Multivariable linear regression to assess
               disease, genetic abnormalities or     associations between single metals and tooth
               malformations.                        eruption
                                                   • Covariables (based on questionnaires and
                                                     hospital medical records): age, education,
                                                     pre-pregnancy BMI, lifestyle factors,
                                                     reproduction status, personal health, clinical
                                                     information (serum phosphorus, alkaline
                                                     phosphatase, fasting glucose), and perinatal
                                                     information (delivery method, gestational age,
                                                     gender, birth weight, duration of breastfeeding,
                                                     vitamin D supplementation at 6 and 12 months
                                                     of age).
59         Health Council of the Netherlands | No. 2022/27                                                                                                  2                                   61
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<pre> chapter 06 | Adverse effects on development                                                                                       Tin and selected inorganic tin compounds | page 61 of 97
  Reference    Population and study design          Exposure assessment and statistical               Health assessment          Results on developmental        Bias and confounding       Remarks
                                                    analyses                                                                     toxicity
  Zhao, et al  Design: prospective cohort study     Concentration of tin was not measured in blood    Placental characteristics, Spearman correlation            Approximately 90% of
  (2020)33                                          Concentrations of tin and 10 other metals in      retrieved from medical     coefficients for tin with other women had higher
               Study location: Hangzhou, China      urine collected at baseline, measured by ICP-MS records by medical           metals in urine ranged          education
                                                                                                      personnel:                 between 0.27 and 0.49
               Study period: 2016-beginning of      Concentrations in urine presented as creatinine   • Placental weight (g)                                     Natural labour rate was
               2017                                 corrected (CC) levels in μg/g creatinine          • Chorionic disc plate     Tin was not retained in any of  99% for participants with
                                                                                                        area (cm2)               the multivariable models        placental data and metal
               Population: women (n=512 with        LOD for tin in urine: 0.051 μg/g creatinine; 100% • Chorionic disc           associating metals in urine     levels available, compared
               urine measurements; n=483 with       of samples > LOD                                    eccentricity (cm)        with placental characteristics  to 65.1% for participants
               blood measurements) enrolled in                                                        • Placental thickness      or birth weight.                included in baseline
               20-28 weeks of pregnancy in the      Statistical analysis:                               (cm)                                                     investigation
               Hangzhou Birth Cohort and the        • Spearman correlations between metal             • Placental-foetal birth   No associations between tin
               newborns from these                    concentrations                                    weight ratio (%)         concentrations in urine and     Metal concentrations only
               pregnancies, all born in the         • Multivariable analysis using elastic net and    • Birth weight (g)         any of the outcomes in          measured once (20-28
               hospital as specified by protocol      unpenalized regression models to assess                                    univariable linear regression   weeks of gestation).
                                                      association between outcomes and multiple                                  analysis.
               Exclusion criteria: subjects with no   metals, adjusted for covariables
               data on placental weight, multiple • Sensitivity analysis: linear regression with one
               pregnancy, assisted conception,        metal and outcome at a time, with Benjamini-
               or missing data on demographic         Hochberg method to control for False
               characteristics.                       Discovery Rate
                                                    Covariables selected using directed acyclic
                                                    graphs (DAGs): maternal age at conception,
                                                    maternal education, second hand smoke,
                                                    household income, pre-pregnancy BMI, infant
                                                    sex, and gestational age
60         Health Council of the Netherlands | No. 2022/27                                                                                                        2                                 62
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<pre> chapter 06 | Adverse effects on development                                                                                        Tin and selected inorganic tin compounds | page 62 of 97
  Reference    Population and study design           Exposure assessment and statistical               Health assessment          Results on developmental     Bias and confounding     Remarks
                                                     analyses                                                                     toxicity
  Goodrich et  Study design: prospective cohort      Exposure assessment: tin concentrations were      Gestational age, birth     No associations were found   No co-exposure to other  The study may
  al. (2019)34 study                                 measured in spot urine samples collected at first weight, birth length, and  between urine tin levels and metals included into the have been
                                                     prenatal visit using isotope chromatography       head circumference         birth weight or any of the   multivariable analysis   underpowered to
               Study location: Michigan, US          plasma tandem mass spectrometry (ICPMS)           measured the day after     foetal anthropometry                                  detect all
                                                     following a protocol based on CDC method          delivery                   parameters                                            potentially existing
               Study period: 2012-2015               3018.3 with modifications                                                                                                          associations
                                                                                                       Foetal anthropometry
               Population: Subset from ongoing       Statistical analysis: multivariable linear        (biparietal diameter, head
               Michigan Mother-Infant Pairs          regression models adjusted for gravity,           circumference, abdominal
               (MMIP) Study including 56 women       gestational age, and infant gender (when          circumference, and femur
               recruited during their first prenatal appropriate)                                      length) abstracted from
               visit at 8-14 weeks of gestation.                                                       clinical ultrasound in
                                                                                                       second trimester
               Eligible criteria: at least 18 years
               old, natural conception, singleton
               pregnancy, intention to deliver at
               the University of Michigan
               hospital, complete survey data.
               availability of all biospecimen from
               mother and child, and family not
               included in previous exposure
               assessment. Additional criteria:
               non-Hispanic Caucasian ethnicity,
               non-smoking, and full-term birth.
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<pre> chapter 06 | Adverse effects on development                                                                                            Tin and selected inorganic tin compounds | page 63 of 97
  Reference      Population and study design             Exposure assessment and statistical                Health assessment         Results on developmental    Bias and confounding         Remarks
                                                         analyses                                                                     toxicity
  Bloom, et al   Design: prospective cohort study        • Tin and 20 other metals measured in both         Measures of intra-uterine No associations between     Smoking status was           Strong point of the
  (2015)                                                   maternal and paternal urine (some elements       growth                    maternal and paternal tin   defined on the basis of      study is use of
  (+ correc-     Study location: various counties in       other than tin also measured in blood)           • gestational age at      concentrations in urine and cotinine measurements        pre-conception
  tion)35,36     central Michigan and along the          • Spot urine samples were collected before           delivery (days since    any of the outcomes.                                     exposure,
                 gulf coast in Texas, USA                  conception.                                        ovulation, determined                               Serum lipids were included   including of father
                                                         • Metals measured with ICP-MS expressed as           on basis of daily urine                             as covariables to adjust for
                 Study period: 2005-2009                   μg/L                                               hormone                                             Persistent Organic           Participants
                                                         • Tin in paternal pre-pregnancy urine                measurements (Fertility                             Pollutants                   presumed to be at
                 Population: 501 couples planning • Median (33rd %tile-67th %tile): 0.33 (0.20-0.5)           Monitor))                                                                        risk of
                 pregnancy participating in the          • Percentage above LOD: 84                         • birth weight (kg), low                                                           environmental
                 Longitudinal Investigation of           • Tin in maternal pre-pregnancy urine                birth weight <2500 g                                                             exposure, but
                 Fertility and the Environment           • Median (33rd %tile-67th %tile): 0.31 (0.16-0.62) • birth length (cm)                                                                most values were
                 (LIFE) study. Couples recruited         • Percentage above LOD: 80                         • head circumference                                                               relatively low
                 from the general population with        • Baseline questionnaire on demographics,            (cm)                                                                             compared to US
                 presumed exposure to persistent           health-related behaviours, medical history and   • ponderal index                                                                   population
                 organic pollutants                        reproductive histories                             (100*(kg/m3))
                                                         • Samples and questionnaires collected and         • secondary sex ratio
                 Inclusion criteria: heterosexual          administered at the home by research nurse.        (ratio live male/female
                 relationship, women aged 18-40                                                               births)
                 yrs, no use of injectable               Statistical analysis:
                 contraceptive within 12 months,         • Associations between metals and outcomes,
                 and menstrual cycle length of             Spearman rank and Mann-Whitney U-test
                 21-42 days.                             • Multivariable linear regression analysis with
                                                           maternal and paternal exposures entered
                 Exclusion criteria: couples with          simultaneously, adjusted for covariables: age
                 sterilized partner or prior infertility   mother, age difference mother and father,
                 diagnosis: 54 couples without             maternal and paternal smoking, income race,
                 pregnancy; 100 couples withdrew;          serum lipids, and creatinine
                 2 twin pregnancies; 110                 • Cox-proportional hazards for outcome time of
                 miscarriages                              delivery (gestational age)
                 Final study population: 235
                 singleton pregnancies
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<pre> chapter 06 | Adverse effects on development                                                                                             Tin and selected inorganic tin compounds | page 64 of 97
  Reference     Population and study design           Exposure assessment and statistical                  Health assessment           Results on developmental        Bias and confounding         Remarks
                                                      analyses                                                                         toxicity
  Shirai, et al Design: prospective cohort study      Various heavy metals measured in single spot         Primary outcomes:           Univariable analysis of tin     Urinary concentrations of    Population:
  (2010)37                                            urine, collected between 9 and 40 weeks of           birth weight (in kg), birth versus outcomes:                tin were low and below limit recruitment not
                Study location: Tokyo, Japan          gestation at regular pregnancy visit to maternity    length (in cm), and head    • correlation between tin and   of detection in almost half  clearly described
                                                      ward:                                                circumference (cm) of the     head circumference:           of samples                   and inclusion and
                Recruitment period: 2007-2008         • Tin measured by ICP-MS                             newborns at time of           r=-0.269 (p<0.05)                                          exclusions criteria
                                                      • Concentrations corrected for urine creatinine      delivery following          • only samples >LOD (n=41):     Measurement in urine         only globally
                Study population: 78 pregnant           concentration, expressed as μg/g creatinine        standard methods              r=-0.519 (p=0.001)            sample only once and at      described
                women visiting the obstetrics         • Detection limit tin: 0.07 μg.(g creatinine)-1                                                                  variable stages of
                outpatient clinic of a hospital and   • Geometric mean (GSD) urinary concentration                                     Multivariable regression: final pregnancy.                   Sample size:
                the babies born from these              of tin in μg.(g creatinine)-1: 0.232 (7.28), range                             model with only tin as                                       relatively small
                pregnancies.                            <0.06–11.8 (47.4% of samples <LOD).                                            independent variable (other                                  study with maybe
                                                                                                                                       variables excluded on basis                                  insufficient power
                Inclusion criteria: no clinical signs Statistical analyses:                                                            of lack of statistical
                of disease.                           • Correlations                                                                   significance). Partial                                       According to the
                                                      • Multivariable linear regression analyses with                                  regression coefficient for                                   authors, GSD
                                                        adjustment for confounders and co-exposure                                     head circumference: -0.178,                                  concentrations for
                                                        to other metals                                                                p=0.017                                                      tin were much
                                                      • Covariables: maternal BMI, maternal age,                                                                                                    lower than those
                                                        maternal or parental smoking, sex of newborn,                                                                                               reported in an
                                                        birth order, and gestational age. In analysis                                                                                               American (2.84
                                                        with birth length, maternal BMI was replaced                                                                                                μg.(g creatinine)-1)
                                                        by maternal height.                                                                                                                         and a Japanese
                                                      • Smoking status of mother (n=8, 10.3%) and                                                                                                   study (2.0 μg.(g
                                                        partner (n=34, 43.6%) obtained through                                                                                                      creatinine)-1 )
                                                        interviews by medical staff.
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<pre> chapter 06 | Adverse effects on development                                                                                    Tin and selected inorganic tin compounds | page 65 of 97
 Table 16b Human studies on adverse effects on development: cohort studies: case-control studies
  Reference   Population and study          Exposure assessment and statistical             Health assessment          Results on developmental          Bias and confounding             Remarks
              design                        analyses                                                                   toxicity
  Frye et al. Design: case-control study    Exposure assessment:                            Common validated           Mean prenatal tin concentration    Despite not being statistically The study was
  (2020)38                                  Elemental bio-imaging using laser ablation-     measures were used to      was lower among cases             significant in the analyses, age underpowered to
              Study location: Eight states  inductively coupled plasma mass-                assess neurodevelopment    compared to controls (0.00012     and sex as well as comorbidity   detect all
              in the US and Canada          spectrometry (LA-ICP-MS) measured               and behaviour in children  vs. 0.00022; p<0.05), but did not and other confounders may have   potentially
                                            concentrations of tin in deciduous teeth with a with ASD.                  meet the stringent p-value of     confounded the results due to    existing
              Study period: Not specified   trimester-by-trimester resolution pre- and                                 0.01.                             large differences between cases  associations
                                            postnatally.                                    The Vineland Adaptive                                        and controls. Control selection
              Population:                                                                   Behaviour Scale (VABS)                                       not well explained and could     Limitations in
              • Cases: 27 patients          Statistical analysis: Linear mixed models,      2nd edition and a social                                     influence results strongly.      reporting
                recruited from a nationally considering all interactions. Because of        communication                                                                                 selection of
                recognized multispecialty   multiple models analysed, the p-value was       questionnaire were used to                                                                    controls
                ASD (autism spectrum        set at ≤0.01                                    document normal
                disorder) clinic, with                                                      development among
                (n=13) or without (n=14)    Age and sex were excluded as co-variables       controls.
                neurodevelopmental          as they did not contribute statistically
                regression.                 significantly to the models
              • Controls: 7 generally
                healthy children who were
                typically developing (2
                siblings of cases and 5
                unspecified others)
              Exclusion criteria:
              chronic treatment with
              medications that would
              detrimentally affect
              mitochondrial function such
              as antipsychotic
              medications; vitamin or
              mineral supplementation
              exceeding the
              recommended daily
              allowance, and prematurity
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<pre> chapter 06 | Adverse effects on development                                                                                    Tin and selected inorganic tin compounds | page 66 of 97
  Reference   Population and study         Exposure assessment and statistical           Health assessment            Results on developmental         Bias and confounding              Remarks
              design                       analyses                                                                   toxicity
  Hou, et al  Design: nested case-control  Tin and 21 other metals measured with         Health outcome: birth weight No increased or decreased ORs    Pre-pregnancy BMI distribution
  (2019)39    study                        ICP-MSin serum samples collected during       • Low birth weight (cases)   were found for any of the tin    different (p=0.001) between
                                           prenatal examination.                           <2500gr; normal birth      concentration quartiles          cases and controls, with more
              Study location: Guangxi                                                      weight: 2500-4000 gr       compared to the highest quartile cases being underweight (BMI
              Province, China              LOD=0.010 μg/L; 64.3% samples above LOD                                    in the single metal analyses.    <18.5), but adjusted for in the
                                                                                         Measures obtained from                                        analyses
              Study period: 2015-2016      Median (IOR) serum concentration tin cases    medical records database
                                           versus controls: 0.38 (0.18-0.79) vs 0.40                                                                   Gestational age at delivery lower
              Population: 246 women with   (0.18-0.84) μg/L                                                                                            in cases than controls (35.5
              low birth weight children                                                                                                                versus 39.1, p<0.001), as
              (cases) and 409 women        Statistical analysis:                                                                                       expected when selecting low
              with normal birth weight     • Spearman correlations between 22                                                                          birth weight children
              children (controls) from the   maternal serum metal levels.
              Guangxi Birth Cohort Study   • Single metal analysis using conditional
                                             logistic regression with quartiles of metal
              Controls were randomly         concentrations
              selected in a 1:2 ratio      • Multi-metal analysis: selection of metals
              according to maternal age,     using elastic net regression
              infant gender, gestational   • Covariables: pre-pregnancy BMI, alcohol
              age at sample collection,      intake pre-pregnancy, passive smoking
              and enrolment hospital         during pregnancy, gravidity, and parity
                                             (collected by interview and from medical
              Exclusion criteria: multiple   database)
              pregnancy, gender
              information missing, serum
              sample missing
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<pre> chapter 06 | Adverse effects on development                                                                                 Tin and selected inorganic tin compounds | page 67 of 97
  Reference   Population and study         Exposure assessment and statistical           Health assessment          Results on developmental         Bias and confounding               Remarks
              design                       analyses                                                                 toxicity
  Ovayolu, et Design: case-control study   Tin and 13 other metals measured by ICP-MS Neural tube defect (NTD),     Tin levels in cases were higher  Amniocentesis in controls was      Relatively small
  al (2019)40                              in amniotic fluid obtained by amniocentesis   diagnosed by ultrasound in than in controls, mean (SD):     performed because of               study
              Study location: Hospital,    LOD not reported                              pregnancy weeks 16-37:     -1.35 (2.28) versus 0.40 (0.55), age-related risk or increased risk
              Gaziantep, Turkey                                                          • Anencephaly              p-value 0.018                    in triple test                     No multivariable
                                           Statistical analysis:                         • Spina bifida                                                                                 analysis with
              Study period: 2017-2018      • Differences in metal concentrations using   • Acrania                                                   Measurement of tin in one          control for
                                             t-tests.                                    • Encephalocele                                             sample only, obtained at different confounding by
              Population:                  • Further case-control comparisons on:        • Iniencephaly                                              gravitational ages, but matched    maternal age and
              • Cases: n=36 pregnant         maternal age, BMI, parity, gravidity,                                                                   between cases and controls with    history of abortion
                women with foetuses with     abortion, gestational age at amniocentesis,                                                             a mean difference of 2 weeks.      or co-exposure to
                a neural tube defect         frequency of seafood consumption, passive                                                                                                  other metals
                (NTD);                       smoking, and presence of dental amalgam                                                                 Measurements in samples
              • controls: n=39 pregnant      (obtained by obstetric anamnesis at                                                                     collected after embryogenesis;
                women with unaffected        amniocentesis)                                                                                          might not be representative of
                foetuses; matched for      • No multivariable analysis                                                                               exposure during embryogenesis
                maternal BMI and
                gestational age (wks)                                                                                                                Cases were younger than
                                                                                                                                                     controls (27.1 versus 31.3 years,
              Exclusion criteria: age <18                                                                                                            p=0.014) and less frequently had
              yrs, assisted conception,                                                                                                              a history of abortion (0.2 versus
              previous NTD, chronic                                                                                                                  0.5, p=0.036)
              diseases, drug use, non-use
              of folic acid in early weeks
              of pregnancy, and obstetric
              complications
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<pre> chapter 06 | Adverse effects on development                                                                                         Tin and selected inorganic tin compounds | page 68 of 97
  Reference   Population and study          Exposure assessment and statistical               Health assessment             Results on developmental          Bias and confounding               Remarks
              design                        analyses                                                                        toxicity
  Yan, et al  Design: case-control study    Tin and 8 other essential trace metals in         Neural tube defect in foetus: Tin concentrations in maternal    Differences between cases and      An unexpected
  (2017)41                                  unpainted maternal hair, grown from 1 month       • Anencephaly (n=85)          hair, median, interquartile range controls for several co-variables, inverse
              Study location: Shanxi and    before conception to 2 months after               • Spina bifida (n=79)         (IQR) and adjusted odds ratios    that were adjusted for in the      association was
              Hebei Provinces, China        conception, assuming a hair growth rate of 1      • Encephalocele (n=24)        (95% CI)                          logistic regression analyses       observed
                                            cm per month                                      • Unspecified (n=3)                                                                                between tin
              Study period: 2003-2007                                                                                       Total NTD’s (n=191):              No multivariable analyses with     concentrations in
                                            Hair samples were cut into segments of 3-5                                      • cases: 0.040 (0.010-0.101)      co-exposure to other metals        maternal hair and
              Population:                   mm and metals were measured with ICP-MS                                         • controls: 0.051 (0.011-0.134)                                      anencephaly in
              • Cases: 191 women with a                                                                                     • P-value 0.102                   To maximize the sample size,       offspring
                pregnancy complicated by    Tin was expressed as ng/mg hair                                                 Adjusted OR: 0.76 (0.50-1.16)     matched pairs were separated
                a neural tube defect (live                                                                                                                    for the analysis with
                births, stillbirths, and    Detection rate for tin was 84%. LOD for tin                                     Anencephaly (n=85):               unconditional logistic regression
                pregnancy terminations);    was not reported                                                                • Cases: 0.034 (0.006-0.076)
                Controls: 261 women who                                                                                     • Controls: 0.051 (0.011-0.134);
                delivered healthy infants   Statistical analysis:                                                           • P-value 0.049
                in the same birthing        • Comparison of tin hair concentrations                                         Adjusted OR: 0.54 (0.30-0.97)
                hospital, loosely matched     between groups: Mann-Whitney U test
                on county/city of residence • Unconditional logistic regression with                                        Spina bifida (n=79):
                and last menstrual period     dichotomized metal concentrations based                                       • Cases: 0.048 (0.014-0.096)
                                              on median value in controls as cut-off and                                    • Controls: 0.051 (0.011-0.134)
                                              correction for co-variables.                                                  • P-value 0.536
                                            • Dose-response relations were evaluated                                        Adjusted OR: 0.94 (0.54-1.64)
                                              using quartiles of metal concentrations
                                              based on quartiles in controls.                                               Dose-response analyses
                                            • Covariables: maternal age, occupation,                                        showed a linear relationship of
                                              education, gravidity, history of previous birth                               monotonically decreasing ORs
                                              defects, periconceptual folate                                                for anencephaly with increasing
                                              supplementation, fever or flu during early                                    concentrations.
                                              pregnancy, alcohol consumption (yes/no),
                                              active or passive smoking during
                                              periconceptual period, and dietary habits
                                              (collected by face-tot-face interview within
                                              first week after the end of pregnancy).
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<pre> chapter 06 | Adverse effects on development                                                                                          Tin and selected inorganic tin compounds | page 69 of 97
  Reference   Population and study           Exposure assessment and statistical            Health assessment               Results on developmental         Bias and confounding               Remarks
              design                         analyses                                                                       toxicity
  Manduca,    Design: case-control study     Tin and 22 other metals measured in hair       Birth defects in newborns:      Tin concentrations in ppm in     Exposure assessment of parents     Similar to tin, Hg
  et al                                      samples from newborn, collected immediately neural tube defect (n=11),         birth defect cases versus normal by questionnaires for birth defect and Se levels
  (2014)42    Study location: Gaza,          after birth, analyzed by ICP-MS                renal defects (n=5), cleft lip/ newborns, median (IQR): 0.23     cases more detailed than for       were elevated in
              Palestine                                                                     palate, gastro-intestinal,      (0.08-0.54) versus 0.04 (0.02-   other cases and controls           birth defect cases
                                             Questionnaires administered to the mothers, heart, abdominal, and              0.09), P=0.002                                                      versus normal
              Study period: 2011             including occupation, place of residence,      multiple defects, all not                                        No multivariable analysis with     newborns, with all
                                             reproductive history within the family, if     further specified.              Tin concentrations in ppm in     control for confounding by         three metals
              Population: babies born in     possible verified with objective sources (data                                 cases with NTD: 0.32 (0.14-      co-variables or co-exposure to     observed in high
              maternity hospital             on military activity and sequelae collected by Preterm birth                   1.04) and in cases with renal    other metals                       load in 26 of 48
              • Cases: 48/55 newborns        NGOs), only for parents of birth defect cases                                  defects: 0.15 (0.06-0.30)                                           cases. Individual
                with birth defects and                                                                                                                                                          contributions of
                enough hair for testing      Statistical analysis:                                                          Tin concentrations in ppm in                                        these metals
                and 9/77 randomly chosen • Differences in metal concentrations                                              preterm babies without birth                                        were not
                preterm babies without         between cases and controls using Mann-                                       defect versus normal newborns:                                      analyzed/
                birth defect                   Whitney U test                                                               0.25 (0.23-0.89) versus 0.04                                        reported
              • Controls: 12/3,892           • No multivariable analyses                                                    (0.02-0.09), P=0.002
                randomly chosen full term
                healthy babies
              Exclusion criteria:
              Not enough hair at birth.
              Known history of birth
              defects within the family (for
              preterm and full term
              babies)
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<pre> chapter 06 | Adverse effects on development                                                                                 Tin and selected inorganic tin compounds | page 70 of 97
 Table 12c Human studies on adverse effects on development: cohort studies: cross-sectional studies
  Reference      Population and study          Exposure assessment and              Health assessment           Results on developmental         Bias and confounding      Remarks
                 design                        statistical analyses                                             toxicity
  Wang, et al    Design: cross-sectional study ICP-MS measured concentrations       Occurrence of spontaneous   Tin in serum, mean (SD):         Healthy pregnant women    Pearson correlation
  (2020)43                                     of tin and 18 other metals in serum  abortion in 1st trimester,  • Women with SA: 0.28 (0.26)     who did not deliver       coefficients were used
                 Study location: hospital      samples collected at enrolment in    diagnosed by ultrasound and   mg/L                           successfully were excuded inappropriately:
                 Beijing, China                the study                            β-hCG levels                • Healthy pregnant women: 0.06   retrospectively           correlating concentrations
                                                                                    G                             (0.04) mg/L                                              with a dichotomous
                 Study period: Nov 2018-Dec    Statistical analysis:                estational age estimates    • p<0.001                        Prevalence of alcohol     variable (yes/no
                 2019                          • Pearson’s correlations between a   based on ultrasound                                          consumption was twice as  spontaneous abortion)
                                                 range of variables including metal                             Tin concentration was correlated high among women with
                 Population:                     concentrations and spontaneous     Measurement of various      with spontaneous abortion        SA (12/56 vs 6/55)        Strong risk of bias and
                 • 56 women with                 abortion                           hormones in blood (thyroid  (r=0.50, no p-value given)                                 confounding
                   spontaneous abortion (SA)   • Random forest regressie for        hormones, estradiol,                                         History of abnormal
                   in 1st trimester (median      multivariable analysis.            progesterone)               The contribution of tin to the   pregnancies more frequent Large influence of
                   gestational age 8.3 weeks),                                                                  occurrence of spontaneous        among wmen with SA (18% co-exposure to other
                   aged 18-35 yrs                                                                               abortion was ranked 6th in the   versus 5%)                metals
                 • 55 healthy women of                                                                          random forest analysis, with
                   similar age with normal                                                                      several other metals ranked
                   early pregnancy (median                                                                      higher
                   gestational age 7.4 weeks)
                   who later delivered
                   successfully
                 • 41 non-pregnant healthy
                   women of similar age
                 Exclusion criteria: basal
                 diseases (unspecified),
                 hypertension, polycystic
                 ovary syndrome, uterine
                 polyps, uterine fibroids
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<pre> chapter 06 | Adverse effects on development                                                                                     Tin and selected inorganic tin compounds | page 71 of 97
  Reference       Population and study           Exposure assessment and               Health assessment           Results on developmental           Bias and confounding         Remarks
                  design                         statistical analyses                                              toxicity
  Kot et al.      Study design: cross-sectional  Exposure assessment:                  Gestational age, placental  A negative correlation was found   No multivariable analysis    Multiple comparisons
  (2019)44        study                          Tin concentrations measured in the    parameters (length, width,  between placenta length and tin    with control for confounding (>1200) were not taken
                                                 placenta, fetal membrane, and         weight) and newborn         levels in the fetal membrane       by co-variables or           into account in the
                  Study location: Not specified  umbilical cord by                     parameters (weight, length, (Pearson’s correlation coefficient co-exposure to other         statistical significance
                                                 spectrophotometric atomic             and Apgar score).           -0.35, p<0.05)                     metals                       level applied
                  Study period: Not specified    absorption in inductively coupled
                                                 argon plasma                                                                                         Potential bias by inclusion  The description of the
                  Population: 83 women with a                                                                                                         of only properly developing  methods was too limited
                  properly developing            Statistical analysis:                                                                                pregnancies                  for proper quality
                  pregnancy and a course of      Correlations were analysed on the                                                                                                 assessment
                  delivery without complications basis of Pearson’s correlation
                  (i.e., preterm delivery,       coefficient (r)
                  preeclampsia)
  Cabrera-        Study design: cross-sectional  Cord blood samples were analysed Birth weight                     No correlation was observed
  Rodríguez et    study                          for 44 elements, including tin, using                             between tin levels in cord blood
  al. (2018)45                                   inductively coupled plasma-mass-                                  and birth weight
                  Study location: La Palma,      spectrometry
                  Spain
                                                 Statistical analysis:
                  Study period: March 2015-      correlations between the elements
                  April 2016                     and birth weight were assessed
                                                 using Pearson’s or Spearman’s
                  Population: 471 umbilical      correlation coefficients, as
                  cord blood samples (91.4%      appropriate. Multivariable analyses
                  of total number of births)     were performed for selected
                                                 elements only, but not for tin.
                                                 Adjustment for baseline
                                                 characteristics that were associated
                                                 with the outcome
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<pre> chapter 06 | Adverse effects on development                                                    Tin and selected inorganic tin compounds | page 72 of 97
 Prospective cohort studies                                                  for a nested case-control study. Inverse probability weighting was applied
 Howe et al. (2020a) investigated whether prenatal exposure to mixtures of   to account for this selection. Tin and 16 other metals were measured in
 heavy metals was associated with lower birth weight for gestational age in  urine samples, which were collected at 26 weeks of pregnancy (median
 a predominantly lower-income Hispanic pregnancy cohort in Los Angeles       (IQR) tin concentration 0.62 (0.35-1.22) μg/kg). The outcomes included
 (USA).29 Ten metals, including tin, were measured in spot urine samples of  repeated echocardiographic measures of foetal growth at 26 weeks
 262 pregnant women participating in the MADRES cohort. Urine samples        (median) and 35 weeks (median) of pregnancy, as well as birthweight,
 were collected in the first half of pregnancy (median gestational age 13.1  birth length, and placental weight. Without adjustment for co-exposures,
 weeks). Tin was not included in the primary analysis, but the secondary     associations were observed between tin in urine and repeated measures
 analysis showed an inverse linear relationship with birth weight adjusted   of head circumference and femur length, but no associations between tin
 for all relevant covariables while setting all other metals to their median and any of the foetal growth parameters were found in multi-metal models.
 values.                                                                     However, tin was associated with increased placental weight (adjusted β
                                                                             coefficient 38.9, 95% CI 2.8-75.0) and seafood-related exposures
 In the same MADRES cohort, Howe et al. (2020b) evaluated the                (arsenic, mercury, and tin) with decreased growth of head circumference
 associations between the same exposures and foetal growth parameters        and foetal weight.
 assessed at mid-pregnancy.30 The methods of measurement and analysis
 were the same as described above, but the study population was              A possible association between exposure to heavy metals during the first
 restricted to 193 pregnant women who enrolled prior to a routine            trimester of pregnancy and primary tooth eruption, was studied by Wu et
 anatomy ultrasound scan. No associations were observed between tin          al. (2020).32 Exposure to 12 metals, including tin, was measured in urine
 concentrations in urine and any of the outcome measures.                    samples collected in the first trimester of pregnancy from 244 women.
                                                                             No associations were found between tin concentration and time of tooth
 In a study on a sub-cohort from the LIFECODES birth cohort study, Kim et    eruption and number of teeth erupted at age one.
 al. (2020) investigated whether exposure to metals negatively impacted
 intra-uterine growth.31 The study included 130 women who experienced a      Associations between prenatal exposure to heavy metals and birth weight
 preterm delivery and 352 women with a term delivery, originally selected    and placental characteristics were studied by Zhao et al. (2020) in the
71        Health Council of the Netherlands | No. 2022/27                                                              2                               73
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<pre> chapter 06 | Adverse effects on development                                                      Tin and selected inorganic tin compounds | page 73 of 97
 Hangzhou Birth Cohort Study (China).33 Women were enrolled in weeks          235 couples with singleton pregnancies in a prospective cohort study on
 20-28 of gestation and concentrations of tin and 10 other metals were        fertility and environmental factors (LIFE study).35,36 Concentrations of tin
 measured in urine samples collected at baseline from 512 women. Median       and 20 other metals were measured in maternal and paternal spot urine
 (IQR) urinary concentration of tin was 9.13 (6.13-13.6) μg (g-creatinine)-1. samples, collected from all participants before conception, and frozen and
 In analyses relating urinary tin concentrations to placental weight,         stored for later analysis. For tin, no associations were found between
 chorionic plate area, chorionic disc eccentricity, placental thickness,      maternal and paternal urine concentrations and any of the outcome
 placental-foetal birth weight ratio, and birth weight, no associations were  measures, i.e., gestational age, birth weight, birth length, head
 observed.                                                                    circumference, ponderal index, and secondary sex ratio.
 Goodrich et al. conducted a prospective cohort study designed to             Shirai et al. (2010) evaluated the associations between maternal exposure
 characterize exposures to various substances, including tin, among           to heavy metals and birth weight, birth length, and head circumference.37
 pregnant women in the first trimester and to determine associations          They measured the concentrations of 10 metals, including tin, in spot
 with birth weight and foetal biometrics (biparietal diameter, head           urine samples of 78 pregnant women visiting the obstetrics outpatient
 circumference, abdominal circumference, and femur length).34 Urinary tin     clinic of a hospital in Tokyo, Japan. Tin concentration (μg per g-creatinine)
 concentration were measured in samples collected at 8-14 weeks of            was negatively associated with head circumference in univariable
 gestation among 56 mothers with full-term newborns from the Michigan         (correlation coefficient r=-0.269, p<0.05) and multivariable analysis
 Mother-Infant Pairs (MMIP) Study. Associations between tin                   (partial regression coefficient -0.178, p=0.017).
 concentrations and birth weight and second trimester foetal biometrics
 were examined via multivariable linear regression analyses adjusting for a   Case-control studies
 number of baseline characteristics. No associations were found between       Frye et al. (2020) studied the associations between either prenatal or early
 urinary tin levels and birth weight or foetal anthropometry parameters.      postnatal exposure to 10 metals (including tin) and autism spectrum
                                                                              disorders (ASD) with or without neurodevelopmental regression (NDR)
 Bloom et al. (2015) investigated the associations between parental           in children.38 In 27 cases with autism spectrum disorder and 7 healthy
 exposure to heavy metals and intra-uterine growth and preterm delivery in    controls, prenatal and early postnatal metal exposures were measured in
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<pre> chapter 06 | Adverse effects on development                                                     Tin and selected inorganic tin compounds | page 74 of 97
 deciduous teeth using validated tooth-matrix biomarkers with a               foetuses as controls. Tin and 13 other metals were measured by ICP-MS
 trimester-by-trimester resolution. The mean prenatal tin concentration       in amniotic fluid, obtained by amniocentesis around 20 weeks of
 was lower among cases compared to controls (0.00012 vs. 0.00022 (unit        pregnancy. The mean (SD) tin level in cases was higher than in controls:
 unclear); p<0.05), but this difference did not meet the p-value of 0.01      1.35 (2.28) μg/L versus 0.40 μg/L (0.55), p=0.018. Multivariable analyses
 taking into account multiple testing. Method of control selection is crucial including co-exposure to other metals and correction for differences in
 but was not explained and may have influenced results.                       baseline variables were not performed.
 Hou et al. (2019) investigated the associations between prenatal serum       Yan et al. (2017) also conducted a case-control study to investigate the
 concentrations of tin and 21 other metals and low birth weight.39 A nested   associations between ‘essential trace metals’, including tin, and neural
 case-control study within a prospective birth cohort study was performed,    tube defect in offspring.41 The researchers identified 191 women (period
 including 246 women with low birth weight infants and 406 women with         2003-2007) with a pregnancy complicated by a neural tube defect in
 normal birth weight infants. Serum tin concentrations did not differ         Shanxi Province and Hebei Province, China. These were matched on
 between cases and controls: median (inter quartile range (IQR)) 0.38         residence (same county/city) and time since last menstrual period to 261
 (0.18-0.79) µg/L in cases versus 0.40 (0.18-0.84) µg/L in controls, and      women who delivered healthy infants in the same birthing hospital.
 all odds ratios for tin concentration quartiles were close to unity. In a    Tin and eight other metals were measured in hair grown in the
 multi-metal model, also adjusted for additional covariables, tin was among   periconceptional period, using ICP-MS on processed hair segments.
 15 metals selected, but the implications of this result for tin were not     An association was found for anencephaly, with lower levels of tin
 further discussed.                                                           corresponding to higher risk, but not for spina bifida or all neural tube
                                                                              defects together. Median (IQR) tin concentration in the anencephaly group
 The possible association between trace metal elements and neural tube        was 0.034 (0.006-0.076) ng/mg hair versus 0.051 (0.011-0.134) ng/mg
 defects was studied by Ovaloyu et al (2019) in a case-control study,         hair in controls, p=0.049. The odds ratio for anencephaly comparing
 conducted in Turkey in the period 2017-2018.40 Cases were 36 pregnant        above- versus below-median tin concentrations, adjusted for multiple
 women with foetuses with a neural tube defect. These were matched for        co-variables, was 0.54 (95% CI: 0.30-0.97). However, co-exposure to
 maternal BMI and gestational age to 39 pregnant women with unaffected        other metals was not taken into account.
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<pre> chapter 06 | Adverse effects on development                                                     Tin and selected inorganic tin compounds | page 75 of 97
 Manduca et al. (2014) conducted a case-control study in the Gaza strip,      samples collected at enrolment in the study. Tin serum levels were found
 investigating whether exposure to heavy metals from military attacks was     to be different between women with and without spontaneous abortion:
 associated with birth defects and preterm birth.42 Cases were 48 babies      mean (SD) 0.28 (0.26) mg/L versus 0.06 (0.04) mg/L, p<0.001, but large
 born with a birth defect, including 11 neural tube defects, in the major     differences were also seen for alcohol consumption and a history of
 maternity hospital in 2011 and 9 preterm born infants without birth defects. abnormal pregnancy. In multivariable analyses, tin seemed to be less
 Controls were 12 full term healthy babies, randomly chosen among 3,892       strongly associated with spontaneous abortion than some other metals.
 births in the same hospital. Tin and 22 other metals were analysed by
 ICP-MS in newborn hair samples, collected immediately after birth.           Kot et al. determined the levels of 14 different metals, including tin, in
 Median (IQR) tin concentrations in hair were higher in birth defect cases    the placenta, foetal membranes, and umbilical cord and examined the
 and preterm born babies than in healthy newborns without birth defects:      correlations with placenta parameters (length, width, weight), gestational
 0.23 (0.08-0.54) ppm and 0.25 (0.23-0.89) ppm, respectively versus 0.04      age, and newborn parameters (weight, height, Apgar score).44 A total of
 (0.02-0.09) ppm, p=0.002 for both comparisons. The analyses were not         170 samples were obtained, comprising 81 placentas, 67 foetal
 controlled for potential confounders or co-exposure to other metals,         membranes, and 22 umbilical cords from 83 mothers aged from 17 to 44.
 although increased levels of tin coincided with increased levels of mercury  The only statistically significant (p<0.05) correlation coefficient (-0.35)
 and selenium in more than half of the children with a birth defect.          found for tin among many comparisons was one between placenta length
                                                                              and tin levels in the foetal membrane. There is high risk that this is a
 Cross-sectional studies                                                      chance finding amidst the >1200 comparisons done. No correlations were
 Wang et al. (2020) carried out a cross-sectional study to determine          observed between tin levels in any of the tissues and gestational age or
 whether exposure to metals was associated with spontaneous abortion.43       the neonatal parameters.
 The study included 56 women with spontaneous abortion in the first
 trimester treated at a gynaecology hospital in Beijing, China in the period  Cabrera-Rodríguez et al. analysed a total of 471 umbilical cord blood
 2018-2019, as well as 55 women with an undisturbed pregnancy in the 1st      samples in La Palma, Spain, which amounted to approximately 92% of the
 trimester who later delivered successfully and 41 non-pregnant healthy       total number of births recorded in 1 year.45 The cord blood levels of 44
 women. Tin and 18 other metals were measured by ICP-MS in serum              elements were assessed and studied in relation to birth weight by use of
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<pre> chapter 06 | Adverse effects on development                                                       Tin and selected inorganic tin compounds | page 76 of 97
 multivariable analysis adjusting for risk factors for birth weight deviations. Tin dichloride was tested for developmental toxicity in rats, mice,
 No correlation was observed between tin concentration and birth weight.        hamsters, and rabbits. For none of the species, effects on development
                                                                                were reported.17
 6.3      Short summary and overall relevance of the provided
          information on adverse effects on development                         In a multigeneration study in rats, no effects were observed on the
                                                                                numbers of offspring per litter or on birth weight. A teratogenicity study
 Animal data                                                                    with animals of the F2 generation did not show any visceral or skeletal
 Group 1: In reproduction/developmental toxicity screening test in rats,        malformations. Microscopic changes were observed in the liver and
 exposure to tin metal powder (0, 100, 300 and 1,000 mg/kg bw/day) did          spleen in the F3 pups, whereas mortality was increased in the F2 in the
 not affect litter development. In a prenatal developmental toxicity study in   first 10 days of lactation.1,16,17
 rats, treatment with 0, 30, 300 or 1,000 mg tin/kg bw did not reduce
 reproductive performance or affect developmental parameters.13                 In a developmental study with mice, oral exposure to tin dichloride (0, 2,
                                                                                10, 20 mg/kg bw/day) resulted in increased post-implantation loss and a
 Group 2: A slightly lower average number of pups per mother,                   decreased number of live foetuses at 10 and 20 mg/kg bw/day.28 A
 accompanied by lower weight of the litter was observed in rats exposed         decreased foetal body weight was observed at 2 mg/kg bw/day and
 to tin sulphide (0, 100, 300 or 1,000 mg/kg bw/day).26 No consistent           higher. A treatment-related reduction in the ossification of the foetal
 differences were observed in offspring weights and external malformations      skeleton was reported at 2 and 10 mg/kg bw/day but no details were
 between exposed groups and controls. In the highest dose group, an             provided.
 increase in number of livers with a marked structure was noted.
                                                                                No data on developmental toxicity are available for tin compounds of
 Group 3: No reduction in the number of live foetuses, foetal weight, or        group 4.
 placental weight was observed in pregnant rats administered tin fluoride
 in the diet (0, 7.8, 15.6, or 31.3 mg/kg bw/day).27
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<pre> chapter 06 | Adverse effects on development                                                   Tin and selected inorganic tin compounds | page 77 of 97
 Epidemiological data                                                       eccentricity, placental thickness, placental-foetal birth weight ratio, and
 Cohort studies                                                             birth weight.33
 Howe et al. (2020a) investigated whether prenatal exposure to mixtures of
 heavy metals was associated with lower birth weight for gestational age in Goodrich et al. (2019) did not observe any associations between urinary
 a pregnancy cohort in Los Angeles (USA).29 An inverse linear relationship  tin concentrations and birth weight or the foetal anthropometry parameters
 was shown between urinary tin levels and birth weight after adjustment for biparietal diameter, head circumference, abdominal circumference, and
 relevant covariables. No associations were observed between tin            femur length.34
 concentrations in urine and foetal growth parameters assessed at
 mid-pregnancy in the same cohort (Howe et al, 2020b).30                    Bloom et al. (2015) investigated the associations between parental
                                                                            exposure to heavy metals and intra-uterine growth and preterm delivery
 Kim et al. (2020) investigated whether exposure to metals negatively       in 235 singleton pregnancies.35 No associations were found between
 impacted intra-uterine growth in a cohort study among 130 women who        maternal and paternal tin urine concentrations and any of the outcome
 experienced a preterm delivery and 352 women with a term delivery.31       measures.
 Without adjustment for co-exposures, associations were observed
 between tin in urine and head circumference and femur length, but no       Shirai et al. (2010) evaluated the associations between maternal exposure
 associations with foetal growth parameters were found in multi-metal       to heavy metals and birth weight, birth length, and head circumference in
 models. However, tin was associated with increased placental weight.       78 pregnant women in Tokyo, Japan.37 A negative association was found
                                                                            between urinary tin concentration and head circumference.
 Wu et al. (2020) found no associations between urinary tin levels
 measured in 244 women during the first trimester of pregnancy and time     Case-control and cross-sectional studies
 of tooth eruption or number of teeth erupted at age one.32                 Frye et al. (2020) performed a case-control study among 27 children with
                                                                            autism spectrum disorder and 7 healthy controls, assessing prenatal tin
 Zhao et al. (2020) did not observe any associations between urinary tin    exposure in deciduous teeth. The mean tin concentration was lower
 concentrations and placental weight, chorionic plate area, chorionic disc
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<pre> chapter 06 | Adverse effects on development                                                      Tin and selected inorganic tin compounds | page 78 of 97
 among cases compared to controls, but did not reach statistical              in birth defect cases and in preterm born babies than in healthy newborns
 significance taking into account multiple testing.38                         without birth defects, but the analyses were not controlled for potential
                                                                              confounders or co-exposures.
 Hou et al. (2019) conducted a nested case-control study within a
 prospective birth cohort study including 246 women with low birth weight     Wang et al. (2020) carried out a cross-sectional study including 56 women
 infants and 406 women with normal birth weight infants.39 Serum tin          with spontaneous abortion in the first trimester, 55 women with an
 concentrations did not differ between cases and controls.                    undisturbed pregnancy, and 41 non-pregnant healthy women.43 Tin serum
                                                                              levels were found to be different between women with and without
 Ovaloyu et al (2019) investigated the association between trace metal        spontaneous abortion and appeared to be highly correlated with other
 elements and neural tube defects by comparing 36 pregnant women with         metals. Large differences were also seen for alcohol consumption and a
 affected foetuses to 39 pregnant women with unaffected foetuses as           history of abnormal pregnancy
 controls.40 The mean tin level in amniotic fluid was higher in cases than in
 controls, but no multivariable analyses were performed.                      Kot et al. (2019) determined tin levels in 81 placentas, 67 foetal
                                                                              membranes, and 22 umbilical cords from 83 women. No correlations were
 Yan et al. (2017) conducted a case-control study including 191               observed between tin levels in any of these tissues and gestational age,
 pregnancies complicated by a neural tube defect and 261 women who            birth weight, birth length, Apgar score, and placenta dimensions, except
 delivered healthy infants.41 An association was found between lower tin      for tin levels in foetal membranes and placenta length.44
 levels measured in hair grown in the periconceptional period and
 anencephaly, but not spina bifida or all neural tube defects together.       Cabrera-Rodríguez et al (2018) analysed a total of 471 umbilical cord
 Co-exposure to other metals was not taken into account.                      blood samples. No correlation was observed between tin concentration in
                                                                              cord blood and birth weight.45
 Manduca et al. (2014) conducted a study in the Gaza strip including 48
 cases with a birth defect, 9 preterm born infants without birth defects, and
 12 full term healthy babies.42 Median tin concentrations in hair were higher
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<pre> chapter 06 | Adverse effects on development                                                       Tin and selected inorganic tin compounds | page 79 of 97
 6.4     Comparison with the CLP criteria                                      of 10 and 20 mg/kg bw/day were observed.28 Further, a decreased foetal
 Developmental toxicity studies have been conducted with metallic tin, tin     body weight was observed at 2 mg/kg bw/day and higher and a reduction
 sulphide, tin fluoride, and tin dichloride.                                   in the ossification of the foetal skeleton was reported at 2 and 10 mg/kg
                                                                               bw/day. The Committee notes that the reporting of the latter study was
 Group 1: For metallic tin, no treatment-related effects were observed in a    very limited, and no information was provided on maternal toxicity.
 reproduction/developmental screening test in rats, with the exception of a
 decreased offspring weight at the highest dose (1000 mg/kg bw/day).13         Overall, no consistent and dose-related effects on development were
 No developmental toxicity was noted in a prenatal developmental toxicity      observed in animal studies. Only for tin dichloride, some developmental
 study in rats up to 1000 mg/kg bw/day.                                        findings were reported including mortality occurring in offspring from rats
                                                                               during lactation. However, the Committee cannot evaluate the respective
 Group 2: No statistically significant developmental effects were observed     study as only abstracts are available.1,16,17 In a developmental toxicity
 in a reproduction/developmental toxicity screening test with tin sulphide,    study with mice, clear developmental toxicity was observed (increased
 administered to rats up to a dose of 1000 mg/kg bw/day.25                     post-implantation loss, decreased number of live foetuses).28 In absence
                                                                               of data on maternal toxicity no conclusion can be drawn on the origin of
 Group 3: Administration of tin fluoride to rats in the diet (up to 31.3 mg/kg these effects.
 bw/day) during pregnancy did not affect developmental parameters.27
 In a series of prenatal developmental toxicity studies with multiple species  More than half of the epidemiological studies do not show any
 (mouse, rat, rabbit, and hamster), no developmental toxicity was reported     associations between exposure to tin and adverse effects on
 after exposure to daily doses of tin dichloride up to 50 mg/kg bw/day.17      developmental parameters. In three prospective cohort studies with
 In a multigeneration study with rats (only abstracts of this study are        adjustment for multiple co-variables and co-exposure to other metals,
 available), no developmental effects were observed.1,16,17 Several effects    however, potential associations are observed between exposure to tin
 were reported in pups after birth, however it is unclear in which             and birth weight, placental weight, and head circumference, each in only
 generation. In a developmental study with mice, increased                     one study.29,31,37 Three case-control studies point towards associations
 post-implantation loss and a decreased number of live foetuses at doses       between tin exposure and neural tube defects, but these studies lack
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<pre> chapter 06 | Adverse effects on development                              Tin and selected inorganic tin compounds | page 80 of 97
 adjustment for co-exposure and confounders.40-42 A potential association
 with spontaneous abortion is reported in a cross-sectional study that
 precludes conclusions due to intrinsic limitations.43
 As a result, no conclusions can be drawn regarding associations between
 exposure to tin and adverse effects on development in humans.
 Conclusion
 The Committee concludes that a lack of appropriate data precludes the
 assessment of tin and inorganic tin compounds for effects on
 development.
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<pre> chapter 07 | Adverse effects on or via lactation      Tin and selected inorganic tin compounds | page 81 of 97
 07
 adverse effects on
 or via lactation
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<pre> chapter 07 | Adverse effects on or via lactation                                                Tin and selected inorganic tin compounds | page 82 of 97
 7.1     Adverse effects on lactation                                         pooled, and analysed for selected pollutants and heavy metals including
 No information was found for adverse effects on lactation.                   tin. The tin concentration in both areas was below the limit of
                                                                              quantification of 2 ng/mL.46
 7.2     Adverse effects via lactation
                                                                              Tin concentrations in breast milk in women (n=58) from Brazil showed a
 Animal data                                                                  median level below the limit of quantification (0.1 µg/L), with a maximum
 In a multigeneration study with rats, the mortality of F2 generation litters level of 0.230 µg/L. In the same study, the median level in drinking water
 during the first 10 days of lactation was higher compared to controls, but   was 0.240 µg/L and in soil 3.10 µg/L.47
 decreased following an increase in iron in the diet of the dams.1
 Haematological studies showed a marked decrease in haemoglobin in the        The presence of a wide spectrum of major and trace elements, including
 pups at weaning age, that was related to the tin content of the diet. After  tin, was analysed in human milk (n=53).48 Also, exposure of the infant to
 weaning and increase of the dietary iron concentration, haemoglobin          these chemicals was assessed. The content of tin was higher (p<0.01) in
 content returned to normal, and mortality decreased.                         infant formula samples (measured as concentration in milk and fat) than in
                                                                              human milk. The concentration of tin in human milk was not influenced by
 The Committee notes that it is not clear whether the observed mortality      BMI or age of the mothers. Total tin intake via human milk could not be
 was related to effects of tin on or via lactation.                           assessed as all samples tested showed tin levels below the limit of
                                                                              detection (30 µg/L).
 Human data
 The presence of tin in human milk was measured in five studies and           The concentration of twelve elements, including tin, was analysed in
 showed that levels are low. There is no information on effects on the        human milk from Brazilian donors (n=50) with a lactation period greater
 infants fed with human milk.                                                 than 15 days. The mean tin concentration in human milk was 2.78 µg/L
                                                                              (SD=1.48), with a maximum level of 9.46 µg/L.49
 Milk specimens from mothers of the general population of the Venice
 (n=29) and Rome (n=10) areas were collected over the 1998-2001 period,
81      Health Council of the Netherlands | No. 2022/27                                                                2                                 83
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<pre> chapter 07 | Adverse effects on or via lactation                            Tin and selected inorganic tin compounds | page 83 of 97
 In random samples of breast milk from first time Swedish mothers (n=60)
 in early lactation (days 14-21), a mean tin concentration of 0.40 µg/L
 (SD=0.099) was determined, with a maximum level of 0.77 µg/L.50
 Assuming a mean infant body weight during lactation of 4.5 kg, a daily
 milk intake of 900 mL, and a (worst case) tin level in human milk of 10
 μg/L, the Committee calculates an exposure to the breastfed infant of 2
 µg/kg bw/day. This exposure levels is three orders of magnitude lower
 than the tolerable daily intake (TDI) of 2 mg/kg bw/day previously set by
 the WHO51, which is based on gastric irritancy with a threshold
 concentration of about 200 mg/kg in the food.16 The Committee notes that
 the TDI is not based on data representative for exposure of small infants.
 7.3     Comparison with the CLP criteria
 No data on tin in lactating animals are available. In humans, tin levels up
 to 10 μg/L have been determined. These levels are approximately
 1000-fold below the TDI previously set by the WHO. It should be noted
 that this TDI is based on local toxicity after a high exposure, but infants
 were not taken into account when establishing the TDI. In absence of
 indications for effects of tin on the development of offspring, the
 Committee considers the margin between tin exposure and the TDI
 sufficiently large to conclude that effects via lactation are not expected.
 No data on effects on lactation as such are available.
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<pre> chapter 08 | Conclusions on classification and labelling Tin and selected inorganic tin compounds | page 84 of 97
 08
 conclusions on classification
 and labelling
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<pre> chapter 08 | Conclusions on classification and labelling              Tin and selected inorganic tin compounds | page 85 of 97
 The Committee recommends classification according to Regulation (EC)
 1272/2008 of the European Union. For tin and inorganic tin compounds,
 the Committee concludes that:
 • Lack of appropriate data precludes the assessment for effects on
    fertility;
 • Lack of appropriate data precludes the assessment for effects on
    development;
 • Classification for effects on or via lactation is not indicated.
84        Health Council of the Netherlands | No. 2022/27                                    2                               86
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<pre> References                                            Tin and selected inorganic tin compounds | page 86 of 97
 references
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<pre> References                                                                                     Tin and selected inorganic tin compounds | page 87 of 97
 1
   World Health Organisation (WHO). Tin and inorganic tin compounds.         9
                                                                                Hiles RA. Absorption, distribution and excretion of inorganic tin in rats.
   IPCS Concise International Chemical Assessment Documents. 2005.              Toxicol Appl Pharmacol 1974; 27(2): 366-79.
 2
   Health Council of the Netherlands. Tin and inorganic tin compounds.       10
                                                                                Dimitrov NV, Meyer C, Nahhas F, Miller C, Averill BA. Effect of tin on
   Health-based recommendation occupational exposure limit. The                 immune responses of mice. Clin Immunol Immunopathol 1981; 20(1):
   Hague, 2005; 2005/06OSH.                                                     39-48.
 3
   CRC. Handbook of Chemistry and Physics. 96th edition ed.                  11
                                                                                European Chemicals Agency (ECHA). ECHA’s dissemination website.
 4
   Agency for Toxic Substances and Disease Registry (ATSDR).                    https://echa.europa.eu/nl/information-on-chemicals/registered-
   Toxicological profile for tin and tin compounds. 2005.                       substances. Accessed: June 10th, 2021.
 5
   Scientific Committee on Occupational Exposure Limits (SCOEL).             12
                                                                                European Chemicals Agency (ECHA). Read-Across Assessment
   European Commission. Recommendation from the Scientific                      Framework (RAAF). 2017; ECHA-17-R-01-EN.
   Committee on Occupational Exposure Limits for tin and inorganic tin       13
                                                                                European Chemicals Agency (ECHA). Registration dossier Tin. https://
   compounds. November 2003; SCOEL/SUM/97.                                      echa.europa.eu/nl/registration-dossier/-/registered-dossier/15457.
 6
   Caserta D, Mantovani A, Ciardo F, Fazi A, Baldi M, Sessa MT, et al.          Accessed: July 30, 2020.
   Heavy metals in human amniotic fluid: a pilot study. Prenat Diagn 2011;   14
                                                                                Naser DK AK, Abbas AK, Al-Chalabi SMM. he effect of metal
   31(8): 792-6.                                                                nanoparticle on LH, FSH and testosterone in male rats. Indian Journal
 7
   Skaug V, Eilertsen E, Skogstad A, Levy FES, Berlinger B, Thomassen           of Public Health Research and Development 2020; 11(3): 837-41.
   Y, et al. Kinetics and tissue distribution of bismuth, tin and lead after 15
                                                                                European Chemicals Agency (ECHA). Registration dossier Tin
   implantation of miniature shotgun alloy pellets in rats. J Trace Elem        Sulphide. https://echa.europa.eu/nl/registration-dossier/-/registered-
   Med Biol 2018; 48: 224-32.                                                   dossier/2149. Accessed: April 30, 2020.
 8
   Iwai-Shimada M, Kameo S, Nakai K, Yaginuma-Sakurai K, Tatsuta N,          16
                                                                                European Food and Safety Authority (EFSA). Re-evaluation of
   Kurokawa N, et al. Exposure profile of mercury, lead, cadmium, arsenic,      stannous chloride (E 512) as food additive. EFSA Journal May 2018.
   antimony, copper, selenium and zinc in maternal blood, cord blood and     17
                                                                                European Chemicals Agency (ECHA). Registration dossier Tin
   placenta: the Tohoku Study of Child Development in Japan. Environ            Dichloride. https://echa.europa.eu/nl/registration-dossier/-/registered-
   Health Prev Med 2019; 24(1): 35.                                             dossier/13167. Accessed: May 25, 2022.
86      Health Council of the Netherlands | No. 2022/27                                                               2                                   88
</pre>

====================================================================== Einde pagina 87 =================================================================

<br><br>====================================================================== Pagina 88 ======================================================================

<pre> References                                                                                    Tin and selected inorganic tin compounds | page 88 of 97
 18
    National Toxicology Program (NTP). National Institute of Environmental  25
                                                                               Research Institute for Organic Syntheses Inc. C. Tin Sulfide -
    Health Sciences. Carcinogenesis bioassay of stannous chloride (CAS         Reproduction/Developmental Toxicity Screening Test (Unpublished
    no. 7772-99-8) in F344/N rats and B6C3F1/N mice (feed study). 1982.        report; Available for consultation at The Health Council of The
 19
    Yousef MI. Protective role of ascorbic acid to enhance reproductive        Netherlands). 2010; 10-197.
    performance of male rabbits treated with stannous chloride. Toxicology  26
                                                                               Tribotecc GmbH (owner) - data shared with The Health Council of The
    2005; 207(1): 81-9.                                                        Netherlands. Tin sulfide - Reproduction/Developmental Toxicity
 20
    Bai D, Li Q, Xiong Y, Zhao J, Bai L, Shen P, et al. Editor’s Highlight:    Screening Test (OECD 421). 2010.
    Effects of Intraperitoneal Injection of SnS2 Flowers on Mouse Testicle. 27
                                                                               Theuer RC, Mahoney AW, Sarett HP. Placental transfer of fluoride and
    Toxicol Sci 2018; 161(2): 388-400.                                         tin in rats given various fluoride and tin salts. J Nutr 1971; 101(4):
 21
    Wang YX, Wang P, Feng W, Liu C, Yang P, Chen YJ, et al.                    525-32.
    Relationships between seminal plasma metals/metalloids and semen        28
                                                                               El-Makawy AI, Girgis SM, Khalil WK. Developmental and genetic
    quality, sperm apoptosis and DNA integrity. Environ Pollut 2017; 224:      toxicity of stannous chloride in mouse dams and fetuses. Mutat Res
    224-34.                                                                    2008; 657(2): 105-10.
 22
    Wang YX, Sun Y, Feng W, Wang P, Yang P, Li J, et al. Association of     29
                                                                               Howe CG, Claus Henn B, Eckel SP, Farzan SF, Grubbs BH, Chavez
    urinary metal levels with human semen quality: A cross-sectional study     TA, et al. Prenatal Metal Mixtures and Birth Weight for Gestational Age
    in China. Environ Int 2016; 91: 51-9.                                      in a Predominately Lower-Income Hispanic Pregnancy Cohort in Los
 23
    Wang YX, Sun Y, Huang Z, Wang P, Feng W, Li J, et al. Associations of      Angeles. Environ Health Perspect 2020; 128(11): 117001.
    urinary metal levels with serum hormones, spermatozoa apoptosis and     30
                                                                               Howe CG Claus Henn B, Farzan SF, Habre R, Eckel SP, Grubbs BH, et
    sperm DNA damage in a Chinese population. Environ Int 2016; 94:            al. Prenatal metal mixtures and fetal size in mid-pregnancy in the
    177-88.                                                                    MADRES study. Environ Res 2020: Environ Res 2021; 196:110388.
 24
    Guzikowski W, Szynkowska MI, Motak-Pochrzest H, Pawlaczyk A,            31
                                                                               Kim SS, Meeker JD, Aung MT, Yu Y, Mukherjee B, Cantonwine DE, et
    Sypniewski S. Trace elements in seminal plasma of men from infertile       al. Urinary trace metals in association with fetal ultrasound measures
    couples. Arch Med Sci 2015; 11(3): 591-8.                                  during pregnancy. Environ Epidemiol 2020; 4(2): e075.
87      Health Council of the Netherlands | No. 2022/27                                                                2                              89
</pre>

====================================================================== Einde pagina 88 =================================================================

<br><br>====================================================================== Pagina 89 ======================================================================

<pre> References                                                                                      Tin and selected inorganic tin compounds | page 89 of 97
 32
    Wu H, Xu B, Guan Y, Chen T, Huang R, Zhang T, et al. A metabolomic        38
                                                                                 Frye RE, Cakir J, Rose S, Delhey L, Bennuri SC, Tippett M, et al. Early
    study on the association of exposure to heavy metals in the first            life metal exposure dysregulates cellular bioenergetics in children with
    trimester with primary tooth eruption. Sci Total Environ 2020; 723:          regressive autism spectrum disorder. Transl Psychiatry 2020; 10(1):
    138107.                                                                      223.
 33
    Zhao H, Tang J, Zhu Q, He H, Li S, Jin L, et al. Associations of prenatal 39
                                                                                 Hou Q, Huang L, Ge X, Yang A, Luo X, Huang S, et al. Associations
    heavy metals exposure with placental characteristics and birth weight in     between multiple serum metal exposures and low birth weight infants in
    Hangzhou Birth Cohort: Multi-pollutant models based on elastic net           Chinese pregnant women: A nested case-control study. Chemosphere
    regression. Sci Total Environ 2020; 742: 140613.                             2019; 231: 225-32.
 34
    Goodrich JM, Ingle ME, Domino SE, Treadwell MC, Dolinoy DC, Burant        40
                                                                                 Ovayolu A, Ovayolu G, Karaman E, Yuce T, Ozek MA, Turksoy VA.
    C, et al. First trimester maternal exposures to endocrine disrupting         Amniotic fluid levels of selected trace elements and heavy metals in
    chemicals and metals and fetal size in the Michigan Mother-Infant Pairs      pregnancies complicated with neural tube defects. Congenit Anom
    study. J Dev Orig Health Dis 2019; 10(4): 447-58.                            (Kyoto) 2020; 60(5): 136-41.
 35
    Bloom MS, Buck Louis GM, Sundaram R, Maisog JM, Steuerwald AJ,            41
                                                                                 Yan L, Wang B, Li Z, Liu Y, Huo W, Wang J, et al. Association of
    Parsons PJ. Birth outcomes and background exposures to select                essential trace metals in maternal hair with the risk of neural tube
    elements, the Longitudinal Investigation of Fertility and the Environment    defects in offspring. Birth Defects Res 2017; 109(3): 234-43.
    (LIFE). Environ Res 2015; 138: 118-29.                                    42
                                                                                 Manduca P, Naim A, Signoriello S. Specific association of teratogen
 36
    Bloom MS, Buck Louis GM, Sundaram R, Maisog JM, Steuerwald AJ,               and toxicant metals in hair of newborns with congenital birth defects or
    Parsons PJ. Corrigendum to Birth outcomes and background                     developmentally premature birth in a cohort of couples with
    exposures to select elements, the Longitudinal Investigation of Fertility    documented parental exposure to military attacks: observational study
    and the Environment (LIFE). Environ Res 2015; 138: 118-29.                   at Al Shifa Hospital, Gaza, Palestine. Int J Environ Res Public Health
 37
    Shirai S, Suzuki Y, Yoshinaga J, Mizumoto Y. Maternal exposure to            2014; 11(5): 5208-23.
    low-level heavy metals during pregnancy and birth size. J Environ Sci     43
                                                                                 Wang R, Zhang L, Chen Y, Zhang S, Zhuang T, Wang L, et al. Elevated
    Health A Tox Hazard Subst Environ Eng 2010; 45(11): 1468-74.                 non-essential metals and the disordered metabolism of essential
88      Health Council of the Netherlands | No. 2022/27                                                                 2                                90
</pre>

====================================================================== Einde pagina 89 =================================================================

<br><br>====================================================================== Pagina 90 ======================================================================

<pre> References                                                                                     Tin and selected inorganic tin compounds | page 90 of 97
    metals are associated to abnormal pregnancy with spontaneous                  with human milk lyophilizate: A preclinical study. Environ Res 2020;
    abortion. Environ Int 2020; 144: 106061.                                      188: 109733.
 44
    Kot K, Kosik-Bogacka D, Lanocha-Arendarczyk N, Malinowski W,               50
                                                                                  Bjorklund KL, Vahter M, Palm B, Grander M, Lignell S, Berglund M.
    Szymanski S, Mularczyk M, et al. Interactions between 14 Elements in          Metals and trace element concentrations in breast milk of first time
    the Human Placenta, Fetal Membrane and Umbilical Cord. Int J                  healthy mothers: a biological monitoring study. Environ Health 2012;
    Environ Res Public Health 2019; 16(9): 1615.                                  11: 92.
 45
    Cabrera-Rodriguez R, Luzardo OP, Gonzalez-Antuna A, Boada LD,              51
                                                                                  World Health Organisation (WHO). 663. Tin (WHO Food Additives
    Almeida-Gonzalez M, Camacho M, et al. Occurrence of 44 elements in            Series 24)(1989). https://inchem.org/documents/jecfa/jecmono/
    human cord blood and their association with growth indicators in              v024je13.htm. Accessed: May 2022.
    newborns. Environ Int 2018; 116: 43-51.
 46
    Abballe A, Ballard TJ, Dellatte E, di Domenico A, Ferri F, Fulgenzi AR,
    et al. Persistent environmental contaminants in human milk:
    concentrations and time trends in Italy. Chemosphere 2008; 73(1
    Suppl): S220-7.
 47
    Cardoso OO, Juliao FC, Alves RI, Baena AR, Diez IG, Suzuki MN, et al.
    Concentration profiles of metals in breast milk, drinking water, and soil:
    relationship between matrices. Biol Trace Elem Res 2014; 160(1):
    116-22.
 48
    Martinez MA, Castro I, Rovira J, Ares S, Rodriguez JM, Cunha SC, et
    al. Early-life intake of major trace elements, bisphenol A,
    tetrabromobisphenol A and fatty acids: Comparing human milk and
    commercial infant formulas. Environ Res 2019; 169: 246-55.
 49
    Oliveira MM, Trevilato TMB, Segura-Munoz SI, Aragon DC, Alves LG,
    Nadal M, et al. Essential and toxic elements in human milk concentrate
89       Health Council of the Netherlands | No. 2022/27                                                                2                              91
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<pre> Annex A - Literature search strategy                  Tin and selected inorganic tin compounds | page 91 of 97
 annex A
 literature search
 strategy
90     Health Council of the Netherlands | No. 2022/27                       2                               92
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<pre> Annex A - Literature search strategy                                                                                           Tin and selected inorganic tin compounds | page 92 of 97
                                                                                                   Query      Results                                                                        Number of records
                                                                                                   #14        ‘toxicokinetics’/exp OR toxicokinetic*:ti,ab                                              13,954
 A scientific evaluation of the data on the toxicity of tin and inorganic tin
                                                                                                   #13        #4 AND (#11 OR #12)                                                                          209
 compounds was already performed by the Dutch Health Council in 2005,                              #12        ‘pregnancy outcome*’:ti,ab OR pregnan*:ti OR fertilit*:ti OR                             428,025
                                                                                                              ‘fecundit*’:ti OR (((differential OR effect* OR agent*) NEAR/3
 therefore, in agreement with the Health Council, the search is limited to                                    fertilit*):ti,ab) OR ((breast NEAR/3 milk):ti,ab) OR ((milk NEAR/3
                                                                                                              secret*):ti,ab) OR ‘lactation’:ti,ab OR ‘infertil*’:ti OR ‘subfertil*’:ti
 data from 2002 or later. To be complete, the developmental toxicity study
                                                                                                   #11        ‘fertility’/exp OR ‘lactation’/exp OR ‘breast milk’/exp OR ‘pregnancy’/                1,220,775
 by Theuer et al. (1971) that was mentioned in the report from 2005 was                                       exp OR ‘parameters concerning the fetus, newborn and pregnancy’/
                                                                                                              exp OR ‘infertility’/exp
 also included in this report.                                                                     #10        #4 AND #9                                                                                    166
                                                                                                   #9         #5 OR #6 OR #7 OR #8                                                                     276,736
                                                                                                   #8         (((repro* OR development*) NEAR/3 toxic*):ti,ab) OR teratogen*:ti,ab                      38,787
 Embase                                                                                                       OR reprotox*:ti,ab OR ‘embryotox*’:ti
                                                                                                   #7         ‘reproductive toxicity’/exp OR ‘teratogenicity’/exp OR ‘developmental                    218,329
 Table 1 presents the search terms and the results for the database
                                                                                                              toxicity’/exp OR ‘fetotoxicity’/exp OR ‘embryotoxicity’/exp OR
 Embase. Keywords were searched for in title and abstract.                                                    ‘organogenesis’/exp
                                                                                                   #6         ((prenatal OR maternal OR paternal) NEAR/3 expos*):ti,ab                                  28,619
 Table 1 Search strategy and result for Embase                                                     #5         ‘prenatal exposure’/exp OR ‘maternal exposure’/exp OR ‘paternal                           27,798
                                                                                                              exposure’/exp
  Query  Results                                                                Number of records
                                                                                                   #4         #1 OR #2 OR #3                                                                            26,616
  #27    #25 AND [2019-2021]/py                                                                64
                                                                                                   #3         ‘12013-46-6’:rn OR ‘68187-53-1’:rn OR ‘68187-12-2’:rn OR ‘12185-56-                       10,381
  #26    #25 AND [2002-2020]/py                                                               344
                                                                                                              7’:rn OR ‘12027-61-1’:rn OR ‘12027-70-2’:rn OR ‘12058-66-1’:rn OR
  #25    #10 OR #13 OR #17 OR #24                                                             528
                                                                                                              ‘15578-26-4’:rn OR ‘12067-23-1’:rn OR ‘69011-60-5’:rn OR ‘69029-52-
  #24    #4 AND (#21 OR #23)                                                                  173             3’:rn OR ‘1374645-21-2’:rn OR ‘85536-73-8’:rn OR ‘69012-35-7’:rn OR
  #23    #20 AND #22                                                                      140,180             ‘68187-05-3’:rn OR ‘7440- 31-5’:rn OR ‘68187-54-2’:rn OR ‘301-10-
  #22    ‘murine’/exp OR ‘experimental animal’/exp OR ‘animal experiment’/              5,388,125             0’:rn OR ‘13814-97-6’:rn OR ‘7772-99-8’:rn OR ‘7783-47-3’:rn OR
         exp OR ‘leporidae’/exp OR rat:ti,ab OR rats:ti,ab OR mouse:ti,ab OR                                  ‘18282-10-5’:rn OR ‘1315-01-1’:rn OR ‘21651-19-4’:rn OR ‘84776-04-
         mice:ti,ab OR hamster*:ti,ab OR pig*:ti,ab OR monkey:ti,ab OR                                        5’:rn OR ‘7488-55-3’:rn OR ‘1314-95-0’:rn OR ‘7646-78-8’:rn OR
         rabbit:ti,ab                                                                                         ‘49556-16-3’:rn OR ‘53408-94-9’:rn OR ‘814-94-8’:rn OR ‘69011-52-
  #21    #20 AND [humans]/lim                                                             170,069             5’:rn OR ‘84696-55-9’:rn
  #20    #18 OR #19                                                                       436,152  #2         ‘stannic chloride’/exp OR ‘stannous chloride’/exp OR ‘stannous                             4,239
  #19    ‘metabolism’:ti OR ‘adme’:ti,ab OR ‘absorption distribution metabolism           236,847             fluoride’/exp OR ‘stannous pyrophosphate’/exp OR ‘tin derivative’/exp
         excretion’:ti,ab                                                                          #1         ‘tin’/exp OR ‘tin’:ti,ab OR ‘tin(ii)’:ti,ab OR ‘stannous’:ti,ab OR                        24,106
  #18    ‘xenobiotic metabolism’/exp OR ‘metal metabolism’/mj OR                          227,567             ‘stannum’:ti,ab OR ‘stannate’:ti,ab OR ‘stannium’:ti,ab OR
         ‘metabolism’/mj                                                                                      ‘dipotassium hexahydroxostannate’ OR ‘ditin pyrophosphate’ OR ‘ditin
  #17    #4 AND (#14 OR #15 OR #16)                                                            58             trisulphide’ OR ‘zinc hydroxystannate’
  #16    ((environment* OR human OR biologic*) NEAR/3 ‘exposure                               122
                                                                                                  Ti, ab: search in title and abstract; mj: major topic, term is major focus of the article.
         monitor*’):ti,ab
  #15    ‘bioaccessibility’ OR ‘bioelut*’:ti,ab                                             2,961
91       Health Council of the Netherlands | No. 2022/27                                                                                                            2                                        93
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<pre> Annex A - Literature search strategy                                                                                Tin and selected inorganic tin compounds | page 93 of 97
 PubMed                                                                                            This resulted in 289 records.
 The following search terms were used for the database PubMed:
 Table 2 Search strategy and result for PubMed                                                     Scopus
  Search  Query                                                                       Items found  The following search terms were used for the database Scopus:
  #17    #16 AND 2002:2021[dp]                                                                 343
                                                                                                   ((TITLE-ABS-KEY (tin OR “tin(II)” OR stannous OR stannum OR stannate
  #16    #6 OR #9 OR #12 OR #15                                                                683
  #15    #1 AND #13 AND #14                                                                    163 OR stannium OR “dipotassium hexahydroxostannate” OR “ditin pyrophos-
  #14    rat[tw] OR rats[tw] OR mouse[tw] OR mice[tw] OR hamster*[tw] OR pig[tw]        23,056,508
                                                                                                   phate” OR “ditin trisulphide” OR “zinc hydroxystannate”)) AND ((TITLE-
         OR pigs[tw] OR monkey*[tw] OR rabbit*[tw] OR human*[tw] OR man[tw] OR
         men[tw] OR woman[tw] OR women[tw] OR child*[tw] OR infant*[tw] OR                         ABS-KEY ( ( prenatal OR maternal OR paternal ) W/3 expos* )) OR
         newborn*[tw] OR fetus*[tw] OR neonate*[tw]
                                                                                                   (TITLE-ABS-KEY ( ( ( repro* OR development* ) W/3 toxic* ) OR tera-
  #13    “Tin/metabolism”[Majr] OR “Metabolism”[Majr:NoExp] OR metabolism[ti] OR           219,558
         adme[tw] OR absorption distribution metabolism excretion[tw]                              togen* OR reprotox* OR embryotox* )) OR (TITLE-ABS-KEY ( pregnancy-
  #12    #1 AND (#10 OR #11)                                                                   311
  #11    Exposure monitor*[tw] AND (environment*[tw] OR human[tw] OR                           514
                                                                                                   outcome* OR differential-fertilit* OR ( breast W/3 milk ) OR ( milk W/3
         biologic*[tw])                                                                            secret* ) OR lactation )) OR (TITLE ( pregnan* OR fertilit* OR subfertil*
  #10    “Toxicokinetics”[Mesh] OR “Toxicological Phenomena”[Mesh] OR                      459,192
         toxicokinetic*[tw] OR bioaccessib*[tw] OR bioelut*[tw]                                    OR infertil* OR fecundit* OR organogenesis*)))) OR ((TITLE-ABS-KEY (tin
  #9     #1 AND (#7 OR #8)                                                                     176
                                                                                                   OR “tin(II)” OR stannous OR stannum OR stannate OR stannium OR
  #8     Pregnancy outcome*[tw] OR pregnan*[ti] OR fertilit*[ti] OR differential           363,275
         fertilit*[tw] OR breast milk[tw] OR milk secret*[tw] OR lactation[tw]                     “dipotassium hexahydroxostannate” OR “ditin pyrophosphate” OR “ditin
  #7     “Fertility”[Mesh] OR fertility[tw] OR “Lactation”[Mesh] OR “Milk,               1,048,611
         Human”[Mesh] OR “Milk”[Mesh:NoExp] OR “Pregnancy”[Mesh:NoExp] OR                          trisulphide” OR “zinc hydroxystannate”)) AND ((TITLE-ABS-KEY ( toxicoki-
         “Pregnancy Outcome”[Mesh]
                                                                                                   netic* OR bioaccessib* OR bioelut* OR ( ( environment* OR human OR
  #6     #1 AND (#2 OR #3 OR #4 OR #5)                                                         105
  #5     Reproductive toxic*[tw] OR developmental toxicity[tw] OR fetotoxic*[tw] OR         29,557 biologic* ) W/3 exposure-monitor* ) )) OR (TITLE-ABS-KEY ( adme OR
         teratogen*[tw] OR reprotox*[tw] OR embryotox*[tw]
                                                                                                   absorption-distribution-metabolism-excretion ) OR TITLE ( metabolism )))
  #4     “Teratogens”[Mesh] OR “Toxicogenetics”[Mesh]                                        8,629
  #3     Prenatal exposure[tw] OR maternal exposure[tw] OR paternal exposure[tw]           160,319 AND (TITLE-ABS-KEY ( rat OR rats OR mouse OR mice OR hamster*
         OR infertility[tw] OR subfertility[tw] OR fecundity[tw] OR organogenesis[tw]
  #2     “Prenatal Exposure Delayed Effects”[Mesh] OR “Maternal Exposure”[Mesh]            220,019
                                                                                                   OR pig OR pigs OR monkey* OR rabbit* OR human* OR man OR men
         OR “Paternal Exposure”[Mesh] “Organogenesis”[Mesh] OR “Infertility”[Mesh]                 OR woman OR women OR child* OR infant* OR newborn* OR fetus* OR
  #1     “Tin”[Mesh]OR “Tin Compounds”[Mesh] OR tin[tw] OR “tin(II)”[tw] OR                 22,394
         stannous[tw] OR stannum[tiab] OR stannate[tw] OR stannium[tw] OR                          neonate*))) AND PUBYEAR > 2001
         dipotassium hexahydroxostannate[tw] OR ditin pyrophosphate[tw] OR ditin
         trisulphide[tw] OR zinc hydroxystannate[tw]                                               This resulted in 212 records.
92       Health Council of the Netherlands | No. 2022/27                                                                                     2                               94
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<pre> Annex A - Literature search strategy                                                                         Tin and selected inorganic tin compounds | page 94 of 97
 Toxcenter                                                                              ECHA database
 A search was performed in Toxcenter using the searches as shown below:                 A list of 30 tin and inorganic tin compounds was searched for in the
 Table 3 Search strategy and result for Toxcenter                                       REACH database. Registration dossiers of 12 compounds were available
  Search    Search term                                                        #        and were consulted: tin, tin sulphide, tin oxide, ditin pyrophosphate, tin
  number                                                                       records
                                                                                        dichloride, tin difluoride, tin sulphate, tin disulphide, tin dioxide, disodium
  L1        SEA 12013-46-6 OR 68187-53-1 OR 68187-12-2 OR 12185-56-7 OR             242
            12027-61-1 OR 12027-70-2 OR 12058-66-1 OR 15578-26-4                        tin trioxide, disodium tin hexahydroxide and tin bis(tetrafluoroborate).
  L2        SEA 12067-23-1 OR 69011-60-5 OR 69029-52-3 OR 1374645-21-2 OR        20,719
            85536-73-8 OR 69012-35-7 OR 68187-05-3 OR 7440-31-5
  L3        SEA 68187-54-2 OR 301-10-0 OR 13814-97-6 OR 7772-99-8 OR 7783-47-3    9,243 Secondary sources
            OR 18282-10-5 OR 1315-01-1
  L4        SEA 21651-19-4 OR 84776-04-5 OR 7488-55-3 OR 1314-95-0 OR 7646-       2,112 The secondary sources that were consulted were as followed:
            78-8 OR 49556-16-3 OR 53408-94-9 OR 814-94-8 OR 69011-52-5 OR
            84696-55-9
                                                                                        • A concise international chemical assessment document number 65 on
  L5        SEA L1 OR L2 OR L3 OR L4                                             30,577     tin and inorganic tin compounds, from the World Health Organization
  L6        SEA (PRENATAL OR MATERNAL OR PATERNAL)(3W)EXPOS?                     55,239
  L7        SEA (REPRO? OR DEVELOPMENT?) (3W)TOXIC? OR TERATOGEN? OR            114,855     (WHO), within the framework of The International Programme on
            REPROTOX?
                                                                                            Chemical Safety (IPCS);
  L8        SEA PREGNANCY-OUTCOME? OR DIFFERENTIAL FERTILIT? OR                  43,767
            BREAST(3W)M                                                                 • A toxicological profile for tin and tin compounds, from the Agency for
            ILK OR MILK(3W)SECRET? OR LACTATION
  L9        SEA (PREGNAN? OR FERTILIT?)/TI                                       82,021
                                                                                            Toxic Substances and Disease Registry (ATSDR);
  L10       SEA TOXICOKINETIC? OR BIOACCESSIB? OR BIOELUT? OR                    27,220 • A recommendation from the Scientific Committee on Occupational
            (ENVIRONMENT? OR HUMAN OR BIOLOGIC?)(3W) EXPOSURE
            MONITOR?                                                                        Exposure Limits (SCOEL) for tin and inorganic tin compounds.
  L11       SEA ADME OR ABSORPTION DISTRIBUTION METABOLISM EXCRETION            137,277
            OR
            METABOLISM/TI                                                               In addition, RIVM-reports and evaluations and the RIVM-website ‘Risico’s
  L12       SEA L5 AND (L6 OR L7 OR L8 OR L9)                                       124
  L13       SEA L5 AND (L10 OR L11)                                                 153
                                                                                        van stoffen’a were consulted.
  L14       SEA L13/HUM,ANI                                                          22
  L15       SEA L12 OR L14                                                          144
  L16       SEA L15 AND 2002-2020/PY                                                 80
                                                                                        a
                                                                                          https://rvs.rivm.nl
93       Health Council of the Netherlands | No. 2022/27                                                                             2                                  95
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<pre> Annex A - Literature search strategy                                      Tin and selected inorganic tin compounds | page 95 of 97
 Overall evaluation of results literature search
 The obtained records were evaluated, duplicates were removed, and
 records were included if considered relevant based on title and abstract.
 Additionally, publications cited in the selected publications, but not
 selected during the primary search, were reviewed if considered
 appropriate.
94      Health Council of the Netherlands | No. 2022/27                                          2                               96
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<pre> Committee                                                                                                                                    Tin and selected inorganic tin compounds | page 96 of 97
 Committee and consulted experta
 Members of the Subcommittee on the Classification of Reproduction Toxic Substances                                    Scientific secretaries
 for the advisory report Tin and selected inorganic tin compounds                                                      •  D. Boers, Health Council of the Netherlands, Den Haag
 •   M.B.M. van Duursen, Professor Environmental Health and Toxicology, Vrije Universiteit Amsterdam,                  •  S.R. Vink, Health Council of the Netherlands, Den Haag
     chair
 •   W.M.L.G. Gubbels-Van Hal, Regulatory expert (toxicology and risk assessment) (retired), Oss
 •   M.W.G.D.M. van de Loo, Study Director Developmental and Reproductive Toxicology,
     Charles River Laboratories, Den Bosch
 •   N. Roeleveld, Reproductive epidemiologist; Radboud university medical center,
     Nijmegen (until March 18th, 2022)
 •   L.J.M. Smits, Professor of Clinical Epidemiology and Risk-Based Care, Maastricht University
 •   J.G. Theuns-Van Vliet, Reproductive toxicologist; Erasmus UMC, Rotterdam (until March 18th, 2022)
 •   P.J.J.M. Weterings, Toxicologist; Weterings Consultancy BV, Rosmalen (until January 1st, 2022)
 •   E.C.M. Tonk, Toxicologist; Charles River Laboratories BV, Den Bosch structurally consulted expert
 Observera
 •   J.J.A. Muller, Bureau Reach, National Institute of Public Health and the Environment, Bilthoven
 a
   Consulted experts are consulted by the committee because of their expertise. Consulted experts and observers
   are entitled to speak during the meeting. They do not have any voting rights and do not bear any responsibility for
   the content of the committee’s advisory report.
95           Health Council of the Netherlands | No. 2022/27                                                                                                                 2                      97
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<pre> The Health Council of the Netherlands, established in 1902, is an independent scientific advisory 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. Tin and selected inorganic tin compounds.
 The Hague: Health Council of the Netherlands, 2022; publication no. 2022/27.
 All rights reserved
96         Health Council of the Netherlands | No. 2022/27                                                               2
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