<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>Indium and indium compounds
    Evaluation of the effects on reproduction, recommendation for classification
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<pre></pre>

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<pre>Aan de staatssecretaris van Sociale Zaken en Werkgelegenheid
Onderwerp             : aanbieding advies Indium and indium compounds
Uw kenmerk            : DGV/MBO/U-932542
Ons kenmerk           : U-7401/HS/fs/543-C13
Bijlagen              :1
Datum                 : 30 oktober 2012
Geachte staatssecretaris,
Graag bied ik u hierbij het advies aan over de effecten van Indium en indiumverbindingen
op de vruchtbaarheid en het nageslacht; het betreft ook effecten op de lactatie en via de
moedermelk op de zuigeling. Dit advies maakt deel uit van een uitgebreide reeks waarin
voor de voortplanting giftige stoffen worden geclassificeerd volgens richtlijnen van de
Europese Unie. Het gaat om stoffen waaraan mensen tijdens de beroepsuitoefening kunnen
worden blootgesteld.
Dit advies is opgesteld door een vaste commissie van de Gezondheidsraad, de Subcommis-
sie Classificatie Reproductietoxische stoffen. Het is vervolgens getoetst door de Beraads-
groep Gezondheid en omgeving van de raad.
Ik heb dit advies vandaag ter kennisname toegezonden aan de staatssecretaris van Infra-
structuur en Milieu en aan de minister van Volksgezondheid, Welzijn en Sport.
Met vriendelijke groet,
prof. dr. W.A. van Gool,
voorzitter
Bezoekadres                                                         Postadres
Parnassusplein 5                                                    Postbus 16052
2 5 11 V X D e n        Haag                                        2500 BB Den     Haag
E - m a il : h . st o u t e n @ g r. n l                            w w w. g r. n l
Te l e f o o n ( 0 7 0 ) 3 4 0 7 0 0 4
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<pre></pre>

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<pre>Indium and indium compounds
Evaluation of the effects on reproduction, recommendation for classification
Subcommittee on the Classification of Reproduction Toxic Compounds
A Committee of the Health Council of the Netherlands
to:
the State Secretary of Social Affairs and Employment
No. 2012/17, The Hague, October 30, 2012
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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 & Sport, Infrastructure & the Environment, Social Affairs &
Employment, Economic Affairs, Agriculture & Innovation, and Education,
Culture & Science. 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.
                  The Health Council of the Netherlands is a member of the European
                  Science Advisory Network for Health (EuSANH), a network of science
                  advisory bodies in Europe.
                  The Health Council of the Netherlands is a member of the International Network
                  of Agencies for Health Technology Assessment (INAHTA), an international
                  collaboration of organisations engaged with health technology assessment.
 I NA HTA
This report can be downloaded from www.healthcouncil.nl.
Preferred citation:
Health Council of the Netherlands. Indium and indium compounds. Evaluation
of the effects on reproduction, recommendation for classification. The Hague:
Health Council of the Netherlands, 2012; publication no. 2012/17.
all rights reserved
ISBN: 978-90-5549-909-0
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<pre>   Contents
   Samenvatting 9
   Executive summary 11
   Scope 13
.1 Background 13
.2 Committee and procedure 13
.3 Effects on or via lactation 14
.4 Data 15
.5 Presentation of conclusions 15
.6 Final remark 16
   Indium and insoluble indium compounds 17
.1 Introduction 17
.2 Human studies 19
.3 Animal studies 19
.4 Conclusion 23
   Soluble indium compounds 27
.1 Introduction 27
.2 Human studies 28
   Contents                                 7
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<pre> .3 Animal studies 29
 .4 Conclusion 32
    References 35
    Annexes 37
A   The Committee 39
B   The submission letter (in English) 41
C   Comments on the public draft 43
D   Regulation (EC) 1272/2008 of the European Community 45
E   Additional considerations to Regulation (EC) 1272/2008 57
F   Fertility and developmental toxicity studies 59
    Indium and indium compounds
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<pre>Samenvatting
In het voorliggende advies heeft de Gezondheidsraad indium en
indiumverbindingen onder de loep genomen. Indium wordt gebruikt in lagers
voor auto’s en vliegtuigen, in soldeer en legeringen en in kernreactoren. Indium
en indiumverbindingen, inclusief indiumantimonide (InSb), indiumarsenide
(InAs) en indiumfosfide (InP), worden ook gebruikt in halfgeleiders, transistoren
en transistor materialen. Indiumoxide wordt gebruikt om glas te kleuren.
Indiumsulfaat wordt gebruikt voor het galvaniseren van materiaal en
radioisotopen van indium en indiumverbindingen (inclusief indiumtrichloride)
worden gebruikt in de behandeling van kanker en in diagnostische beeldvorming
van organen. Dit advies past in een reeks adviezen waarin de Gezondheidsraad
op verzoek van de minister van Sociale Zaken en Werkgelegenheid de effecten
van stoffen op de voortplanting beoordeelt. Het gaat vooral om stoffen waaraan
mensen tijdens de beroepsuitoefening kunnen worden blootgesteld. De
Subcommissie Classificatie reproductietoxische stoffen van de Commissie
Gezondheid en beroepsmatige blootstelling aan stoffen van de raad, hierna
aangeduid als de commissie, kijkt zowel naar effecten op de vruchtbaarheid van
mannen en vrouwen als naar effecten op de ontwikkeling van het nageslacht.
Daarnaast worden effecten op de lactatie en via de moedermelk op de zuigeling
beoordeeld.
Samenvatting                                                                      9
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<pre>  Op basis van Verordening (EG) 1272/2008 van de Europese Unie doet de
  commissie een voorstel voor classificatie. De commissie komt tot de volgende
  aanbevelingen:
  • indium(3+)zouten (mits goed oplosbaar):
      • voor effecten op de fertiliteit adviseert de commissie om
         indium(3+)zouten (mits goed oplosbaar) niet te kenmerken wegens
         onvoldoende geschikte gegevens
      • voor effecten op de ontwikkeling adviseert de commissie
         indium(3+)zouten (mits goed oplosbaar) in categorie 1B (stoffen waarvan
         verondersteld wordt dat zij toxisch zijn voor de menselijke voortplanting)
         te classificeren en met H360D (kan het ongeboren kind schaden) te
         kenmerken
      • voor effecten op of via lactatie, adviseert de commissie om
         indium(3+)zouten (mits goed oplosbaar) niet te kenmerken wegens
         onvoldoende geschikte gegevens.
  • indiumphosphide en indiumarsenide:
      • voor effecten op de fertiliteit adviseert de commissie om indiumphosphide
         en indiumarsenide in categorie 2 (stoffen die ervan verdacht worden dat
         zij toxisch zijn voor de menselijke voortplanting) te classificeren en met
         H361f (wordt ervan verdacht de vruchtbaarheid te schaden) te kenmerken
      • voor effecten op de ontwikkeling adviseert de commissie
         indiumphosphide en indiumarsenide niet te kenmerken wegens
         onvoldoende geschikte gegevens
      • voor effecten tijdens of via lactatie, adviseert de commissie om
         indiumphosphide en indiumarsenide niet te kenmerken wegens
         onvoldoende geschikte gegevens.
  • onoplosbare indiumzouten en slecht oplosbare indiumzouten anders dan
      indiumphosphide en indiumarsenide:
      • wegens onvoldoende geschikte gegevens adviseert de commissie om deze
         indiumzouten niet te kenmerken voor effecten op fertiliteit en
         ontwikkeling en effecten op of via lactatie.
0 Indium and indium compounds
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<pre>Executive summary
In the present report, the Health Council of the Netherlands reviewed indium and
indium compounds. Indium is used in bearings for cars and aircrafts, in solders
and low-melting alloys, and in nuclear reactor control rods. Indium and its
compounds, including indium antimonide (InSb), indium arsenide (InAs), and
indium phosphide (InP), find application in semiconductor devices, transistors,
and transistor materials. Indium oxide is used for colouring glass. Indium
sulphate is used in electroplating, and radioisotopes of indium and indium
compounds (including indium trichloride) are employed in the treatment of
cancer and in diagnostic imaging of body organs. This report is part of a series in
which the Health Council evaluates the effects of substances on reproduction at
the request of the Minister of Social Affairs and Employment. It mainly concerns
substances to which man can be occupationally exposed. The Subcommittee on
the Classification of Reproduction Toxic Substances of the Dutch Expert
Committee on Occupational Safety of the Health Council, hereafter called the
Committee, evaluates the effects on male and female fertility and on the
development of the progeny. Furthermore, the Committee considers the effects of
a substance on lactation and on the progeny via lactation.
The Committee recommends classification according to Regulation (EC) 1272/
2008 of the European Union. These recommendations are:
• indium (3+) salts (if well soluble):
Executive summary                                                                   11
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<pre>      • for effects on fertility, the Committee recommends not classifying indium
         (3+) salts (provided they are well soluble) due to a lack of appropriate data
      • for effects on development, the Committee recommends classifying
         indium (3+) salts (provided they are well soluble) in category 1B
         (presumed human reproductive toxicant) and labelling with H360D (may
         damage the unborn child)
      • for effects on or via lactation, the Committee recommends not labelling
         indium (3+) salts (provided they are well soluble) due to a lack of
         appropriate data.
  •   indium phosphide and indium arsenide:
      • for effects on fertility, the Committee recommends classifying indium
         phosphide and indium arsenide in category 2 (suspected human
         reproductive toxicant) and labelling with H361f (suspected of damaging
         fertility)
      • for effects on development, the Committee recommends not classifying
         indium phosphide and indium arsenide due to a lack of appropriate data
      • for effects on or via lactation, the Committee recommends not labelling
         indium phosphide and indium arsenide due to a lack of appropriate data.
  •   insoluble indium salts and poorly soluble indium salts other than indium
      phosphide and indium arsenide:
      • for effects on fertility and development and for effects on or via lactation,
         the Committee recommends not classifying insoluble indium salts and
         poorly soluble indium salts other than indium phosphide and indium
         arsenide due to a lack of appropriate data.
2 Indium and indium compounds
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<pre> hapter 1
        Scope
1.1     Background
        As a result of the Dutch regulation on registration of compounds toxic to
        reproduction that came into force on 1 April 1995, the Minister of Social Affairs
        and Employment requested the Health Council of the Netherlands to classify
        compounds toxic to reproduction. This classification is performed by the Health
        Council’s Subcommittee on the Classification of Reproduction Toxic Substances
        of the Dutch Expert Committee on Occupational Safety (DECOS). The
        classification is performed according to European Union Regulation (EC) 1272/
        2008 on classification, labelling and packaging (CLP) of substances and
        mixtures. The CLP guideline is based on the Globally Harmonised System of
        Classification and Labelling of Chemicals (GHS). The Subcommittee’s advice
        on the classification will be applied by the Ministry of Social Affairs and
        Employment to extend the existing list of compounds classified as reproductive
        toxicant (category 1A and B and 2) or compound with effects on or via lactation.
1.2     Committee and procedure
        This document contains the classification of indium and indium compounds by
        the Health Council’s Subcommittee on the Classification of Reproduction Toxic
        Substances, hereafter called the Committee. The members of the Committee are
        Scope                                                                             13
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<pre>    listed in Annex A. The submission letter (in English) to the State Secretary can
    be found in Annex B.
    In 2012, the President of the Health Council released a draft of the report for
    public review. The individuals and organizations that commented on the draft
    report are listed in Annex C. The Committee has taken these comments into
    account in deciding on the final version of the report.
    The classification is based on the evaluation of published human and animal
    studies concerning adverse effects with respect to fertility and development as
    well as lactation of the above mentioned compound.
    Classification for reproduction (fertility (F) and development (D)):
    Category 1              Known or presumed human reproductive toxicant (H360(F/D))
         Category 1A        Known human reproductive toxicant
         Category 1B        Presumed human reproductive toxicant
    Category 2              Suspected human reproductive toxicant (H361(f/d))
    No classification for effects on fertility or development
    Classification for lactation:
                            Effects on or via lactation (H362)
                            No labelling for lactation
    The classification and labelling of substances is performed according to the
    guidelines of the European Union (Regulation (EC) 1272/2008) presented in
    Annex D. The classification of compounds is ultimately dependent on an
    integrated assessment of the nature of all parental and developmental effects
    observed, their specificity and adversity, and the dosages at which the various
    effects occur. The guideline necessarily leaves room for interpretation, dependent
    on the specific data set under consideration. In the process of using the
    regulation, the Committee has agreed upon a number of additional considerations
    (see Annex E).
1.3 Effects on or via lactation
    The recommendation for classifying substances for effects on or via lactation is
    also based on Regulation (EC) 1272/2008. The guideline defines that substances
    which are absorbed by women and have been shown to interfere with lactation or
    which may be present (including metabolites) in breast milk in amounts
    sufficient to cause concern for the health of a breastfed child, shall be classified
    and labelled. Unlike the classification of substances for fertility and
 4  Indium and indium compounds
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<pre>    developmental effects, which is based on hazard identification only (largely
    independent of dosage), the labelling for effects on or via lactation is based on
    risk characterization and 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 the general population, e.g. the acceptable daily intake (ADI).
1.4 Data
    Literature searches were conducted in the on-line databases Toxline, Toxcenter,
    and Medline starting from 1950 up to 2008, and an update in PubMed in October
    2011. Literature was selected primarily on the basis of the text of the abstracts.
    Publications cited in the selected articles, but not selected during the primary
    search, were reviewed if considered appropriate. In addition, handbooks and a
    collection of most recent reviews were consulted. References are divided in
    literature cited and literature consulted but not cited.
    The Committee describes both the human and animal studies in the text. The
    animal data are described in more detail in Annex F as well. Of each study, the
    quality of the study design (performed according to internationally
    acknowledged guidelines) and the quality of documentation are considered.
1.5 Presentation of conclusions
    The classification is given with key effects, species and references specified. In
    case a substance is not classified as toxic to reproduction, one of two reasons is
    given:
    • lack of appropriate data precludes assessment of the compound for
         reproductive toxicity
    • sufficient data show that no classification for toxic to reproduction is
         indicated.
    Scope                                                                                15
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<pre>1.6 Final remark
    The classification of compounds is based on hazard evaluation only (Niesink et
    al., 199511), which is one of a series of elements guiding the risk evaluation
    process. The Committee emphasizes that for derivation of health-based
    occupational exposure limits these classifications should be placed in a wider
    context. For a comprehensive risk evaluation, hazard evaluation should be
    combined with dose-response assessment, human risk characterization, human
    exposure assessment, and recommendations of other organizations.
 6  Indium and indium compounds
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<pre> hapter 2
        Indium and insoluble indium
        compounds
2.1     Introduction
        name             : indium
        CAS number       : 7440-74-6
        EINECS-number    : 231-180-0
        synonyms         : -
        appearance       : soft, white metal with bluish tinge
        use              : in bearing alloys for cars and aircrafts; as a thin film on moving surfaces
                           made from other metals; in dental alloys; in semiconductor research; in
                           nuclear reactor control rods (in the form of a Ag-In-Cd alloys)
        chemical formula : In
        molecular weight : 114.82
        boiling point    : 2072 °C
        melting point    : 156.60 °C
        solubility       : soluble in acids, insoluble in alkalis
        name             : indium phosphide
        CAS-no           : 22398-80-7
        EINECS-number    : 244-959-5
        synonyms         : indium monophosphide
        appearance       : brittle mass with metallic appearance
        use              : semiconductors such as indium phosphide for laser diodes used in fiber
                           optic communication systems.
        chemical formula : InP
        molecular weight : 145.79
        Indium and insoluble indium compounds                                                          17
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<pre>  melting point       :  1070 °C
  solubility          :  insoluble in hot or cold water; soluble in acids; very slightly soluble in
                         sodium hydroxide
  EU classification :    H350, H371, H361f*
  * proposal of the EC Committee for Risk Assessment2
  name                :  indium arsenide
  CAS number          :  1303-11-3
  EINECS-number :        215-115-3
  synonyms            :  indium monoarsenide
  appearance          :  grey cubic crystals
  use                 :  application in semiconductor devices, transistors, transistor materials.
  chemical formula :     InAs
  molecular weight :     189.740
  melting point       :  942 °C
  solubility          :  low solubility in water
  EU classification       H331; H301*
  * concerns arsenic compounds with the exception of those specified elsewhere in Annex VI to
  Regulation (EC) No 1272/2008
  name                :  indium oxide
  CAS number          :  1312-43-2
  EINECS-number :        215-193-9
  synonyms            :  indium sesquioxide, indium trioxide, indium (III) oxide, diindium trioxide
  appearance          :  white to pale-yellow powder
  use                 :  used for colouring glass
  chemical formula :     In2O3
  molecular weight :     277.6
  solubility          :  insoluble in water; soluble in hot mineral acids
  Data from ECB3, HSDB10, and Merck16
  The toxicity of indium compounds is dependent on the form (solubility) of the
  compound administered, the dose, and the route of administration. Ionic indium
  compounds, such as InCl3, are bound to plasma proteins, such as transferrin and
  to a lesser extent albumin. Although they may cause focal liver necrosis at high
  doses, they primarily affect the proximal tubules of the kidney. Indium
  compounds target the endoplasmic reticulum of the liver and kidney, affecting
  both haem- and non-haem-dependent biochemical functions.12
8 Indium and indium compounds
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<pre>2.2 Human studies
    Fertility
    No data are available regarding the effects of exposure to indium or insoluble
    indium compounds on human fertility.
    Development
    No data are available regarding the effects of exposure to indium or insoluble
    indium compounds on development in humans.
    Lactation
    No data are available regarding the excretion of ‘indium’ in breast milk or the
    effects of exposure to indium or insoluble indium compounds on infants during
    the lactation period.
2.3 Animal studies
    Fertility and developmental toxicity studies with indium or indium compounds in
    laboratory animals are summarized in Annex F.
    Fertility studies
    Inhalation
    The US National Toxicology Program (NTP) conducted toxicity and
    carcinogenicity inhalation studies in which rats and mice were exposed to
    particulate aerosols of indium phosphide with a mass median aerodynamic
    diameter of approximately 1.2 µm at concentrations of 0, 1, 3, 10, 30 or 100
    mg/m3, six hours/day, five days/week (week 1-4 and week 10-14) or seven
    days/week (week 5-9), for fourteen weeks, or at concentrations of 0, 0.03, 0.1 or
    0.3 mg/m3, six hours/day, five days/week, for 22 (0.1, 0.3 mg/m3) or 105 weeks
    (0, 0.03 mg/m3). Animals in the two higher concentration groups were
    maintained on filtered air from exposure termination at week 22 until the end of
    the studies. The two-year studies included an interim kill/examination at three
    months. In the fourteen-week studies, apart from the standard organ weight
    Indium and insoluble indium compounds                                             19
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<pre>  recordings and histopathology, sperm motility and vaginal cytology parameters
  were evaluated in eight to ten animals exposed to 0, 3, 10 and 30 mg/m3. In
  addition, indium testis concentrations were determined in rats in three animals of
  all experimental groups at five time points during exposure and at four time
  points during a sixteen-week post-exposure period.
       In rats exposed to 100 mg/m3, ovarian and uterine atrophy occurred in all
  (9/9) females. The ovaries were small with small follicles and corpora lutea and
  condensed stroma. Uterine horn diameters were decreased, and there were
  shrunken glands and stromal condensation. Large degenerating cells of testicular
  germinal epithelial origin were present within seminiferous tubules of the testes
  (5/10 males) and within the epididymides of all (10/10) males. The glandular
  epithelium was flattened and there was reduced secretory material (atrophy)
  within the prostate (10/10) and seminal vesicles (9/10 males). Relative testis
  weights were increased at concentrations ≥3 mg/ m3 (p<0.05), while absolute
  testis weights were reduced at 100 mg/m3 (p<0.01). No significant differences
  were noted in sperm morphology or vaginal cytology parameters. Indium was
  detected in the testes at much higher concentrations than in blood or serum,
  although still several orders of magnitude less than in the lung. In all groups,
  testicular indium concentrations increased with increasing exposure
  concentration throughout the exposure period, and, unlike blood and serum
  concentrations, continued to increase post-exposure, indicating that indium was
  accumulating in the testes over time.
       Treatment caused statistically significant decreases in mean final body
  weights and body weight changes in all male groups and in females exposed to
  100 mg/m3. Apart from one male exposed to 100 mg/m3, all animals survived.
  Besides the reproductive organs, several other organs were affected, especially
  the lungs.
       In female mice exposed to 30 and 100 mg/ m3, atrophy of the uterus (30
  mg/m3: 4/10; 100 mg/m3: 8/10; controls: 0/10 ) and ovary (30 mg/m3: 9/10; 100
  mg/m3: 9/10; controls: 0/9) was observed. Uterine atrophy consisted of a
  decreased uterine horn diameter, stromal condensation, and shrunken glands.
  Atrophic ovaries contained follicles but either entirely lacking or having only
  very few, poorly developed corpora lutea. In addition, testis weights were altered
  at 10 mg/m3 (relative testis weight increased, p<0.05) and 30 mg/m3 (absolute
  testis weight decreased, relative testis weight increased, both p<0.01). No
  significant differences were noted in sperm morphology or vaginal cytology
  parameters.
       All mice exposed to 100 mg/m3 were removed moribund during week 7
  through 11. Also one male and four females exposed to 30 mg/m3 died before the
0 Indium and indium compounds
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<pre>end of the study. Final mean body weights and mean body weight gains were
statistically significantly decreased in males exposed to concentrations ≥3 mg/m3
and in females exposed to 10 or 30 mg/m3; males exposed to 30 mg/m3 lost
weight during the study. Effects observed on other than the reproductive organs
were generally similar but more severe than those seen in rats at similar
exposures.
    In the two-year study, there were no remarkable findings upon histological
three-month interim and two-year evaluation of the genital systems of male and
female rats and mice exposed to 0.003, 0.01 and 0.3 mg/m3.12
    The Committee notes that the animals of the latter groups were exposed for
only 22 weeks and examined after a 83-week exposure-free period.
Intratracheal instillation
Omura et al. (1996) exposed male rats (n=8) by intratracheal instillation to doses
of indium arsenide of 7.7 mg/kg bw, twice/week for eight weeks. Twenty-four
hours after the final instillation, animals were sacrificed and testes and
epididymides were removed, weighted and examined for sperm characteristics.
Treatment did not affect absolute or relative weights of testes and epididymides
and absolute and relative spermatid counts. Concerning the epididymal sperm
counts, there were no changes in the sperm counts of the whole epididymis and
of the head, but in the epididymal body plus tail a 16% reduction (p<0.05) was
found. Morphological examination did not reveal increased incidences of sperm
abnormalities.14
In a similar study, Omura et al. (1996) exposed male Syrian golden hamsters
(n=8) to indium arsenide according to the same protocol. However, treatment
was discontinued after the 14th instillation since three hamsters died or were
euthanized due to emaciation while the remaining five animals exhibited a
significant body weight loss. Treatment did not affect absolute weights of testes
and epididymides but relative weights were increased (p<0.05). No changes were
found in epididymidal sperm counts or upon histological evaluation of the testes.
Serum concentrations for indium and arsenic, measured at study termination,
were 19.5 and 0.3 µmol/L, respectively.13
Omura et al. (2000) exposed male Syrian hamsters to indium phosphide or
indium arsenide (3 and 4 mg/kg bw, respectively, twice/week) by intratracheal
instillation for eight weeks. Animals were analysed serially over a two-year
period (weeks 0-88 after the last instillation). Indium phosphide significantly
Indium and insoluble indium compounds                                              21
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<pre>  decreased body weight (80-90% of controls during post-exposure weeks 16-64),
  testis weight, and epididymis weight (60-70% of control weight between post-
  exposure weeks 16 and 64) and caudal sperm count (already immediately after
  last instillation, going down to 40-50% of control value between post- exposure
  weeks 16-64). Reproductive organ weights and sperm counts returned to control
  levels 88 weeks after exposure. In addition, severe histopathological changes in
  the testes were observed. From post-exposure weeks 16 to 64, histopathological
  alterations were observed in 30-50% of seminiferous tubuli (vacuolization),
  compared to 14% in the control group. Exposure to indium arsenide resulted in
  similar, but more severe effects, probably due to the fact that serum indium
  concentrations in the arsenide group were more than twice as high as those in the
  phosphide group. There were statistically significant decreases in body weight
  from post-exposure week 0 to the end of the follow up period (70% of controls).
  Reproductive organ weights were also statistically significantly reduced from
  directly after the last instillation until the end of the follow-up period (30-50% of
  control values from post-exposure weeks 16-88). In addition, caudal sperm
  counts were already statistically significantly decreased at post-exposure week 0,
  and decreased even further between post-exposure weeks 16 and 88 (10-30% of
  control values). Furthermore, the frequencies of seminiferous tubuli with
  histopathological changes were increased from post-exposure weeks 0 to 88
  (statistically significant from post-exposure weeks 16-88; 70-90% vs. 14% in
  controls). Effects on organs other than reproductive organs were not analysed.15
  Oral
  No data are available regarding the effects of oral exposure to indium or
  insoluble indium compounds on fertility in laboratory animals.
  Developmental toxicity studies
  Inhalation
  The NTP (2001) conducted developmental toxicity studies as part of the overall
  toxicity assessment of inhalation exposure to indium phosphide. Rats and mice
  were exposed to concentrations of indium phosphide of 0, 1, 10 or 100 mg/m3 on
  gestational days 4-19.
      In rats, exposure to indium phosphide did not induce maternal toxicity other
  than concentration-related increases in lung weights. Foetal toxicity,
2 Indium and indium compounds
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<pre>    malformations, or effects on any developmental parameters were not observed
    either.
        In mice, exposure to 100 mg/m3 resulted in early deaths, reduced body
    weight gain (although not statistically significant), listless appearance and
    laboured breathing. Lung weights were statistically significantly increased in all
    exposed mice. In some foetuses of the high-concentration group, renal
    haemorrhage was observed, but no foetal toxicity, malformations or
    developmental effects could be attributed to exposure.12
    Oral
    No data are available regarding the effects of oral exposure to indium or
    insoluble indium compounds on development in laboratory animals.
    Lactation
    No animal data are available on the excretion of ‘indium’ in breast milk or on
    effects of indium of insoluble indium compounds in pups during the lactation
    period.
2.4 Conclusion
    Fertility
    No data are available regarding the potential effects of indium or insoluble
    indium compounds on human fertility.
        Inhalation studies with indium phosphide in rats and mice12, and intratracheal
    instillation studies with indium phosphide in hamsters15 and with indium
    arsenide in rats14 and hamsters13,15 resulted in decreased reproductive organ
    weight in males and atrophy of the reproductive organs in males as well as in
    females. In addition, caudal epididymal sperm count was decreased and severe
    histopathological changes in the testes were observed. Although general toxicity
    was also observed at doses that affect the reproductive organs, the accumulation
    of indium phosphide in the testes indicates a direct effect on reproductive organs.
    Although the study results indicate that indium is at least partly responsible for
    the toxic effects observed in the reproductive organs, it cannot be excluded that
    phosphide and arsenide also play a role in the reproductive toxicity.
    Indium and insoluble indium compounds                                               23
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<pre>      Therefore, the Committee is of the opinion that for indium phosphide and
  indium arsenide classification in category 2 is justified. Due to a lack of data,
  other poorly soluble indium salts could not be assessed for effects on fertility.
  Development
  No data are available regarding the potential effects of indium or insoluble
  indium compounds on development in humans.
      Inhalation exposure to up to 100 mg/m3 indium phosphide did not result in
  developmental effects in rats and mice.12 Although plasma indium levels were
  not mentioned in this study, it is possible that the lack of effects is caused by a
  low systemic exposure to indium following inhalation. In addition, indium
  phosphide has a low solubility in synthetic simulated body fluids.5 If free indium
  ions are needed to elicit toxic effects, this can also explain the absence of
  developmental effects after administration of indium phosphide. Both theories
  are strengthened by the fact that, besides an increased lung weight, no maternal
  toxicity was observed in rats, and only after exposure to the highest dose tested
  in mice. Nevertheless, fertility effects were observed in an inhalation study with
  similar doses.12
      In conclusion, there are no human data available to draw a conclusion
  regarding effects of indium or insoluble indium compounds on development.
  Since the background of the absence of developmental effects after exposure to
  indium phosphide is not clear, and no data are available concerning the
  developmental effects of indium arsenide, the Committee is of the opinion that a
  lack of appropriate data precludes assessment of indium phosphide and indium
  arsenide for effects on development. Due to a lack of data, other poorly soluble
  indium salts could not be assessed for effects on development either.
  Lactation
  No human or animal data are available regarding the secretion of indium or
  insoluble indium compounds in milk. Therefore, the Committee concluded that a
  lack of appropriate data precludes assessment of indium or insoluble indium
  compounds for effects on or via lactation.
  Proposed classification for fertility
  For indium phosphide and indium arsenide: category 2; H361f.
4 Indium and indium compounds
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<pre>Lack of appropriate data precludes the assessment of other poorly soluble or
insoluble indium salts on fertility.
Proposed classification for developmental toxicity
Lack of appropriate data precludes the assessment of indium phosphide and
indium arsenide, or other poorly soluble or insoluble indium salts for effects on
development.
Proposed labelling for effect on or via lactation
Lack of appropriate data precludes the assessment of indium or poorly soluble or
insoluble indium compounds for effects on or via lactation.
Indium and insoluble indium compounds                                             25
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<pre>6 Indium and indium compounds</pre>

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<pre> hapter 3
        Soluble indium compounds
3.1     Introduction
        name             : indium trichloride
        CAS-no           : 10025-82-8
        EINECS-number    : 233-043-0
        synonyms         : indium chloride
        appearance       : yellowish, deliquescent crystals
        use              : in electroplating using a solution of the salt with dextrose and NaCN;
                           radioisotopes in indium trichloride are used in the treatment of tumours and
                           in organ scanning.
        chemical formula : InCl3
        molecular weight : 221.18
        boiling point      800 °C
        melting point    : 586 °C
        solubility       : soluble in water
        name             : indium nitrate
        CAS-no           : 13465-14-0
        EINECS-number    : 237-393-5
        synonyms         : indium trinitrate, indium(III) nitrate
        appearance       : colourless crystalline solid, powder no odour
        chemical formula : In(NO3)3
        molecular weight : 300.82
        melting point    : 100 °C
        solubility       : very soluble, hydrolyzes in water
        Soluble indium compounds                                                                        27
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<pre>    name             :    indium sulfate
    CAS-no           :   13464-82-9
    EINECS-number    :   236-689-1
    synonyms         :    indium trisulfate, diindium trisulfate, indium sequisulfate, indium(III)
                          sulfate
    appearance       :    white, hygroscopic powder
    use              :    used in electroplating
    chemical formula :    In2(SO4)3
    molecular weight :    517.8
    melting point    :    600 °C
    solubility       :    soluble in water
    Data from ECB3, HSDB10, and Merck16
    Indium is used in bearings for automobiles and aircrafts, in solders and low-
    melting alloys and in nuclear reactor control rods. Indium and its compounds
    find application in semiconductor devices, transistors and transistor materials.
    Indium sulfate is used in electroplating, and radioisotopes of indium and indium
    compounds (including indium trichloride) are employed in the treatment of
    cancer and in diagnostic imaging of body organs.10
    The toxicity of indium compounds is dependent upon the form (solubility) of the
    compound administered, the dose and the route of administration. Ionic indium
    compounds, such as InCl3, are bound to plasma proteins, such as transferrin and
    to a lesser extent albumin. Although they may cause focal liver necrosis at high
    doses, they primarily affect the proximal tubules of the kidney. Indium
    compounds target the endoplasmic reticulum of the liver and kidney, affecting
    both haem- and non-haem-dependent biochemical functions.12
3.2 Human studies
    Fertility
    No data are available regarding the effects of exposure to soluble indium
    compounds on human fertility.
    Development
    No data are available regarding the effects of exposure to soluble indium
    compounds on development in humans.
 8  Indium and indium compounds
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<pre>    Lactation
    No data are available regarding the excretion of ‘indium’ in breast milk or the
    effects of exposure to soluble indium compounds on infants during the lactation
    period.
3.3 Animal studies
    Fertility studies
    Gavage
    Chapin et al. (1995) administered doses of indium trichloride of 0, 50, 150 or 250
    mg/kg bw/day to mice (n=10/sex/group) from experimental days 1 to 20
    (females) or 3 to 20 (males). Mice were mated during experimental day 7-11.
    Treatment did not cause effects on ovulation, fertilization or implantation sites or
    changes in male reproductive organ weights, sperm parameters or microscopic
    structure of testes and epididymides. Two females of the high-dose group died.
    Decreased body weight gains (p<0.05) were recorded in all treated female groups
    and mid- and high-dose males. The latter animals also had decreased absolute
    liver weights (p<0.05), but relative liver weights were not affected. In addition,
    high-dose males showed reduced lymphocyte and haemoglobin values.1
    Developmental toxicity studies
    Gavage
    In the high-dose group in the experiment described above, Chapin et al. (1995)
    reported an approximately 50% decrease in the number of live implants and a
    trend toward more dead implants/dam.
        In a concomitant study, pregnant mice (n=10/group) were given indium
    trichloride doses of 0, 50, 150 or 250 mg/kg bw/day on gestational days 8-14 or
    gestational days 6-15. When given during gestational days 8-14, reduced body
    weights were observed in the dams of the mid- and high-dose groups (p<0.05),
    but no further maternal toxicity was reported. At 250 mg/kg bw/day, the body
    weight of the pups on postnatal day 1 was reduced (p<0.05).
        When administered during gestational days 6-15, body weight gains of the
    dams were not affected, but absolute and relative liver weights were reduced in
    the high-dose dams (p<0.05). In the two high-dose groups, there were dose-
    Soluble indium compounds                                                             29
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<pre>  related increases in early (not statistically significant) and late resorptions
  (p<0.05). In addition, at 250 mg/kg bw/day, there were changes in the number of
  live foetuses/litter (decrease), the number of dead foetuses/litter (increase) and
  the body weight of live foetuses (decrease) (all p<0.05). No statistically
  significant increases in skeletal or soft tissue abnormalities were found.1
  Nakajima et al. (1998) treated pregnant rats with single doses of indium
  trichloride (0, 75, 150, 300 mg indium/kg bw) on gestational day 9. Foetuses
  were examined for growth and malformation on gestational day 20. In the
  pregnant rats, there were no toxicological signs including changes in body
  weight, food consumption and necropsy findings. In the high dose group, not
  statistically significant increases in foetal mortality (16% vs. 8.3% in controls)
  and in the number of foetuses with malformations of the tail (11.7% vs. 1.3%)
  and with skeletal malformations (10.3% vs. 0%) were observed. Indium
  concentrations in the serum of pregnant rats (approx. 1.6 µg/mL, for one to six
  hours after administration) showed low bioavailability of indium by oral
  administration, probably explaining the lack of developmental effects observed
  after oral exposure to indium.8
  Ungváry et al. (2000) administered doses of indium trichloride of 0, 50, 100, 200
  or 400 mg/kg bw/day to rats on gestational days 6-15. In a second study, single
  doses of 0 or 400 mg indium trichloride/kg bw/day were given on one of
  gestational days 8, 9, 10, 11, 12, 13, 14 and 15. Pups were examined on
  gestational day 21. A dose-dependent decrease in food intake and body weight
  gain was observed in the dams, being significant at doses ≥100 mg/kg bw/day
  (p<0.05). At 400 mg/kg bw/day, maternal toxicity was reported, including
  increased relative liver, brain and pancreas weights, statistically significantly
  decreased bilirubin concentrations and AST and ALT serum activities, and
  effects on kidneys (congestion; cortico-medullar haemorrhage). At doses ≥100
  mg/kg bw/day, statistically significant increases were observed in the number of
  malformed foetuses (0.8%, 0.8%, 4.7%, 38.6%, 100% in control, 50, 100, 200,
  400 mg/kg bw groups, respectively); the defects included tail and limb,
  neurocranial, viscerocranial and visceral anomalies. In addition, doses ≥200
  mg/kg bw/day caused increased post-implantation loss (controls: 2.9%; 200
  mg/kg bw: 23.6%; 400 mg/kg bw: 72.1%) and reduced foetal weight (both
  p<0.05). The NOAEL for developmental toxicity was 50 mg/kg bw/day.
      After single oral doses of 400 mg/kg/day, reduced foetal body weight and
  retarded growth of the skeleton and internal organs of surviving foetuses was
0 Indium and indium compounds
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<pre>observed regardless of the day of exposure, but effects were highest when given
on gestational day 11 and 12.17
    The developmental effects observed after single oral doses of 400 mg indium
trichloride/kg bw reached statistical significance with less animals/group than
used in the Nakajima et al. (1998) study and at a lower dose (expressed as mg
indium/kg bw). The Committee could not find an obvious explanation for the
difference in results between the study of Nakajima et al. (1998) and Ungváry
et al. (2000).
In a similar study by Ungváry et al. (2000), indium trichloride (0, 50, 100 or 200
mg/kg bw/day) was administered to New Zealand rabbits on gestational days
6-20. Animals were examined on gestational day 30. At 200 mg/kg bw/day,
maternal toxicity was observed. Food intake and body weight gain were
significantly reduced (p<0.05), 4 out of 17 dams died, and autopsy and
histological examination showed similar results as in highest dose rats. In
addition, in the 200 mg/kg bw dose group, there were increases in the number of
post-implantation losses (13.9%; controls: 1.1%) and in the frequencies of
foetuses with skeletal retardation (7x; controls: 1 x) (both <0.05). Moreover, at
doses of ≥100 mg/kg bw/day, gross renal anomalies (renal agenesia and ectopia
renis; controls: 0 x; 100 mg/kg bw: 1+1; 200 mg/kg bw: 1+3) were reported,
although this increase was not statistically significant. The NOAEL for
developmental toxicity was 50 mg/kg bw/day.17
Intravenous
Single intravenous injections of doses of indium trichloride of 0.1-0.4 mg/kg bw
into Wistar or Sprague Dawley rats on gestational days 9, 10 or 11 caused
decreased foetal weights, increased foetal mortality and increased incidences of
malformations and variations. Effects were dependent on time of administration,
dose and strain. There were no signs of toxicity in the dams.6-9
    Single intravenous injections of indium trichloride of 0.8 or 1.6 mg/kg bw
into mice on gestational days 7, 8 or 9 induced reduced foetal weights at doses
≥0.8 mg/kg bw and foetal death at 1.6 mg/kg bw, but no gross malformations.9
    When golden hamsters were injected with doses of indium nitrate of 0.5-20
mg/kg bw on gestational day 8 and their embryos recovered 4, 5 or 6 days later, a
high incidence of skeletal malformations (at doses of 0,5 and 1.0 mg/kg bw) and
mortality of all embryos (at >2 mg/kg bw) were observed.4
Soluble indium compounds                                                           31
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<pre>    Lactation
    No animal data are available on the excretion of ‘indium’ in breast milk or on
    effects of soluble indium compounds in pups during the lactation period.
3.4 Conclusion
    Fertility
    No data are available regarding the potential effects of soluble indium
    compounds on human fertility.
        In an oral study in mice with indium trichloride (doses up to 250 mg/kg bw/
    day), no effects on ovulation, fertilization or implantation were observed in
    either of the dose groups, and no effects were found on microscopic structure of
    selected male tissues or reproductive parameters, whereas at doses ≥50 mg/kg
    general toxicity was observed in the parents (males as well as females).1 Other
    fertility studies in mice or in other animal species with soluble indium (3+) salts
    were not available.
        Therefore, the Committee is of the opinion that a lack of appropriate data
    precludes assessment of soluble indium (3+) compounds for effects on fertility.
    Developmental toxicity
    No data are available regarding the potential effects of soluble indium
    compounds on development in humans.
        In animals, developmental toxicity was observed in rats, mice and rabbits
    after oral administration of indium trichloride. Increased resorptions were
    observed in mice at doses without maternal toxicity.1 In addition, at oral doses of
    indium trichloride that induced slight maternal toxicity (restricted to reduced
    food intake and body weight gain), external malformations, visceral anomalies,
    skeletal malformations and skeletal variations were observed in rats.17 At oral
    doses that induced reduced liver weights but no further toxicity in pregnant mice,
    the number of live foetuses/litter was decreased, while the number of dead
    foetuses/litter was increased.1
        These findings were supported by intravenous studies in which injection of
    indium trichloride or nitrate induced similar effects in rats, mice or hamsters.4,6-9
        The Committee is of the opinion that the developmental effects occurred
    independently from maternal toxicity. Therefore, based on the data from animal
 2  Indium and indium compounds
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<pre>studies the Committee recommends classification of soluble indium (3+) salts in
category 1B.
Lactation
No human or animal data are available regarding the secretion of soluble indium
compounds in milk.
    Therefore, the Committee concluded that a lack of appropriate data precludes
assessment of soluble indium compounds for effects on or via lactation.
Proposed classification for fertility
Lack of appropriate data precludes the assessment of soluble indium (3+) salts for
effects on fertility.
Proposed classification for developmental toxicity
For soluble indium (3+) salts: category 1B; H360D.
Proposed labelling for effect on or via lactation
Lack of appropriate data precludes the assessment of soluble indium compounds
for effects on or via lactation.
Soluble indium compounds                                                           33
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<pre>4 Indium and indium compounds</pre>

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<pre>References
Chapin RE, Harris MW, Hunter ES, III, Davis BJ, Collins BJ, Lockhart AC. The reproductive and
developmental toxicity of indium in the Swiss mouse. Fundam Appl Toxicol 1995; 27: 140-148.
European Chemicals Agency (ECHA): Committee for Risk Assessement. Background document to
the opinion of the Committee for Risk Assessment on a proposal for harmonised classification and
labelling of indium phosphide EC number: 244-959-5, CAS number:22398-80-7. 2010.
European Chemicals Bureau (ECB), http://ecb.jrc.it/classification-labelling/. 2008.
Ferm VH, Carpenter SJ. Teratogenic and embryopathic effects of indium, gallium, and germanium.
Toxicol Appl Pharmacol 1970; 16: 166-170.
International Agency for Research on Cancer (IARC). Indium phosphide. In: Cobalt in hard metals
and cobalt sulfate, gallium arsenide, indium phosphide and vanadium pentoxide. Lyon, France:
IARC; 2006: 197-224. (IARC monographs on the evaluation of carcinogenic risks to humans; Vol
86). Internet: http://monographs.iarc.fr/ENG/Monographs/vol86/mono86.pdf.
Nakajima M, Mitsunaga K, Nakazawa K, Usami M. In vivo/in vitro study in rat embryos on indium-
caused tail malformations. Reprod Toxicol 2008; 25: 426-432.
Nakajima M, Takahashi H, Nakazawa K, Usami M. Fetal cartilage malformation by intravenous
administration of indium trichloride to pregnant rats. Reprod Toxicol 2007; 24: 409-413.
Nakajima M, Takahashi H, Sasaki M, Kobayashi Y, Awano T, Irie D et al. Developmental toxicity of
indium chloride by intravenous or oral administration in rats. Teratog Carcinog Mutagen 1998; 18:
231-238.
Nakajima M, Takahashi H, Sasaki M, Kobayashi Y, Ohno Y, Usami M. Comparative developmental
toxicity study of indium in rats and mice. Teratog Carcinog Mutagen 2000; 20: 219-227.
References                                                                                        35
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<pre>0 National Library of Medicine (NLM), editor. Indium; Indium compounds; Indium trichloride; indium
  phosphide. In: Hazardous Substances Data Bank (HSDB) [cited July 2011].
1 Niesink RJM, de Vries J, Hoolinger MA (eds). Toxicology, Principles and Applications. Boca Raton
  FL, USA: CRC Press; 1995.
2 National Toxicology Program (NTP). NTP technical report on the toxicology and carcinogenesis
  studies of indium phosphide (CAS No. 22398-90-7) in F344/N rats and B6C3F1 mice (inhalation
  studies). Research Triangle Park NC, USA: NTP; 2001. NTP Tech Rep Ser (499). Internet: http://
  ntp.niehs.nih.gov/ntp/htdocs/LT_rpts/tr499.pdf.
3 Omura M, Hirata M, Tanaka A, Zhao M, Makita Y, Inoue N, et al. Testicular toxicity evaluation of
  arsenic-containing binary compound semiconductors, gallium arsenide and indium arsenide, in
  hamsters. Toxicol Lett 1996; 89: 123-129.
4 Omura M, Tanaka A, Hirata M, Zhao M, Makita Y, Inoue N, et al. Testicular toxicity of gallium
  arsenide, indium arsenide, and arsenic oxide in rats by repetitive intratracheal instillation. Fundam
  Appl Toxicol 1996; 32: 72-78.
5 Omura M, Yamazaki K, Tanaka A, Hirata M, Makita Y, Inoue N. Changes in the testicular damage
  caused by indium arsenide and indium phosphide in hamsters during two years after intratracheal
  instillations. J Occup Health 2000; 42: 196-204.
6 The Merck Index, 14th edition. An Encyclopedia of Chemicals, Drugs, and Biologicals. 2006.
7 Ungvary G, Szakmary E, Tatrai E, Hudak A, Naray M, Morvai V. Embryotoxic and teratogenic
  effects of indium chloride in rats and rabbits. J Toxicol Environ Health A 2000; 59: 27-42.
  Literature used but not cited
  Nakajima M, Usami M, Nakazawa K, Arishima K, Yamamoto M. Developmental toxicity of indium:
  embryotoxicity and teratogenicity in experimental animals. Congenit Anom 2008; 48:
  145-150.
  Nakajima M, Sasaki M, Kobayashi Y, Ohno Y, Usami M. Developmental toxicity of indium in
  cultured rat embryos. Teratog Carcinog Mutagen 1999; 19(3): 205-209.
  Usami M, Nakajima M, Mitsunaga K, Miyajima A, Sunouchi M, Doi D. Proteomic analysis of
  indium embryotoxicity in cultured postimplantation rat embryos. Reprod Toxicol 2009; 28: 477-488.
6 Indium and indium compounds
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<pre>A The Committee
B The submission letter (in English)
C Comments on the public draft
D Regulation (EC) 1272/2008 of the European Community
E Additional considerations to Regulation (EC) 1272/2008
F Fertility and developmental toxicity studies
  Annexes
                                                         37
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<pre>8 Indium and indium compounds</pre>

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<pre>nnex A
     The Committee
     •  A.H. Piersma, chairman
        Professor of Reproductive and Developmental Toxicology, Utrecht
        University, Utrecht; National Institute for Public Health and the
        Environment, Bilthoven
     •  D. Lindhout
        Professor of Medical Genetics, Paediatrician (not practising), Clinical
        Geneticist, University Medical Centre, Utrecht
     •  N. Roeleveld
        Reproductive Epidemiologist, Radboud University Nijmegen Medical
        Centre, Nijmegen
     •  J.G. Theuns-van Vliet
        Reproductive Toxicologist, TNO Triskelion BV, Zeist
     •  D.H. Waalkens-Berendsen
        Reproductive Toxicologist, Zeist
     •  P.J.J.M. Weterings
        Toxicologist, Weterings Consultancy BV, Rosmalen
     •  A.S.A.M. van der Burght, scientific secretary
        Health Council of the Netherlands, Den Haag
     •  J.T.J. Stouten, scientific secretary
        Health Council of the Netherlands, Den Haag
     The Committee                                                              39
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<pre>  The first draft of the present document was prepared by dr. B. Tiesjema, of the
  National Institute for Public Health and the Environment (RIVM), Bilthoven, the
  Netherlands, by contract with the Ministry of Social Affairs and Employment.
  The Health Council and interests
  Members of Health Council Committees are appointed in a personal capacity
  because of their special expertise in the matters to be addressed. Nonetheless, it
  is precisely because of this expertise that they may also have interests. This in
  itself does not necessarily present an obstacle for membership of a Health
  Council Committee. Transparency regarding possible conflicts of interest is
  nonetheless important, both for the chairperson and members of a Committee
  and for the President of the Health Council. On being invited to join a
  Committee, members are asked to submit a form detailing the functions they
  hold and any other material and immaterial interests which could be relevant for
  the Committee’s work. It is the responsibility of the President of the Health
  Council to assess whether the interests indicated constitute grounds for non-
  appointment. An advisorship will then sometimes make it possible to exploit the
  expertise of the specialist involved. During the inaugural meeting the
  declarations issued are discussed, so that all members of the Committee are
  aware of each other’s possible interests.
0 Indium and indium compounds
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<pre>nnex B
     The submission letter (in English)
     Subject           : Submission of the advisory report Indium and indium compounds
     Your reference    : DGV/MBO/U-932342
     Our reference     : U 7401 /HS/fs/543-C13
     Enclosed          :1
     Date              : October 30, 2012
     Dear State Secretary,
     I hereby submit the advisory report on the effects of Indium and indium
     compounds on fertility and on the development of the progeny; it also concerns
     effects on lactation and on the progeny via lactation. This advisory report is part
     of an extensive series in which reproduction toxic substances are classified in
     accordance with European guidelines. This involves substances to which people
     may be exposed occupationally.
     The advisory report was prepared by a permanent committee of the Health
     Council of the Netherlands, the Subcommittee on the Classification of
     Reproduction Toxic Compounds. The advisory report was consequently
     reviewed by the Health Council’s Standing Committee on Health and the
     Environment.
     The submission letter (in English)                                                  41
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<pre>  Today I sent copies of this advisory report to the State Secretary of Infrastructure
  and the Environment and to the Minister of Health, Welfare and Sport, for their
  information.
  Yours sincerely,
  (signed)
  Prof. dr. W.A. van Gool,
  President
2 Indium and indium compounds
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<pre>nnex C
     Comments on the public draft
     • T.J. Lenz, S.S. Leonard. National Institute for Occupational Safety and
       Health, Cincinnati OH, USA.
     Comments on the public draft                                              43
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<pre>4 Indium and indium compounds</pre>

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<pre>nnex D
     Regulation (EC) 1272/2008 of the
     European Community
     3.7            Reproductive toxicity
     3.7.1          Definitions and general considerations
     3.7.1.1        Reproductive toxicity includes adverse effects on sexual function and fertility in adult
     males and females, as well as developmental toxicity in the offspring. The definitions presented
     below are adapted from those agreed as working definitions in IPCS/EHC Document No 225, Princi-
     ples for Evaluating Health Risks to Reproduction Associated with Exposure to Chemicals. For classi-
     fication purposes, the known induction of genetically based heritable effects in the offspring is
     addressed in Germ Cell Mutagenicity (section 3.5), since in the present classification system it is con-
     sidered more appropriate to address such effects under the separate hazard class of germ cell muta-
     genicity.
     In this classification system, reproductive toxicity is subdivided under two main headings:
     (a) adverse effects on sexual function and fertility;
     (b) adverse effects on development of the offspring.
     Some reproductive toxic effects cannot be clearly assigned to either impairment of sexual function
     and fertility or to developmental toxicity. Nonetheless, substances with these effects, or mixtures con-
     taining them, shall be classified as reproductive toxicants.
     Regulation (EC) 1272/2008 of the European Community                                                      45
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<pre>  3.7.1.2         For the purpose of classification the hazard class Reproductive Toxicity is differentiated
                  into:
  •     adverse effects
        •    on sexual function and fertility, or
        •    on development;
  •     effects on or via lactation.
  3.7.1.3         Adverse effects on sexual function and fertility
  Any effect of substances that has the potential to interfere with sexual function and fertility. This
  includes, but is not limited to, alterations to the female and male reproductive system, adverse effects
  on onset of puberty, gamete production and transport, reproductive cycle normality, sexual behaviour,
  fertility, parturition, pregnancy outcomes, premature reproductive senescence, or modifications in
  other functions that are dependent on the integrity of the reproductive systems.
  3.7.1.4         Adverse effects on development of the offspring
  Developmental toxicity includes, in its widest sense, any effect which interferes with normal devel-
  opment of the conceptus, either before or after birth, and resulting from exposure of either parent
  prior to conception, or exposure of the developing offspring during prenatal development, or postna-
  tally, to the time of sexual maturation. However, it is considered that classification under the heading
  of developmental toxicity is primarily intended to provide a hazard warning for pregnant women, and
  for men and women of reproductive capacity. Therefore, for pragmatic purposes of classification,
  developmental toxicity essentially means adverse effects induced during pregnancy, or as a result of
  parental exposure. These effects can be manifested at any point in the life span of the organism. The
  major manifestations of developmental toxicity include (1) death of the developing organism, (2)
  structural abnormality, (3) altered growth, and (4) functional deficiency.
  3.7.1.5         Adverse effects on or via lactation are also included in reproductive toxicity, but for
  classification purposes, such effects are treated separately (see Table 3.7.1 (b)). This is because it is
  desirable to be able to classify substances specifically for an adverse effect on lactation so that a spe-
  cific hazard warning about this effect can be provided for lactating mothers.
6 Indium and indium compounds
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<pre>3.7.2        Classification criteria for substances
3.7.2.1      Hazard categories
3.7.2.1.1    For the purpose of classification for reproductive toxicity, substances are allocated to
one of two categories. Within each category, effects on sexual function and fertility, and on develop-
ment, are considered separately. In addition, effects on lactation are allocated to a separate hazard cat-
egory.
Table 3.7.1(a) Hazard categories for reproductive toxicants.
Categories                      Criteria
CATEGORY 1                      Known or presumed human reproductive toxicant
                                Substances are classified in Category 1 for reproductive toxicity when
                                they are known to have produced an adverse effect on sexual function
                                and fertility, or on development in humans or when there is evidence
                                from animal studies, possibly supplemented with other information, to
                                provide a strong presumption that the substance has the capacity to
                                interfere with reproduction in humans. The classification of a sub-
                                stance is further distinguished on the basis of whether the evidence for
                                classification is primarily from human data (Category 1A) or from
                                animal data (Category 1B).
                Category 1A Known human reproductive toxicant
                                The classification of a substance in Category 1A is largely based on
                                evidence from humans.
                Category 1B Presumed human reproductive toxicant
                                The classification of a substance in Category 1B is largely based on
                                data from animal studies. Such data shall provide clear evidence of an
                                adverse effect on sexual function and fertility or on development in
                                the absence of other toxic effects, or if occurring together with other
                                toxic effects the adverse effect on reproduction is considered not to be
                                a secondary non-specific consequence of other toxic effects. However,
                                when there is mechanistic information that raises doubt about the rele-
                                vance of the effect for humans, classification in Category 2 may be
                                more appropriate.
CATEGORY 2                      Suspected human reproductive toxicant
                                Substances are classified in Category 2 for reproductive toxicity when
                                there is some evidence from humans or experimental animals, possi-
                                bly supplemented with other information, of an adverse effect on sex-
                                ual function and fertility, or on development, and where the evidence
                                is not sufficiently convincing to place the substance in Category 1. If
                                deficiencies in the study make the quality of evidence less convincing,
                                Category 2 could be the more appropriate classification.
                                Such effects shall have been observed in the absence of other toxic
                                effects, or if occurring together with other toxic effects the adverse
                                effect on reproduction is considered not to be a secondary non-specific
                                consequence of the other toxic effects.
Regulation (EC) 1272/2008 of the European Community                                                        47
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<pre>  Table 3.7.1(b) Hazard category for lactation effects.
  EFFECTS ON OR VIA LACTATION
  Effects on or via lactation are allocated to a separate single category. It is recognised that for many
  substances there is no information on the potential to cause adverse effects on the offspring via lacta-
  tion. However, substances which are absorbed by women and have been shown to interfere with lac-
  tation, or which may be present (including metabolites) in breast milk in amounts sufficient to cause
  concern for the health of a breastfed child, shall be classified and labelled to indicate this property
  hazardous to breastfed babies. This classification can be assigned on the:
  (a) human evidence indicating a hazard to babies during the lactation period; and/or
  (b) results of one or two generation studies in animals which provide clear evidence of adverse effect
  in the offspring due to transfer in the milk or adverse effect on the quality of the milk; and/or
  (c) absorption, metabolism, distribution and excretion studies that indicate the likelihood that the sub-
  stance is present in potentially toxic levels in breast milk.
  3.7.2.2        Basis of classification
  3.7.2.2.1      Classification is made on the basis of the appropriate criteria, outlined above, and an
  assessment of the total weight of evidence (see 1.1.1). Classification as a reproductive toxicant is
  intended to be used for substances which have an intrinsic, specific property to produce an adverse
  effect on reproduction and substances shall not be so classified if such an effect is produced solely as
  a non-specific secondary consequence of other toxic effects.
  The classification of a substance is derived from the hazard categories in the following order of pre-
  cedence: Category 1A, Category 1B, Category 2 and the additional Category for effects on or via lac-
  tation. If a substance meets the criteria for classification into both of the main categories (for example
  Category 1B for effects on sexual function and fertility and also Category 2 for development) then
  both hazard differentiations shall be communicated by the respective hazard statements. Classifica-
  tion in the additional category for effects on or via lactation will be considered irrespective of a clas-
  sification into Category 1A, Category 1B or Category 2.
  3.7.2.2.2      In the evaluation of toxic effects on the developing offspring, it is important to consider
  the possible influence of maternal toxicity (see section 3.7.2.4).
  3.7.2.2.3      For human evidence to provide the primary basis for a Category 1A classification there
  must be reliable evidence of an adverse effect on reproduction in humans. Evidence used for classifi-
  cation shall ideally be from well conducted epidemiological studies which include the use of appro-
  priate controls, balanced assessment, and due consideration of bias or confounding factors. Less
  rigorous data from studies in humans shall be supplemented with adequate data from studies in
  experimental animals and classification in Category 1B shall be considered.
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<pre>3.7.2.3         Weight of evidence
3.7.2.3.1       Classification as a reproductive toxicant is made on the basis of an assessment of the
total weight of evidence, see section 1.1.1. This means that all available information that bears on the
determination of reproductive toxicity is considered together, such as epidemiological studies and
case reports in humans and specific reproduction studies along with sub-chronic, chronic and special
study results in animals that provide relevant information regarding toxicity to reproductive and
related endocrine organs. Evaluation of substances chemically related to the substance under study
may also be included, particularly when information on the substance is scarce. The weight given to
the available evidence will be influenced by factors such as the quality of the studies, consistency of
results, nature and severity of effects, the presence of maternal toxicity in experimental animal stud-
ies, level of statistical significance for inter-group differences, number of endpoints affected, rele-
vance of route of administration to humans and freedom from bias. Both positive and negative results
are assembled together into a weight of evidence determination. A single, positive study performed
according to good scientific principles and with statistically or biologically significant positive results
may justify classification (see also 3.7.2.2.3).
3.7.2.3.2       Toxicokinetic studies in animals and humans, site of action and mechanism or mode of
action study results may provide relevant information which reduces or increases concerns about the
hazard to human health. If it is conclusively demonstrated that the clearly identified mechanism or
mode of action has no relevance for humans or when the toxicokinetic differences are so marked that
it is certain that the hazardous property will not be expressed in humans then a substance which pro-
duces an adverse effect on reproduction in experimental animals should not be classified.
3.7.2.3.3       If, in some reproductive toxicity studies in experimental animals the only effects
recorded are considered to be of low or minimal toxicological significance, classification may not
necessarily be the outcome. These effects include small changes in semen parameters or in the inci-
dence of spontaneous defects in the foetus, small changes in the proportions of common foetal vari-
ants such as are observed in skeletal examinations, or in foetal weights, or small differences in
postnatal developmental assessments.
3.7.2.3.4       Data from animal studies ideally shall provide clear evidence of specific reproductive
toxicity in the absence of other systemic toxic effects. However, if developmental toxicity occurs
together with other toxic effects in the dam, the potential influence of the generalised adverse effects
shall be assessed to the extent possible. The preferred approach is to consider adverse effects in the
embryo/foetus first, and then evaluate maternal toxicity, along with any other factors which are likely
to have influenced these effects, as part of the weight of evidence. In general, developmental effects
that are observed at maternally toxic doses shall not be automatically discounted. Discounting devel-
Regulation (EC) 1272/2008 of the European Community                                                         49
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<pre>  opmental effects that are observed at maternally toxic doses can only be done on a case-by-case basis
  when a causal relationship is established or refuted.
  3.7.2.3.5      If appropriate information is available it is important to try to determine whether devel-
  opmental toxicity is due to a specific maternally mediated mechanism or to a non-specific secondary
  mechanism, like maternal stress and the disruption of homeostasis. Generally, the presence of mater-
  nal toxicity shall not be used to negate findings of embryo/foetal effects, unless it can be clearly dem-
  onstrated that the effects are secondary non-specific effects. This is especially the case when the
  effects in the offspring are significant, e.g. irreversible effects such as structural malformations. In
  some situations it can be assumed that reproductive toxicity is due to a secondary consequence of
  maternal toxicity and discount the effects, if the substance is so toxic that dams fail to thrive and there
  is severe inanition, they are incapable of nursing pups; or they are prostrate or dying.
  3.7.2.4        Maternal toxicity
  3.7.2.4.1      Development of the offspring throughout gestation and during the early postnatal stages
  can be influenced by toxic effects in the mother either through non-specific mechanisms related to
  stress and the disruption of maternal homeostasis, or by specific maternally-mediated mechanisms. In
  the interpretation of the developmental outcome to decide classification for developmental effects it
  is important to consider the possible influence of maternal toxicity. This is a complex issue because
  of uncertainties surrounding the relationship between maternal toxicity and developmental outcome.
  Expert judgement and a weight of evidence approach, using all available studies, shall be used to
  determine the degree of influence that shall be attributed to maternal toxicity when interpreting the
  criteria for classification for developmental effects. The adverse effects in the embryo/foetus shall be
  first considered, and then maternal toxicity, along with any other factors which are likely to have
  influenced these effects, as weight of evidence, to help reach a conclusion about classification.
  3.7.2.4.2      Based on pragmatic observation, maternal toxicity may, depending on severity, influ-
  ence development via non-specific secondary mechanisms, producing effects such as depressed foe-
  tal weight, retarded ossification, and possibly resorptions and certain malformations in some strains
  of certain species. However, the limited number of studies which have investigated the relationship
  between developmental effects and general maternal toxicity have failed to demonstrate a consistent,
  reproducible relationship across species. Developmental effects which occur even in the presence of
  maternal toxicity are considered to be evidence of developmental toxicity, unless it can be unequivo-
  cally demonstrated on a case-by-case basis that the developmental effects are secondary to maternal
  toxicity. Moreover, classification shall be considered where there is a significant toxic effect in the
  offspring, e.g. irreversible effects such as structural malformations, embryo/foetal lethality, signifi-
  cant post-natal functional deficiencies.
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<pre>3.7.2.4.3      Classification shall not automatically be discounted for substances that produce devel-
opmental toxicity only in association with maternal toxicity, even if a specific maternally-mediated
mechanism has been demonstrated. In such a case, classification in Category 2 may be considered
more appropriate than Category 1. However, when a substance is so toxic that maternal death or
severe inanition results, or the dams are prostrate and incapable of nursing the pups, it is reasonable
to assume that developmental toxicity is produced solely as a secondary consequence of maternal
toxicity and discount the developmental effects. Classification is not necessarily the outcome in the
case of minor developmental changes, when there is only a small reduction in foetal/pup body weight
or retardation of ossification when seen in association with maternal toxicity.
3.7.2.4.4      Some of the end points used to assess maternal effects are provided below. Data on
these end points, if available, need to be evaluated in light of their statistical or biological signifi-
cance and dose response relationship.
Maternal mortality:
an increased incidence of mortality among the treated dams over the controls shall be considered evi-
dence of maternal toxicity if the increase occurs in a dose-related manner and can be attributed to the
systemic toxicity of the test material. Maternal mortality greater than 10 % is considered excessive
and the data for that dose level shall not normally be considered for further evaluation.
Mating index
(no. animals with seminal plugs or sperm/no. mated × 100) (*)
Fertility index
(no. animals with implants/no. of matings × 100)
Gestation length
(if allowed to deliver)
Body weight and body weight change:
Consideration of the maternal body weight change and/or adjusted (corrected) maternal body weight
shall be included in the evaluation of maternal toxicity whenever such data are available. The calcula-
() It is recognised that the Mating index and the Fertility index can also be affected by the male.
Regulation (EC) 1272/2008 of the European Community                                                       51
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<pre>  tion of an adjusted (corrected) mean maternal body weight change, which is the difference between
  the initial and terminal body weight minus the gravid uterine weight (or alternatively, the sum of the
  weights of the foetuses), may indicate whether the effect is maternal or intrauterine. In rabbits, the
  body weight gain may not be useful indicators of maternal toxicity because of normal fluctuations in
  body weight during pregnancy.
  Food and water consumption (if relevant):
  The observation of a significant decrease in the average food or water consumption in treated dams
  compared to the control group is useful in evaluating maternal toxicity, particularly when the test
  material is administered in the diet or drinking water. Changes in food or water consumption need to
  be evaluated in conjunction with maternal body weights when determining if the effects noted are
  reflective of maternal toxicity or more simply, unpalatability of the test material in feed or water.
  Clinical evaluations (including clinical signs, markers, haematology and clinical chemistry studies):
  The observation of increased incidence of significant clinical signs of toxicity in treated dams relative
  to the control group is useful in evaluating maternal toxicity. If this is to be used as the basis for the
  assessment of maternal toxicity, the types, incidence, degree and duration of clinical signs shall be
  reported in the study. Clinical signs of maternal intoxication include: coma, prostration, hyperactivity,
  loss of righting reflex, ataxia, or laboured breathing.
  Post-mortem data:
  Increased incidence and/or severity of post-mortem findings may be indicative of maternal toxicity.
  This can include gross or microscopic pathological findings or organ weight data, including absolute
  organ weight, organ-to-body weight ratio, or organ-to-brain weight ratio. When supported by find-
  ings of adverse histopathological effects in the affected organ(s), the observation of a significant
  change in the average weight of suspected target organ(s) of treated dams, compared to those in the
  control group, may be considered evidence of maternal toxicity.
  3.7.2.5        Animal and experimental data
  3.7.2.5.1      A number of internationally accepted test methods are available; these include methods
  for developmental toxicity testing (e.g. OECD Test Guideline 414), and methods for one or two-gen-
  eration toxicity testing (e.g. OECD Test Guidelines 415, 416).
  3.7.2.5.2      Results obtained from Screening Tests (e.g. OECD Guidelines 421 — Reproduction/
  Developmental Toxicity Screening Test, and 422 — Combined Repeated Dose Toxicity Study with
2 Indium and indium compounds
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<pre>Reproduction/Development Toxicity Screening Test) can also be used to justify classification,
although it is recognised that the quality of this evidence is less reliable than that obtained through
full studies.
3.7.2.5.3      Adverse effects or changes, seen in short- or long-term repeated dose toxicity studies,
which are judged likely to impair reproductive function and which occur in the absence of significant
generalised toxicity, may be used as a basis for classification, e.g. histopathological changes in the
gonads.
3.7.2.5.4      Evidence from in vitro assays, or non-mammalian tests, and from analogous substances
using structure-activity relationship (SAR), can contribute to the procedure for classification. In all
cases of this nature, expert judgement must be used to assess the adequacy of the data. Inadequate
data shall not be used as a primary support for classification.
3.7.2.5.5      It is preferable that animal studies are conducted using appropriate routes of administra-
tion which relate to the potential route of human exposure. However, in practice, reproductive toxic-
ity studies are commonly conducted using the oral route, and such studies will normally be suitable
for evaluating the hazardous properties of the substance with respect to reproductive toxicity. How-
ever, if it can be conclusively demonstrated that the clearly identified mechanism or mode of action
has no relevance for humans or when the toxicokinetic differences are so marked that it is certain that
the hazardous property will not be expressed in humans then a substance which produces an adverse
effect on reproduction in experimental animals shall not be classified.
3.7.2.5.6      Studies involving routes of administration such as intravenous or intraperitoneal injec-
tion, which result in exposure of the reproductive organs to unrealistically high levels of the test sub-
stance, or elicit local damage to the reproductive organs, including irritation, must be interpreted with
extreme caution and on their own are not normally the basis for classification.
3.7.2.5.7      There is general agreement about the concept of a limit dose, above which the produc-
tion of an adverse effect is considered to be outside the criteria which lead to classification, but not
regarding the inclusion within the criteria of a specific dose as a limit dose. However, some guide-
lines for test methods, specify a limit dose, others qualify the limit dose with a statement that higher
doses may be necessary if anticipated human exposure is sufficiently high that an adequate margin of
exposure is not achieved. Also, due to species differences in toxicokinetics, establishing a specific
limit dose may not be adequate for situations where humans are more sensitive than the animal
model.
3.7.2.5.8      In principle, adverse effects on reproduction seen only at very high dose levels in animal
studies (for example doses that induce prostration, severe inappetence, excessive mortality) would
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<pre>              not normally lead to classification, unless other information is available, e.g. toxicokinetics informa-
              tion indicating that humans may be more susceptible than animals, to suggest that classification is
              appropriate. Please also refer to the section on maternal toxicity (3.7.2.4) for further guidance in this
              area.
              3.7.2.5.9      However, specification of the actual ‘limit dose’ will depend upon the test method that
              has been employed to provide the test results, e.g. in the OECD Test Guideline for repeated dose tox-
              icity studies by the oral route, an upper dose of 1 000 mg/kg has been recommended as a limit dose,
              unless expected human response indicates the need for a higher dose level.
              3.7.3          Classification criteria for mixtures
              3.7.3.1        Classification of mixtures when data are available for all ingredients or only for some
              ingredients of the mixture
              3.7.3.1.1      The mixture shall be classified as a reproductive toxicant when at least one ingredient
              has been classified as a Category 1A, Category 1B or Category 2 reproductive toxicant and is present
              at or above the appropriate generic concentration limit as shown in Table 3.7.2 for Category 1A, Cat-
              egory 1B and Category 2 respectively.
              3.7.3.1.2      The mixture shall be classified for effects on or via lactation when at least one ingredi-
              ent has been classified for effects on or via lactation and is present at or above the appropriate generic
              concentration limit as shown in Table 3.7.2 for the additional category for effects on or via lactation.
 able 3.7.2 Generic concentration limits of ingredients of a mixture classified as reproduction toxicants or foreffects on or via
actation that trigger classification of the mixture.
 ngredient classified as:     Generic concentration limits triggering classification of a mixture as:
                              Category 1A                Category 1B               Category 2                Additional category
                              reproductive toxicant reproductive toxicant reproductive toxicant for effects on or via l
                                                                                                             actation
Category 1A                   ≥ 0,3 %
 eproductive toxicant         [Note 1]
  ategory 1B                                             ≥ 0,3 %
eproductive toxicant                                     [Note 1]
Category 2                                                                         ≥ 3,0 %
 eproductive toxicant                                                              [Note 1]
Additional category                                                                                          ≥ 0,3 %
or effects on or via                                                                                         [Note 1]
actation
  ote The concentration limits in the table above apply to solids and liquids (w/w units) as well as gases (v/v units).
  ote 1 If a Category 1 or Category 2 reproductive toxicant or a substance classified for effects on or via lactation is present in
he mixture as an ingredient at a concentration above 0,1 %, a SDS shall be available for the mixture upon request.
  4           Indium and indium compounds
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<pre>3.7.3.2        Classification of mixtures when data are available for the complete mixture
3.7.3.2.1      Classification of mixtures will be based on the available test data for the individual
ingredients of the mixture using concentration limits for the ingredients of the mixture. On a case-by-
case basis, test data on mixtures may be used for classification when demonstrating effects that have
not been established from the evaluation based on the individual components. In such cases, the test
results for the mixture as a whole must be shown to be conclusive taking into account dose and other
factors such as duration, observations, sensitivity and statistical analysis of reproduction test systems.
Adequate documentation supporting the classification shall be retained and made available for review
upon request.
3.7.3.3        Classification of mixtures when data are not available for the complete mixture:
               bridging principles
3.7.3.3.1      Subject to paragraph 3.7.3.2.1, where the mixture itself has not been tested to determine
its reproductive toxicity, but there are sufficient data on the individual ingredients and similar tested
mixtures to adequately characterise the hazards of the mixture, these data shall be used in accordance
with the applicable bridging rules set out in section 1.1.3.
3.7.4          Hazard Communication
3.7.4.1        Label elements shall be used for substances or mixtures meeting the criteria for
               classification in this hazard class in accordance with Table 3.7.3
Regulation (EC) 1272/2008 of the European Community                                                        55
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<pre> able 3.7.3 Label elements for reproductive toxicity.
 lassification              Category 1A or Category 1B              Category 2                             Additional category
                                                                                                           for effects on or via
                                                                                                           lactation
GHS Pictograms                                                                                             No pictogram
 ignal Word                 Danger                                  Warning                                No signal word
Hazard Statement            H360: May damage fertility or the       H361: Suspected of damaging fertil- H362: May cause
                            unborn child (state specific effect if ity or the unborn child (state specific harm to breast-fed
                            known)(state route of exposure if it is effect if known) (state route of expo- children.
                            conclusively proven that no other       sure if it is conclusively proven that
                            routes of exposure cause the hazard) no other routes of exposure cause the
                                                                    hazard)
 recautionary Statement     P201                                    P201                                   P201
 revention                  P202                                    P202                                   P260
                            P281                                    P281                                   P263
                                                                                                           P264
                                                                                                           P270
 recautionary Statement     P308 + P313                             P308 + P313                            P308 + P313
 esponse
 recautionary Statement     P405                                    P405
 torage
 recautionary Statement     P501                                    P501
Disposal
 6            Indium and indium compounds
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<pre>nnex E
     Additional considerations to
     Regulation (EC) 1272/2008
     The classification and labelling of substances is performed according to the
     guidelines of the European Union (Regulation (EC)1272/2008) presented in
     Annex B. The classification of compounds is ultimately dependent on an inte-
     grated assessment of the nature of all parental and developmental effects
     observed, their specificity and adversity, and the dosages at which the various
     effects occur. The guideline necessarily leaves room for interpretation, dependent
     on the specific data set under consideration. In the process of using the regula-
     tion, the Committee has agreed upon a number of additional considerations:
     • If there is sufficient evidence to establish a causal relationship between
         human exposure to the substance and impaired fertility or subsequent devel-
         opmental toxic effects in the offspring, the compound will be classified in
         category 1A, irrespective of the general toxic effects (see Annex B,
         3.7.2.2.1.).
     • Adverse effects in a reproductive study, reported without information on the
         parental or maternal toxicity, may lead to a classification other than category
         1B, when the effects occur at dose levels which cause severe toxicity in gen-
         eral toxicity studies.
     • Clear adverse reproductive effects will not be disregarded on the basis of
         reversibility per se.
     Additional considerations to Regulation (EC) 1272/2008                              57
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<pre>  •   The Committee does not only use guideline studies (studies performed
      according to OECD* standard protocols) for the classification of compounds,
      but non-guideline studies are taken into consideration as well.
  Organisation for Economic Cooperation and Development
8 Indium and indium compounds
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<pre> nnex        F
             Fertility and developmental toxicity
             studies
 able 1.1 Fertility studies in laboratory animals with indium compounds: inhalation.
 uthors    species        compound experimen- dose               general toxicity              effects on reproductive organs/
                                        tal period/                                            effects on reproduction
                                        design
NTP        F344/N rats indium           6 h/d, 5 d/ 0, 1, 3, 10, decreased mean final bw       100 mg/m3: atrophy of uterus
2001)      (n=10/sex/ phosphide wk, wk 1-4 30, 100               and bw changes in all         (decreased uterine horn diameter,
           group)                       and wk        mg/m3      exposed male groups and in    stromal condensation, shrunken
                                        10-14; 6 h/d,            females exposed to            glands) and ovaries ( small with
                                        7 d/wk, wk               100 mg/m3; lung, liver,       small follicles, corpora lutea,
                                        5-9                      haematological effects in all condensed stroma);
                                                                 exposed groups                epididymidal, seminiferous
                                                                                               tubular degeneration; flattened
                                                                                               glandular epithelium; prostate,
                                                                                               seminal vesicle atrophy; reduced
                                                                                               absolute testis weight;
                                                                                               ≥3 mg/ m3: increased relative
                                                                                               testis weight
NTP        B6C3F1         indium        6 h/d, 5 d/ 0, 1, 3, 10, all 100 mg/m3 group mice 30, 100 mg/ m3: atrophy of uterus
2001)      mice (n=10/ phosphide        wk, wk 1-4 30, 100       removed moribund; at 30 (decreased uterine horn diameter,
           sex/                         and wk        mg/m3      mg/m3 mortality in 5/20;      stromal condensation, shrunken
           group)                       10-14; 6 h/d,            decreased bw and bw gains glands) and ovary (no or only
                                        7 d/wk, wk               in males at ≥3 mg/m3, in      few, poorly developed corpora
                                        5-9                      females at 10 and 30 mg/ lutea)
                                                                 m3; haematological            10 mg/ m3: increased relative
                                                                 changes; lung lesions         testis weight
                                                                                               30 mg/m3: increased absolute,
                                                                                               decreased relative testis weight
 =day(s); h=hour(s); n=number; wk=week(s)
             Fertility and developmental toxicity studies                                                                      59
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<pre> able 1.2 Fertility studies in laboratory animals with indium compounds: intratracheal instillation.
 uthors        species        compound experimental         dose        general toxicity       effects on reproductive organs/
                                         period/design                                         effects on reproduction
Omura et al. male Wistar indium          2x/wk; 8 wk;       7.7 mg/kg not reported             no effect on absolute, relative
1996)          rats           arsenide sacrifice 24 h after bw                                 testis, epididymis weight; on
               (n=8/group)               final instillation                                    absolute, relative spermatid count;
                                                                                               on whole and head epididymidal
                                                                                               sperm count; 16% decrease in
                                                                                               epididymidal body+tail sperm
                                                                                               count (p<0.05)
Omura et al. male Syrian indium          2x/wk; 7 wk;       7.7 mg/kg mortality in 3/8         no effect on absolute testis,
1996)          golden         arsenide treatment            bw          (emaciation);          epididymis weight; increased
               hamsters                  discontinued after             significant bw loss in relative weights (p<0.05); no effect
               (n= 4-8/                  14th instillation              remaining 5/8          on epididymidal sperm count; no
               group)                                                   (leading to treatment histological testicular changes
                                                                        termination)
Omura et al. male Syrian indium          2x/wk for 8 wk; 4 mg/kg decreased bw gain decreased testis, epididymis
2000)          golden         arsenide analysis up to 2 y bw            (70% of controls, wk weight, caudal sperm count; severe
               hamsters                  following                      0-64)                  histopathological changes in the
               (n= 4-8/                  treatment                                             testes: vacuolization of
               group)                    (wk 0-88)                                             seminiferous tubuli
Omura et al. male Syrian indium          2x/wk for 8 wk; 3 mg/kg decreased bw gain decreased testis, epididymis
2000)          golden         phosphide analysis up to 2 y bw           (80-90% of controls, weight, caudal sperm count; severe
               hamsters                  following                      wk 16-64)              histopathological changes in testes
                (n= 4-8/                 treatment                                             (vacuolization of seminiferous
               group)                    (wk 0-88)                                             tubuli)
 w=body weight; n=number; wk=week(s); y=year(s)
 able 1.3 Fertility studies in animals with indium compounds: gavage.
 uthors       species       compound experimental           dose        general toxicity       effects on reproductive organs/
                                          period/design                                        effects on reproduction
 hapin et al. Swiss mice indium           males: d 3-20,    0, 50, 150, males:                 250 mg: decreased number of
1995)         (n=10/sex/ trichloride females: d 1-20 250 mg/kg 250, 150 mg/kg: bw              implants, trend towards increased
              group)                      (mating on        bw/d        loss; decreased liver  number of dead implants/dam; no
                                          d 7-11)                       weight                 effects on ovulation, fertilization,
                                                                        250 mg: reduction      total number of implantations
                                                                        lymphocytes,
                                                                        haemoglobin
                                                                        females:
                                                                        all groups: decreased
                                                                        bw gain;
                                                                        250 mg/kg: mortality
                                                                        in 2/10
 w=body weight; d=day(s); n=number; wk=week(s)
 0            Indium and indium compounds
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<pre> able 2.1 Developmental toxicity studies in laboratory animals with indium compounds: inhalation.
 uthors         species          compound       experimental concentration general toxicity                       developmental
                                                period/design                                                     toxicity
NTP (2001)      Sprague-         indium         gd 4-19a;       0, 1, 10, 100 concentration-related increase      no significant
                Dawley rats      phosphide      analysis after mg/m3           in lung weights                    observed
                (n=unknown)                     birth
NTP (2001)      Swiss CD-1       indium         gd 4-17a;       0, 1, 10, 100 at all concentrations: increased    no significant
                mice             phosphide      analysis after mg/m3           lung weight;                       foetal toxicity
                (n=unknown)                     birth                          100 mg/m3: early deaths,           observed
                                                                               listless appearance, laboured
                                                                               breathing
 exposure schedule (hours/day, days/week) not reported
 d=gestational day(s); n=number
 able 2.2 Developmental toxicity studies in animals with indium compounds: gavage.
 uthors    species      compound experi-         dose         general toxicity developmental toxicity               remarks
                                      mental
                                      period/
                                      design
  hapin et Crl:CD-1 indium            gd 8-14;   0, 50, 150, 150, 250 mg/kg: 250 mg/kg: increased number of
 l. (1995) (ICR) BR trichloride necropsy         250 mg/kg decreased bw        dead pups, decreased foetal bw
           mice                       pnd 4      bw/d
           (n=10/
           group)
  hapin et Crl:CD-1 indium            gd 6-15,   0, 50, 150, 250 mg/kg:        no increases in skeletal or soft     maternal
 l. (1995) (ICR) BR trichloride necropsy         250 mg/kg decreased           tissue abnormalities                 NOAEL:
           mice                       gd 16      bw/d         absolute,        250 mg/kg: increased number of       150 mg/kg
           (n=11-15/                                          relative liver   late resorptions, of dead            bw;
           group)                                             weight           foetuses/ litter; reduced number     foetal
                                                                               of live foetuses/litter; reduced     NOAEL: 50
                                                                               bw live foetuses                     mg/kg bw
                                                                               150 mg/kg: increased number of
                                                                               late resorptions
Nakajima Wistar rats indium           gd 9:      0, 75, 150, no effect on      no statistically significant effects foetal
 t al.     (n=7-10/     trichloride necropsy     300 mg/kg maternal bw,        on foetal mortality, foetal          NOAEL: ≥
1998)      group)                     gd 20      bw           food             weight, number of tail or skeletal   300 mg/kg
                                                              consumption; no malformations                         bw
                                                              necropsy         [300 mg/kg: decreased foetal
                                                              findings         weight (of 5%; ns); increased
                                                                               incidence (10-12%) of tail
                                                                               malformations (kinked tail,
                                                                               brachyury; ns)]
             Fertility and developmental toxicity studies                                                                      61
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<pre>Ungváry    Sprague-     indium      gd 6-15,      0, 50, 100, 400 mg/kg:         ≥100 mg/kg: increased number        maternal and
 t al.     Dawley rats trichloride  necropsy      200, 400     increased         of foetuses with external           foetal
2000)      (n=21-33/                gd 21         mg/kg bw/d relative liver,     malformations (≥100 mg/kg:          NOAEL: 50
           group)                                              pancreas, brain   cleft palate; rudimentary,          mg/kg bw/d
                                                               weight;           missing tail;
                                                               decreased          ≥200 mg/kg: club foot;
                                                               bilirubin         400 mg/kg: exencephalia,
                                                               concentration,    rudimentary mandible,
                                                               serum AST and     syndactilia)
                                                               ALAT activities;  ≥200 mg/kg: increased post-
                                                               kidney lesions    implantation loss; decreased
                                                               (congestion,      foetal weight; increased number
                                                               cortico-medullar  of foetuses with visceral
                                                               haemorrhage)      anomalies (≥200 mg/kg: ectopia
                                                               ≥100 mg/kg:       renis, ectopia testis, dilated
                                                               decreased food    pelvis renalis, dilated ureter; 400
                                                               intake, bw gain   mg/kg: ectopia ovaries), with
                                                                                 major skeletal anomalies
                                                                                 (cranium, sternum, ribs,
                                                                                 vertebrae)
                                                                                 400 mg/kg: decreased placental
                                                                                 weight
Ungváry    Sprague-     indium      gd 8, 9, 10,  0, 400 mg/ maternal toxicity   all exposure days: decreased
 t al.     Dawley rats trichloride  11, 12, 13,   kg bw        not discussed     foetal bw, retarded skeleton and
2000)      (n=3-5                   14 or 15;     (single                        internal organ growth in
           dams/                    necropsy      dose)                          surviving foetuses;
           group)                   gd 21                                        gd 9, 10, 11, 12, 15: mortality in
                                                                                 10-20%
                                                                                 gd 11, 12: gross (external)
                                                                                 anomalies
                                                                                 gd 10, 11, 14: increased
                                                                                 frequency of skeletal
                                                                                 malformations
                                                                                 gd 14, 15: internal organ
                                                                                 anomalies.
Ungváry    New          indium      gd 6-20;      0, 50, 100, 200 mg/kg:          200 mg/kg: increased number of     maternal
 t al.     Zealand      trichloride necropsy      200 mg/kg mortality (4/17),    abortions and full resorptions;     NOAEL:
2000)      rabbits                  gd 30         bw/d         reduced food      increased frequency of foetuses     100 mg/kg
           (n=12-17/                                           intake, bw gain;  with skeletal retardation           bw;
           group)                                              autopsy results   (sternum hypoplasia, double         foetal
                                                               to those found in vertebral ossification centers,     NOAEL: 50
                                                               highest dosed     shortened rib 13, dilated cranial   mg/kg bw
                                                               rats (see above)  sutures)
                                                                                 ≥100 mg/kg: gross renal
                                                                                 anomalies (unilateral renal
                                                                                 agenesis, dystopia renis)
 d=gestational day(s); n=number; ns=not statistically significant
  2          Indium and indium compounds
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<pre> able 2.3 Developmental toxicity studies in animals with indium compounds: intravenous injection
 uthors    species       compound experimen- dose                general toxicity developmental toxicity              remarks
                                     tal period/
                                     design
 erm/      golden        indium      gd 8,         0.5, 1, 2, 5, maternal toxicity ≥2 mg/kg: mortality in all         maternal
  arpenter hamsters      nitrate     recovery of 10, 20 mg/ not extensively embryos                                   NOAEL: 10
1970)      (n= 1-23/                 embryos at kg bw            investigated; 20 0.5,1 mg/kg: high incidence of      mg/kg bw;
           group)                    gd 12, 13                   mg/kg: mortality malformations of the digits of      foetal
                                     or 14                       with 48 h         the extremities (fusion, stunting, LOAEL: 0.5
                                                                                   polydactyly)                       mg/kg bw
Nakajima Crj:Wistar indium           gd 9,         0, 0.1, 0.2, no maternal        0.4 mg/kg: decreased foetal,       maternal
 t al.     rats (n=8- trichloride necropsy         0.4 mg/kg toxicity observed placental weigth; increased            NOAEL: 0.4
1998)      10/group)                 gd 20         bw                              incidence of gross (kinked tail,   mg/kg bw;
                                                                                   brachyury, cleft palate), visceral foetal
                                                                                   (undescended testis, dilatation of NOAEL: 0.2
                                                                                   renal pelvis), skeletal (fused     mg/kg bw
                                                                                   sternebrae, ribs) malformations,
                                                                                   or skeletal variations (number of
                                                                                   ossified sternebrae)
Nakajima ICR             indium      gd 7, 8 or 9; 0, 0.8, 1.6 decreased bw in all treatment groups gd 8 and 1.6      1.6 mg gd 8
 t al.     Crj:CD-1 trichloride necropsy           mg/kg bw all 1.6 mg             mg gd 7: decreased foetal          and 9:
2000)      mice (n= 6-               gd 18                       treatment groups weight; 0.8 mg gd 8 and 1.6 mg      number of
           7/group)                                              and in 0.8 mg gd gd 7: decreased placental           live foetuses
                                                                 8 group; no       weight; 1.6 mg: increased          insufficient
                                                                 further maternal mortality, most severe at gd 8      for statistical
                                                                 toxicity observed                                    inference
                                                                                                                      maternal
                                                                                                                      NOAEL: 0.8
                                                                                                                      mg/kg bw;
                                                                                                                      foetal
                                                                                                                      LOAEL: 0.8
                                                                                                                      mg/kg bw
Nakajima Crj:Wistar indium           gd 9, 10 or 0, 0.4 mg/      no maternal       in all exposure groups:            maternal
 t al.     rats (n= 5-8/ trichloride 11;           kg bw         toxicity observed decreased foetal weight;           NOAEL: 0.4
2000)      group)                    necropsy                                      increased incidence of gross       mg/kg bw;
                                     gd 20                                         malformations (brachyury,          fetal
                                                                                   kinked tail, cleft palate,         LOAEL: 0.4
                                                                                   oligodactyly, abnormal             mg/kg bw
                                                                                   abdomen), all effects most
                                                                                   severely in the group treated on
                                                                                   gd 10; in gd 9 and 10 groups:
                                                                                   decreased placental weight
             Fertility and developmental toxicity studies                                                                         63
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<pre>Nakajima Sprague-    indium      gd 10;       0, 0.1, 0.2, no obvious      0.3 mg/kg: increased mortality maternal
 t al.   Dawley rats trichloride necropsy     0.3 mg/kg maternal toxicity of implants, decreased foetal,    NOAEL: 0.3
2007)    (n=8-10/                gd 21        bw           observed        placental weight, increased      mg/kg bw;
         group)                                                            incidence of external (anal      fetal
                                                                           atresia, anury, brachyury, small NOAEL: 0.1
                                                                           limb, oligodactyly), skeletal    mg/kg bw
                                                                           (deformed vertebrae, ribs,
                                                                           forepaw phalanx, sternebrae,
                                                                           scapulae, femur, absent ulna or
                                                                           femur) malformations
                                                                           0.2 mg/kg: external (kinked
                                                                           tail), skeletal (deformed
                                                                           vertebrae) malformations
Nakajima Sprague-    indium      gd 10;       0, 0.4 mg/ not mentioned gd 11, 12, 13: caudal hypoplasia,
 t al.   Dawley rats trichloride embryos      kg bw                        reduced number of somite pairs
2008)    (n=3-5/                 examined                                  gd 11, 12: reduced crown-rump
         group)                  on gd 11, 12                              length
                                 or 13                                     gd 11: increased tailbud
                                                                           apoptosis
ALAT=alanine aminotransferase; AST=aspartate aminotransferase; gd=gestational day(s); n=number; pnd=postnatal day(s)
  4        Indium and indium compounds
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