<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>             Health Council of the Netherlands
          Uranium and its compounds
             Evaluation of the effects on reproduction,
             recommendation for classification
2016/05
</pre>

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

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<pre></pre>

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<pre>Aan de minister van Sociale Zaken en Werkgelegenheid
Onderwerp             : aanbieding advies Uranium and its compounds
Uw kenmerk            : DGV/BMO/U-932542
Ons kenmerk           : U-962581/EvV/jh/543-F16
Bijlagen              :1
Datum                 : 18 mei 2016
Geachte minister,
Graag bied ik u hierbij het advies aan over de effecten van uranium en uranium-
verbindingen 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 stof-
fen waaraan mensen tijdens de beroepsuitoefening kunnen worden blootgesteld.
Dit advies is opgesteld door een vaste commissie van de Gezondheidsraad, de Sub-
commissie Classificatie reproductietoxische stoffen. Het is vervolgens getoetst door de
Beraadsgroep Volksgezondheid van de Gezondheidsraad.
Ik heb dit advies vandaag ter kennisname toegezonden aan de minister van VWS en aan
de staatssecretaris van IenM.
Met vriendelijke groet,
prof. dr. J.L. Severens
vicevoorzitter
Bezoekadres                                                         Postadres
Parnassusplein 5                                                    Postbus 16052
2 5 11 V X      Den Haag                                            2500 BB         Den Haag
E - m a i l : p w. v a n . v l i e t @ 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 3 2 7
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<pre></pre>

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<pre>Uranium and its compounds
Evaluation of the effects on reproduction,
recommendation for classification
Subcommittee on the Classification of Reproduction Toxic Substances,
a Committee of the Health Council of the Netherlands
to:
the Minister of Social Affairs and Employment
No. 2016/05, The Hague, May 09, 2016
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<pre>The Health Council of the Netherlands, established in 1902, is an independent
scientific advisory body. Its remit is “to advise the government and Parliament on
the current level of knowledge with respect to public health issues and health
(services) research...” (Section 22, Health Act).
     The Health Council receives most requests for advice from the Ministers of
Health, Welfare and Sport, Infrastructure and the Environment, Social Affairs
and Employment, and Economic Affairs. 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.
This report can be downloaded from www.healthcouncil.nl.
Preferred citation:
Health Council of the Netherlands. Uranium and its compounds. Evaluation of
the effects on reproduction, recommendation for classification. The Hague:
Health Council of the Netherlands, 2016; publication no. 2016/05.
all rights reserved
ISBN: 978-94-6281-077-8
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<pre>   Contents
   Samenvatting 9
   Executive summary 11
   Scope 13
.1 Background 13
.2 Subcommittee and procedure 13
.3 Labelling for lactation 15
.4 Data 15
.5 Presentation of conclusions 15
.6 Final remark 16
   Uranium and uranium compounds 17
.1 Introduction 17
.2 Human studies 21
.3 Animal studies 23
.4 Conclusion 29
   References 33
   Contents                         7
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<pre>  Annexes 39
A The Committee 41
B The submission letter (in English) 43
C Comments on the public draft 45
D Regulation (EC) 1272/2008 of the European Community 47
E Additional considerations to Regulation (EC) 1272/2008 59
F Fertility and developmental toxicity studies 61
  Uranium and its compounds
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<pre>Samenvatting
In het voorliggende advies heeft de Gezondheidsraad uranium en uranium-
verbindingen onder de loep genomen. Uranium komt in variërende concentraties
in de natuur voor; het bestaat uit drie isotopen, die alle radioactief zijn (234U,
235U en 238U). Daarnaast bestaan er 19 uraniumisotopen als gevolg van mense-
lijke activiteiten. Natuurlijk uranium bestaat uit 99,27% 238U, 0,72% 235U, en
0,01% 234U per massa-eenheid. Verarmd uranium bestaat uit een lager percen-
tage 234U en 235U, en een hoger percentage 238U vergeleken met natuurlijk ura-
nium, terwijl verrijkt uranium uit een hoger percentage 234U en 235U, en een lager
percentage 238U bestaat vergeleken met natuurlijk uranium. Voor een juiste eva-
luatie van de reproductietoxische effecten van uranium zou onderscheid gemaakt
moeten worden tussen stralingseffecten en chemische effecten. Volgens het
Amerikaanse Agency for Toxic Substances and Disease Registry (ATSDR) zijn
de risico’s van natuurlijk en verarmd uranium vooral het gevolg van de chemi-
sche kenmerken van uranium en niet zozeer het gevolg van radioactiviteit, in
tegenstelling tot verrijkt uranium. Omdat verrijkt uranium en uraniumisotopen
die ontstaan als gevolg van menselijke activiteiten uitgesloten zijn van de wetge-
ving voor classificatie en labeling, is het voorliggende advies gericht op natuur-
lijk en verarmd uranium.
     Uranium wordt in de industrie gebruikt als laagverrijkte metalen of als kera-
mische UO2-brandstofkorrels. Verarmd uranium wordt gebruikt in traagheidsbe-
sturingsapparaten en tolkompassen, als contragewicht in helikopters en
vliegtuigen, als afschermingsmateriaal en in Röntgenapparatuur. Het kan ook
Samenvatting                                                                       9
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<pre>  worden gebruikt voor de productie van pantserdoordringende munitie. Uranium-
  dioxide wordt gebruikt om de levensduur van gloeidraden in lampen gebruikt
  voor fotografie en filmprojectoren te verlengen. Uraniumverbindingen worden
  ook gebruikt voor kleurschakeringen in de leer- en houtindustrie en de fotografie,
  en als beits in de zijde- en houtindustrie. Ammoniumdiuranaat wordt gebruikt
  om gekleurd glazuur te maken voor keramiek. Uraniumcarbide is een goede
  katalysator voor de productie van synthetisch ammonia.
      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 (GBBS) 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.
  Op basis van Verordening (EG) 1272/2008 van de Europese Unie doet de
  commissie een voorstel voor classificatie. Voor uranium en uraniumverbindingen
  komt de commissie tot de volgende aanbevelingen:
  • voor effecten op de fertiliteit adviseert de Commissie om uranium en
      uraniumverbindingen niet te classificeren wegens onvoldoende geschikte
      gegevens
  • voor effecten op de ontwikkeling adviseert de Commissie uranium niet te
      classificeren wegens onvoldoende geschikte gegevens.
      De Commissie adviseert om uraniumverbindingen te classificeren in
      categorie 2 (stoffen die ervan verdacht worden dat zij toxisch zijn voor de
      menselijke voortplanting) en te kenmerken met H361d (wordt ervan verdacht
      het ongeboren kind te schaden)
  • voor effecten op of via lactatie adviseert de Commissie om uranium en
      uraniumverbindingen niet te kenmerken wegens onvoldoende geschikte
      gegevens.
0 Uranium and its compounds
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<pre>Executive summary
In the present report the Health Council of the Netherlands reviewed uranium
and uranium compounds. Natural uranium, which is found in varying
concentrations in rocks and soil, consists of three isotopes, all of which are
radioactive (234U, 235U en 238U). In addition, 19 uranium isotopes originate from
human activities. Natural uranium consists of 99.27% 238U, 0.72% 235U, and
0.01% 234U by mass. Depleted uranium contains a decreased amount of 234U and
235U, and an increased amount of 238U when compared to natural uranium, while
enriched uranium contains an increased amount of 234U and 235U, and a
decreased amount of 238U when compared to natural uranium. For a proper
evaluation of the effects of uranium on reproductive toxicity, a distinction should
be made between radiation hazards and chemical hazards. According to the U.S.
Agency for Toxic Substances and Disease Registry (ATSDR), natural and
depleted uranium are more likely to be chemical hazards than radiation hazards,
in contrast to enriched uranium. Since enriched uranium and uranium isotopes
originating from human activities are excluded from the classification and
labelling legislation, the current assessment of uranium focuses on natural and
depleted uranium.
    Uranium is used in the commercial nuclear power industry as low-enriched
metal or ceramic UO2 fuel pellets. Depleted uranium is used in inertial guidance
devices and gyro compasses, as counterbalances for helicopter rotors, and
aircraft control surfaces, as radiation shielding material, and as X-ray targets. It
can also be used in the manufacture of armour-piercing ammunition for the
Executive summary                                                                    11
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<pre>  military. Uranium dioxide is used to extend the lives of filaments in large
  incandescent lamps used in photography and motion picture projectors. Uranium
  compounds are used in photography for toning, in the leather and wood
  industries for stains and dyes, and in the silk and wood industries as mordants.
  Ammonium diuranate is used to produce coloured glazes in ceramics. Uranium
  carbide is a good catalyst for the production of synthetic ammonia.
      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 (DECOS) of the Health Council, hereafter called the Committee,
  evaluates the effects on male and female fertility and on the development of the
  progeny. Moreover, 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. For, uranium and uranium compounds these
  recommendations are:
  • for effects on fertility, the Committee recommends not classifying uranium
      and uranium compounds due to a lack of appropriate data
  • for developmental toxicity, the Committee recommends not classifying
      uranium due to a lack of appropriate data.
      The Committee recommends classifying uranium compounds in category 2
      (suspected human reproductive toxicant) and labelling with H361d
      (suspected of damaging the unborn child)
  • for effects on or via lactation, the Committee recommends not labelling
      uranium and uranium compounds due to a lack of appropriate data.
2 Uranium and its 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     Subcommittee and procedure
        This document contains the classification of uranium and uranium compounds
        by the Health Council's Subcommittee on the Classification of Reproduction
        Toxic Substances, hereafter called the Committee. The members of the
        Scope                                                                             13
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<pre>  Committee are listed in Annex A. The submission letter (in English) to the
  Minister can be found in Annex B.
  In 2015, 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 received comments,
  and the replies by the Committee, can be found on the website of the Health
  Council.
  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 compounds.
  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).
4 Uranium and its compounds
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<pre>1.3 Labelling for 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
    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 exceeds 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 1945 up to 2009; updates were performed in
    TOXNET/TOXLINE until June 2015. Literature was selected primarily on the
    basis of the text of the abstracts with a focus on natural and depleted uranium.
    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. Data are described in the
    text and animal studies with respect to fertility and development are summarized
    in Annex F. Of each study, the quality of the study (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:
    Scope                                                                                15
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<pre>    •   Lack of appropriate data preclude assessment of the compound for
        reproductive toxicity.
    •   Sufficient data show that no classification for toxic to reproduction is
        indicated.
1.6 Final remark
    The classification of compounds is based on hazard evaluation (Niesink et al.29)
    only, 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  Uranium and its compounds
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<pre> hapter 2
        Uranium and uranium compounds
2.1     Introduction
        name                      : uranium
        CAS registry number       : 7440-61-1
        EINECS number             : 231-170-6
        synonyms                  : uranium-234, uranium-235, uranium-238, 234U, 235U, and 238U
        colour and physical state : silver-white, lustrous, radioactive metal
        formula                   : U
        atomic weight             : 238.03
        boiling point             : 4131 °C
        melting point             : 1135 °C
        solubility                : insoluble in water, alkalis, alcohol; soluble in acids
        stability and reactivity  : ignites in oxygen at about 170 °C (1)
        use                       : 235U is used in atomic and hydrogen bombs
                                    234U and 235U are used as nuclear fuel on power reactors
        EU classification         : not classified in Annex I of Directive 67/548/EEC
        Uranium and uranium compounds                                                           17
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<pre> ame                          :   uranyl acetate
  AS registry name            :   uranium, bis(acetato-κO)dioxo-, (T-4)-
  AS registry number          :   541-09-3
  INECS number                :   208-767-5
 ynonyms                      :   uranyl diacetate; uranium diacetate dioxide; uranium oxyacetate;
                                  bis(acetato)dioxouranium; diacetatodioxouranium; bis(acetato-O)dioxouran
 olour and physical state     :   yellow crystalline powder
 hemical formula              :   C4 H 6 O 6 U
 tructural formula            :
molecular weight              :   388.12
 oiling point                 :   275 °C
melting point                 :   -
 olubility                    :   freely soluble in water acidified with acetic acid, slightly soluble in alcohol
  tability and reactivity     :   decomposes before reaching bp of 275 °C; loses 2H2O at 110 °C, decomposes in hot water
 se                           :   reagent for precipitation of sodium; in dry copying inks and as activator in bacterial
                                  oxidation processes
  U Classification            :   not classified in Annex I of Directive 67/548/EEC
name                            :   uranyl nitrate
CAS registry name               :   uranium, bis(nitrato- κO)dioxo-, (T-4)-
CAS registry number             :   10102-06-4
EINECS-number                   :   233-266-3
synonyms                        :   uranyl dinitrate; uranium oxynitrate; uranium nitrate oxide; uranium dinitrate dioxide;
                                    dinitratodioxyuranium; bis(nitrato-O)dioxouranium
colour and physical state       :   yellow, rhombic crystals
chemical formula                :   N 2 O 8U
structural formula              :
molecular weight                :   394.04
boiling point                   :   decomposes at 118 °C
melting point                   :   60 °C
solubility                      :   soluble in water and oxygenated solvents, in ethanol, ether
use                             :   source of uranium dioxide; extraction of uranium into non-aqueous solvents
EU Classification               :   not classified in Annex I of Directive 67/548/EEC
Data from ECHA, HSDB, IUCLID and Merck.11,15,21,32
  8            Uranium and its compounds
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<pre>Uranium exists in several isotopic forms, all of which are radioactive. The most
toxicologically important of the 22 currently recognized uranium isotopes are
232U and 233U, originating from human activities, and 234U, 235U, and 238U,
occurring naturally. Natural uranium, including uranium ore, is comprised of
99.27% 238U, 0.72% 235U, and 0.01% 234U by mass.20 Enriched uranium contains
an increased amount of 234U and 235U, and a decreased amount of 238U when
compared to natural uranium, while for depleted uranium the opposite is true.2
For a proper evaluation of the effects of uranium on reproductive toxicity, a
distinction should be made between radiation hazards and chemical hazards.
According to the U.S. Agency for Toxic Substances and Disease Registry
(ATSDR), natural and depleted uranium are more likely to be chemical hazards
than radiation hazards, in contrast to enriched uranium.2 Since enriched uranium
and uranium isotopes originating from human activities are excluded from the
classification and labelling legislation, the current assessment of uranium focuses
on natural and depleted uranium. When a publication does not mention the use of
depleted or enriched uranium specifically, it is assumed that natural uranium is
used. Since the three uranium isotopes chemically behave the same, the chemical
risks found for depleted and natural uranium will also account for enriched
uranium. However, for enriched uranium, ionizing radiation may play an
additional role in reproductive toxicity (see ATSDR-document regarding
ionizing radiation1).
Uranium is extracted chemically from ores and converted into chemical forms
usable in industry. It is used in the commercial nuclear power industry as low-
enriched metal or ceramic UO2 fuel pellets.2 Depleted uranium is used in inertial
guidance devices and gyro compasses, as counterbalances for helicopter rotors,
and aircraft control surfaces, as radiation shielding material, and as X-ray targets.
It can also be used in the manufacture of armour-piercing ammunition for the
military. Uranium dioxide is used to extend the lives of filaments in large
incandescent lamps used in photography and motion picture projectors. Various
uranium compounds are used in photography for toning, in the leather and wood
industries for stains and dyes, and in the silk and wood industries as mordants.
Ammonium diuranate is used to produce coloured glazes in ceramics. Uranium
carbide is a good catalyst for the production of synthetic ammonia. Consequently,
all these compounds can cause occupational exposure. Most of them have not
been investigated for reproductive toxicity. The only exceptions are uranyl
Uranium and uranium compounds                                                         19
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<pre>  acetate and uranyl nitrate, of which the main chemical and physical
  characteristics are listed above. They have been investigated in animal studies.
  The epidemiological studies concern depleted (i.e. metallic) uranium, or uranium
  from natural sources (unspecified compounds, presumably mixtures).
  Occupational exposure to uranium and uranium compounds occurs mainly
  through inhalation. The uptake of the inhaled uranium into the body
  predominantly depends on the size of the aerosol particles and the chemical form
  of the uranium. The ICRP distinguishes three classes of compounds on the basis
  of their solubility in biological fluids: fast, moderate and slow, reflecting the rate
  of elimination from the lungs.17,18 Slowly soluble uranium compounds, such as
  (metallic) uranium and uranium oxides, do not dissolve easily and can
  consequently remain in the lungs for years. More soluble compounds, on the
  other hand, can enter the bloodstream in a matter of days or even hours. Uranyl
  acetate and uranyl nitrate belong to the most readily absorbed compounds.
       Once in the blood, the uranium is distributed throughout the body and
  reaches the organs. It preferentially distributes to bone, liver, and kidney.
  Approximately 67% of the uranium in the blood is filtered out in the kidneys and
  leaves the body in urine within 24 hours.2 Uranium can be transferred to the
  foetus during pregnancy. Concentrations in the foetus and the placenta are 10%
  at the most of those in maternal blood.33
  The toxicity of uranium also depends on its chemical form. With increasing dose
  the kidneys are affected first. Chronic inhalation exposure to uranium compounds
  dissolving fast and to uranium compounds dissolving moderately fast mainly
  causes chemical damage to kidney tubular cells. Chronic inhalation exposure to
  barely soluble uranium compounds mainly leads to damage to the airways.2
  Consequently, the primary target organ of inhaled barely soluble compounds is
  the lung. The primary target organ of dissolved uranium compounds is the kidney.
  The no observed adverse effect level (NOAEL) and the lowest observed adverse
  effect level (LOAEL) for renal toxicity following inhalation vary depending on
  the uranium compound, the animal species used for testing and the duration of the
  experiment.2
  Inhaled uranium is associated with only a low cancer risk, with the main risk
  being associated with the co-inhalation of other toxic and/or carcinogenic agents,
0 Uranium and its compounds
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<pre>      such as the radioactive transformation products of radon gas and cigarette
      smoke.2,16 The International Agency for Research on Cancer (IARC) has not
      published a classification report on uranium.
2.2   Human studies
2.2.1 Fertility
      Zaire and colleagues examined Namibian uranium miners that were exposed
      long-term to a low dose of uranium, from natural sources (six-fold increase in
      uranium excretion in urine when compared to controls). The miners showed a
      3-fold increase in chromosome aberrations in their peripheral blood lymphocytes
      (p<0.0001). Further changes included decreased neutrophil counts (p<0.004) and
      marginally increased lymphocyte counts (p<0.03). In addition, a decrease in
      serum LH and FSH levels was observed (p<0.008).35
      McDiarmid et al. examined 50 male Gulf War veterans with retained depleted
      uranium (DU) fragments (exposed to DU by means of friendly fire) 10 years
      after their first exposure. Cohorts were stratified based on urine uranium
      concentrations. Observed health effects were related both to subtle but
      biologically plausible perturbations in central nervous system function and to a
      general measure of mutagen exposure. No statistically significant differences
      between high and low uranium exposure groups were observed for luteinizing
      hormone, follicle-stimulating hormone, prolactin, testosterone, or thyroid
      measures. The incidences of subnormal sperm count and motility characteristics
      were not statistically significantly different between the high and low urine
      uranium groups. Total sperm count, total progressive sperm, and total rapid
      progressive sperm (as categorized by the World Health Organization) in the high
      urine uranium group were increased compared to the low urine uranium group
      (p<0.05).27
      McDiarmid et al. examined 35 male Gulf War veterans with retained DU
      fragments (exposed to DU by means of friendly fire) 16 years after their first
      exposure. Cohorts were stratified based on urine uranium concentrations. The
      high-uranium group showed a trend toward higher concentrations of urine b2
      microglobulin compared to the low-uranium group (81.7 vs. 69.0 mg/g
      creatinine; p=0.11) and retinol binding protein (48.1 vs. 31.0 mg/g creatinine;
      p=0.07). No statistically significant differences between urine uranium groups
      Uranium and uranium compounds                                                    21
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<pre>      were observed in any of the World Health Organization (WHO, 1987) criteria
      semen characteristics measured.26
2.2.2 Development
      Müller et al. reported that male uranium miners were found to have more first-
      born female children than expected (statistically significant, p not reported). The
      authors suggested that uranium damaged the y-chromosomes of the miners.28
      Sumanovic-Glamuzina et al. determined the prevalence of major congenital
      malformations in West Herzegovina, a part of Bosnia and Herzegovina,
      immediately and five years after 1991-1995 military activities, which allegedly
      included the use of weapons with DU. The study included all live-born and
      stillborn neonates and excluded all aborted foetuses in two one-year cohorts
      (1995 and 2000) of neonates in the Maternity Ward of the Mostar University
      Hospital. Malformations were recorded according to the recommendations of
      the EUROCAT protocol. Major malformations were found in 2.16% of neonates
      in 1995 (95% confidence interval (CI) 1.49-2.82%) and in 2.26% in 2000
      (95% CI 1.50-3.01%). These rates did not differ from the average prevalence in
      EUROCAT centers.31
2.2.3 Lactation
      Wappelhorst et al. measured the transfer of uranium (compounds not further
      specified) from food to milk in nursing mothers. The transfer factor (the portion
      of uranium intake passed on in the milk) was calculated as the uranium
      concentration in food (g/kg) divided by the uranium concentration in milk (g/L).
      Average uranium intake of the mothers was 1.9 ± 1.0 µg/day (0.03 ± 0.02 µg/kg
      bw/day). Mean uranium content of human milk was 0.03 µg/L. The transfer
      factor for uranium was calculated to be 21.3.34
      The International Commission on Radiological Protection (ICRP) assessed the
      transfer of uranium from maternal milk to the infant. Maternal intake included
      acute and chronic intake by ingestion or inhalation during pregnancy or
      breastfeeding. The transfer of uranium from maternal blood to breast milk was
      calculated using biokinetic modelling. The maximum transfer factors from
      mother to child were expressed as a proportion of radioactivity in blood. The
      results indicate that a small fraction of the uranium ingested by mothers is
      transferred to the milk.19
 2    Uranium and its compounds
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<pre>2.3   Animal studies
2.3.1 Fertility
      Oral studies
      Maynard and co-workers exposed weanling rats (50/sex/group) in pairs for 195
      days to a diet containing 0 or 2% uranium nitrate hexahydrate.25 2% in the feed is
      equivalent to 1,000-1,500 mg/kg bw.12 After 195 days, all animals were fed
      control diet for another 170 days. In the first 30 days, 4 females and 5 males from
      the uranium group died. In the remainder of the year, 10% of controls died,
      compared to 17% of the uranium group. Uranium exposure reduced body weight
      gain in males and females (after 7 months males and females weighed 65 and 60
      grams less than controls). Degeneration of the kidneys was observed in the first
      week. Between weeks 4 and 6 regeneration and between week 8 and 14 also
      tubular atrophy was observed. After the recovery period, no renal abnormality
      was observed. In addition, testicular lesions were observed in uranium exposed
      rats, including degeneration and atrophic changes (tubuli with loss of
      spermatozoa, absence of spermatids, loss of primary spermatocytes, presence of
      multinucleated cells). It was shown that 14/44 uranium exposed rats had irregular
      oestrus cycles, accompanied by irregular (n=1) or no (n=13) matings, whereas
      only 2/45 control rats had irregular oestrus cycles (accompanied by no matings).
      A reduction in females that had at least one litter was observed (44/45 in control
      group compared to 30/44 in the uranium group). Moreover, the number of litters
      per female was decreased. In the recovery period, the amount of litters in the
      uranium group returned to normal. Statistics were not mentioned.25
      Other studies indicate that uranium does affect male fertility. Maynard and
      coworkers provided male rats with a chronic diet of uranyl nitrate hexahydrate for
      1-2 years (331 mg U/kg bw/day) (Maynard and colleagues (1953), cited in 2,8).
      This caused severe degeneration in the testes and depletion of germ cells. Female
      rats given oral doses of 664 mg U/kg bw/day as uranyl nitrate hexahydrate for 2
      years had reduced litter sizes. Analysis of general toxicity was not reported and it
      is unclear whether controls were included.
      In addition, in a study of Malenchenko et al. uranyl nitrate hexahydrate added to
      the drinking water of male Wistar rats for 4 months (0.1%, ~ 50 mg/kg bw)
      resulted in decreased testes weight (p<0.05), testicular lesions, and necrosis of
      Uranium and uranium compounds                                                        23
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<pre>  spermatocytes and spermatogonia. Spleen weight and spleen index were
  increased (p<0.05) and morphological changes in the thyroid gland were
  observed. Analysis of general toxicity was not reported.24
  Llobet et al. provided male Swiss mice (24/group) with drinking water
  containing uranyl acetate dihydrate (doses of 0, 10, 20, 40, and 80 mg/kg/day)
  for 64 days. Animals were mated with untreated females (16/group) for 4 days.
  No clinical signs of toxicity were observed. A non-dose-related decrease in the
  pregnancy rate of the females was observed in all dose groups (25-35% in
  uranium treated animals vs. 81% in the control group (p<0.01 or p<0.05). Body
  weights were slightly reduced at 80 mg/kg/day (35.8 ± 2.04 g vs. 37.6 ± 2.53 g in
  the control group, p<0.05). No statistically significant differences in the numbers
  of total implantations, early and late resorptions, and live and dead foetuses were
  observed. Testicular function was not affected by uranium, as evidenced by
  normal testes and epididymis weights and normal spermatogenesis. Also
  histopathologic examination of the testes in mice killed after 64 days of
  treatment did not reveal any significant effects of uranium on tubule diameter,
  tubule alterations, and interstitial alterations (focal atrophy, binucleated cells),
  with the exception of an increase in Leydig cells vacuolization at 80 mg/kg/day
  (p<0.05). Based on effects on pregnancy rates in this study, the no observed
  adverse effect level (NOAEL) for reproductive toxicity of uranium is below
  10 mg/kg/day.23
  Gilman et al. exposed weanling Sprague-Dawley rats (10/sex/group) for 28 days
  to uranyl nitrate hexahydrate (UN) in drinking water (< 0.001, 0.96, 4.8, 24, 120
  and 600 mg UN/L, corresponding to up to 35 mg/kg bw for males and 40 mg/kg
  bw for females). No general toxicity was observed. In addition, no changes in
  reproductive organ weights were found in the epididymis, testes, ovary, or uterus.
  Next, they exposed weanling Sprague-Dawley rats (15/sex/group) for 91 days to
  UN in drinking water (0, 0.96, 4.8, 24, 120, or 600 mg UN/L, corresponding to
  up to 37 mg/kg bw for males and 54 mg/kg bw for females). General toxicity
  consisted of histopathological lesions in the kidney and liver, in both males and
  females, in all groups including the lowest exposure group (p<0.001, p<0.01 or
  p<0.05). Renal lesions of tubules (apical nuclear displacement and vesiculation,
  cytoplasmic vacuolation, and dilation), glomeruli (capsular sclerosis), and
  interstitium (reticulin sclerosis and lymphoid cuffing) were already observed in
  the lowest exposure groups. A lowest observed adverse effect level (LOAEL) of
  0.06 and 0.09 mg UN/kg body wt/day was reported for male and female rats,
4 Uranium and its compounds
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<pre>respectively). No statistically significant changes in reproductive organ weights
were found in the epididymis, testes, ovary, or uterus.14
Gilman et al. also exposed New Zealand rabbits to uranyl nitrate hexahydrate
(UN) in the drinking water (males: 0, 0.96, 4.8, 24, 120, or 600 mg UN/L,
corresponding to up to 28.70 mg UN/kg/day; females: 0, 4.8, 24, or 600 mg
UN/L, corresponding to up to 43.02 mg UN/kg/day) for 91 days. The
hematological and biochemical parameters were not affected in a statistically
significant exposure-related manner. Dose-dependent differences consisted of
histopathological changes limited primarily to kidney. Changes in renal tubules
were characteristic of uranium toxicity (LOAEL for males is 0.05 mg UN/kg
bw/day and LOAEL for females is 0.49 mg U/kg bw/day in this study). No
statistically significant histopathological or organ weight changes in the
epididymis, ovary, testes, or uterus were found.13
Albina et al. exposed male Sprague Dawley rats (8-12/group) to uranyl acetate
dihydrate in the drinking water at doses of 0, 10, 20 and 40 mg/kg bw/day during
3 months. At the end of the experimental period, male rats were mated for 2
weeks with untreated females. On gestation day 14, one half of pregnant rats
were euthanized; the remaining dams were allowed to deliver and wean their
offspring. No deaths or clinical signs of toxicity, including body weight gain
were observed in the dams at any dose. A decrease in the pregnancy rate was
observed at 20 mg/kg bw/day only (p<0.05). The numbers of pregnancies
were 9/12, 6/8, 4/8 and 6/8 in females mated to males exposed to 0, 10, 20 and
40 mg/kg bw/day, respectively. Thus, no dose-effect relationship was observed.
No statistically significant differences in the number of total implants per litter
and the number of viable and nonviable implants per litter were observed.4
    The results reported by Albina et al. are also reported by Linares et al.
However, Linares et al. also examined the effects of uranium on male
reproduction parameters. The number of spermatids per testis was significantly
decreased by uranium administration at 20 and 40 mg/kg bw/day (p<0.05).
Histopathological examination of the testes in male rats killed after 3 months of
treatment revealed few differences in the tubule and interstitial alterations
(progressive but not statistically significant cellular loss, Sertoli cells or germinal
cells, with cytoplasmic vacuolization) between control and uranium-exposed
animals.22
Sánchez et al. treated adult female Sprague Dawley rats with uranyl acetate
dihydrate in the drinking water at doses of 0, 40 and 80 mg/kg bw/day for
Uranium and uranium compounds                                                           25
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<pre>      4 weeks before mating with untreated males, and continued this treatment during
      pregnancy and lactation. No statistically significant effects were found on
      maternal body weight gain or number of implants (total, viable and non viable)/
      litter.30
      Arnault and colleagues treated female C57Bl×CBA mice for 15 weeks with
      uranyl nitrate in drinking water. A first group (0, 12.5 or 100 mg/kg bw/day) was
      euthanized immediately after the end of the 15 weeks administration period; a
      second group (0, 1.25 or 12.5 mg/kg bw/day) was paired with untreated males
      after exposure. Dams were euthanized 3 months after the end of the exposure
      period. No general toxicity was observed on body weight, kidney weight and
      behavior. Mice from the first group had fewer large antral follicles (Ø >200 µm)
      than the untreated mice (p<0.05), but the findings were not dose-related. The
      animals showed a normal amount of secondary and early preantral follicles
      (Ø 70-110 µm). By contrast, dams in the second group had a normal amount of
      large antral follicles, but more secondary and early pre-antral follicles than
      untreated mice (p<0.05). The effects were not dose-related. Changes in follicle
      atresia were not observed.5
2.3.2 Developmental toxicity
      Oral studies
      Domingo et al. dosed pregnant Swiss mice (20/group) with uranyl acetate
      dihydrate (0, 5, 10, 25 or 50 mg/kg bw/day, top dose 1/5 of acute LD50) by
      gavage on gestation day 6-15 and sacrificed on gestation day 18 to assess
      potential maternal and foetal toxicity. Maternal toxicity (reduced weight gain and
      food consumption, increased relative liver weight) was seen at all doses
      (p<0.001, p<0.01 or p<0.05). Dose-related foetotoxicity was observed,
      manifested as reduced foetal body weight and length, an increase in the incidence
      of stunted foetuses and external and skeletal malformations, and developmental
      variations (p<0.001, p<0.01 or p<0.05). External malformations included a
      dose-related increase in the incidence of cleft palate (statistically significant at
      10 mg/kg bw/day and higher doses) and an increase in hematomas (p<0.05 at
      5 and 50 mg/kg bw/day). Undeveloped renal papillae were seen in the 5 and
      25 mg/kg bw/day groups. A dose-related increase in the incidence of skeletal
      abnormalities (bipartite sternebrae and reduced or delayed ossification of the
      hind limb, fore limb, skull, and tail) was seen in the 25 and 50 mg/kg bw/day
 6    Uranium and its compounds
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<pre>groups (p<0.001, p<0.01 or p<0.05). Embryolethality was not found at any of the
dose levels tested.10
Domingo et al. also dosed pregnant Swiss mice (20/group) with uranyl acetate
dihydrate (0, 0.05, 0.5, 5 or 50 mg/kg bw/day, top dose 1/5 of acute LD50) by
gavage from gestation day 13 through postnatal day 21. Two dams in the 5 mg/kg
bw/day group and two dams in the 50 mg/kg bw/day group died during lactation.
In contrast to the study described above, effects on body weight or food intake
were not observed. Further maternal toxicity was not analysed. Number of litters
or litter size was not affected on postnatal day 0. However, litter size was
decreased at postnatal day 21 at 50 mg/kg bw/day (5.5 vs. 8.8 in controls,
p<0.05). The viability index (number of pups viable at day 21/number of pups
born) and the lactation index (number of pups viable at day 21/number of pups
retained at day 4) were decreased in the 50 mg/kg bw/day group (p<0.05). A
reduction in liver weight was observed in pups of all dose groups (p<0.01 or
p<0.05). No statistically significant differences were observed in pup weight or
body length at birth. No statistically significant differences were observed in
developmental signs (pinnae unfolding, lower incisor eruption, eye opening), or
in pup weight or body length.9
Sánchez et al. treated adult female Sprague Dawley rats with uranyl acetate
dihydrate in the drinking water at doses of 0, 40 and 80 mg/kg bw/day for 4
weeks before mating with untreated males, and continued this treatment during
pregnancy and lactation. No statistically significant effects were found on
maternal body weight gain or number of implants (total, viable and non viable)/
litter. No statistically significant effects were found on the body weight of the
pups at post-natal day 1. However, the body weight of the pups (male and
female) was decreased on postnatal days 4 (at 40 mg/kg bw/day), 12 and 21
(at 40 and 80 mg/kg bw/day, p<0.05). No statistically significant effects of
uranium were noted on physical development, neuromotor maturation, and
behavior in the offspring.30
Arnault and colleagues treated female C57Bl×CBA mice for 15 weeks with
uranyl nitrate in drinking water. A first group (0, 12.5 or 100 mg/kg bw/day) was
euthanized immediately after the end of the 15 week administration period; a
second group (0, 1.25 or 12.5 mg/kg bw/day) was paired with untreated males
after exposure. Dams and their female pups were euthanized 3 months after the
end of the exposure period. In the dams, no effect was observed on body weight,
kidney weight and behavior. Female pups had fewer large antral follicles
Uranium and uranium compounds                                                     27
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<pre>  (Ø >200 µm) than the untreated mice (p<0.05), but the effect was not dose-
  related. They had a normal amount of secondary and early preantral follicles
  (Ø 70-110 µm).5
  Subcutaneous injection
  The effects of daily maternal subcutaneous injections of uranyl acetate dihydrate
  (0, 0.5, 1, and 2 mg/kg bw/day, top dose ~ 1/10 of the acute subcutaneous LD50)
  from day 6 to day 15 of gestation were evaluated by Bosque et al. in Swiss mice
  (25 plug-positive dams/dose group). External, internal soft-tissue and skeletal
  examinations of foetuses were performed on gestation day 18. Dose-related
  maternal toxicity occurred in all uranium-treated groups as evidenced primarily
  by deaths (0, 1, 2, and 7 deaths at 0, 0.5, 1 and 2 mg/kg bw/day, respectively) and
  decreased weight gain during gestation (at all dose levels, (p<0.001, p<0.01 or
  p<0.05) and decreased body weight at termination (1 and 2 mg/kg bw/day,
  p<0.01 and p<0.001, respectively). In addition, maternal liver weight (absolute
  and relative) and kidney weight (absolute) were decreased in the 1 and 2 mg/kg
  bw/day dose groups (p<0.001 or p<0.05). Embryo toxicity was also noted in all
  uranium-exposed groups (increased percentage of post-implantation loss,
  p<0.01). Foetotoxicity was indicated by a significant reduction in foetal weight
  at 1 and 2 mg/kg bw/day and by a dose-dependent increase in the number of total
  internal (renal hypoplasia) and total skeletal (decreased ossification) defects,
  statistically significant at all doses (p<0.001, p<0.01 or p<0.05). An increase in
  malformations (cleft palate and bipartite sternebrae) was only detected at 1 and 2
  mg/kg bw/day (p<0.001, p<0.01 or p<0.05).7
  Bosque and coworkers subcutaneously injected pregnant Swiss mice on
  gestation day 10 with a single dose of 4 mg/kg body weight uranyl acetate
  dihydrate (saline was used as control). Mice were killed on gestation day 18.
  Maternal toxicity included death (20%, compared to 0% in controls), lethargy
  and reduced body weight gain (p<0.01). Uranyl acetate administration resulted in
  a significantly increased percentage of resorptions and dead foetuses (together
  36.3 vs 2.21%, p<0.001). In addition, decreases in foetal body weight (p<0.001)
  and increases in the percentage of skeletal anomalies (78.6 vs 10.7% foetuses
  affected in treated vs control group, p<0.05) were observed. Skeletal alterations
  included reduced ossifications, wavy ribs and dorsal hyperkyphosis.6
  Albina et al. injected pregnant Sprague Dawley rats (11-12/group)
  subcutaneously with uranyl acetate dihydrate (0, 0.415 or 0.830 mg/kg bw/day)
8 Uranium and its compounds
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<pre>      on gestation days 6 to 15. Cesarean sections were performed on gestation day 20.
      Maternal toxicity was noted at 0.830 mg/kg bw/day (decreased body weight
      gain, decreased absolute and relative kidney weight (p<0.05)). Foetotoxicity was
      evidenced at 0.415 and 0.830 mg/kg/day by reductions in foetal body weight
      (dose-dependent, p<0.05) and increases in the percentage of skeletally affected
      foetuses (16, 55 and 88% in controls, at 0.415 and at 0.830 mg/kg/day,
      respectively (p<0.003)). The skeletal abnormalities observed were delayed
      ossifications.3
2.4   Conclusion
2.4.1 Fertility
      The human data on the potential effect of uranium and uranium compounds on
      fertility originate from surveillance studies of uranium miners and Gulf war
      veterans. As both populations may have been in contact with other toxic
      substances, the reported effects on fertility are not sufficient to classify uranium
      or uranium compounds for having effects on fertility in humans.
      The animal studies all concern uranium compounds. The studies in rats and mice
      with oral administration of these compounds do not show consistent outcomes.
      Arnault et al. found a reduced number of follicles in female mice, in the absence
      of general toxicity.5 Malenchenko et al. demonstrated male sex organ toxicity,
      but also found signs of toxicity in other organs.24 Lloblet et al.23, and Albina et
      al. and Linares et al.4,22 showed reduced pregnancy rates in mice and rats,
      respectively. They did not provide information as to whether general toxicity
      occurred. The effects on fertility were not dose-dependent in any of these studies.
      Another study, by Sánchez et al., showed unchanged pregnancy rates, so no
      effects on functional fertility, in the absence of general toxicity.30
      In conclusion, based on the inconsistent results, and limited information on
      general toxicity, the committee recommends not to classify uranium and uranium
      compounds for fertility due to a lack of appropriate data.
2.4.2 Developmental toxicity
      The available human data, restricted to uranium miners and a post-war
      population, are not sufficient to allow a conclusion regarding developmental
      effects of uranium or uranium compounds.
      Uranium and uranium compounds                                                        29
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<pre>      The animal data all concern uranium compounds and demonstrate prenatal as
      well as postnatal developmental effects of uranium compounds administered
      orally. Effects on offspring, including decreased litter size, litter viability
      and pup weight, were observed in rats and mice orally treated with uranium
      compounds.5,9,30 These postnatal effects occurred without maternal toxicity.
      The prenatal effects seen in mice treated orally included reduced foetal body
      weight and length, and increased numbers of stunted foetuses and external and
      skeletal malformations.5,9,10,30 The effects seen in one of the studies were dose-
      dependent.10 They were, however, accompanied by maternal toxicity. Overall,
      the Committee considers that exposure to uranium compounds can cause
      prenatal and postnatal effects that may be independent of maternal toxicity.
          The findings from the studies in rats and mice treated orally are supported by
      those from studies in rats and mice injected subcutaneously.3,6,7
      Based on the prenatal and postnatal effects seen in animals, the Committee
      recommends to classify uranium compounds in category 2 (suspected human
      reproductive toxicant) and to label them with H361d (suspected of damaging the
      unborn child). The Committee recommends not to classify uranium due to a lack
      of data.
2.4.3 Lactation
      Two publications are available regarding the transfer of uranium from food to
      milk in nursing mothers. In one of these the results of measurements in milk are
      reported, in the other transfer factors from maternal blood to milk based on
      biokinetic modelling. Together, the studies indicate that a small portion of the
      uranium ingested by mothers is transferred to milk. There are no further human
      or animal data regarding the secretion of uranium compounds in milk or
      regarding the effects on offspring. Therefore, the Committee is of the opinion
      that due to a lack of appropriate data uranium and uranium compounds should
      not be labelled for effects during lactation.
      Proposed classification for fertility
      Lack of appropriate data precludes the assessment of uranium and uranium
      compounds for effects on fertility.
 0    Uranium and its compounds
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<pre>Proposed classification for developmental toxicity
Lack of appropriate data precludes the assessment of uranium for developmental
toxicity. Proposed classification of uranium compounds: category 2; H361d.
Proposed labelling for effect during lactation
Lack of appropriate data precludes the assessment of uranium and uranium
compounds for effects on or via lactation.
Uranium and uranium compounds                                                  31
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<pre>2 Uranium and its compounds</pre>

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<pre>References
Agency for Toxic Substances and Disease Registry (ATSDR). Toxicological profile for Ionizing
Radiation. Atlanta, USA: ATSDR; 1999.
Agency for Toxic Substances and Disease Registry (ATSDR). Toxicological profile for Uranium.
Atlanta, USA: ATSDR; 2013.
Albina ML, Belles M, Gomez M, Sanchez DJ, Domingo JL. Influence of maternal stress on uranium-
induced developmental toxicity in rats. Exp Biol Med (Maywood) 2003; 228(9): 1072-7.
Albina ML, Belles M, Linares V, Sanchez DJ, Domingo JL. Restraint stress does not enhance the
uranium-induced developmental and behavioral effects in the offspring of uranium-exposed male
rats. Toxicology 2005; 215(1-2): 69-79.
Arnault E, Doussau M, Pesty A, Gouget B, van der Meeren A, Fouchet P et al. Natural uranium
disturbs mouse folliculogenesis in vivo and oocyte meiosis in vitro. Toxicology 2008; 247(2-3): 80-7.
Bosque MA, Domingo JL, Llobet JM, Corbella J. Effectiveness of sodium 4,5-dihydroxybenzene-
1,3-disulfonate (Tiron) in protecting against uranium-induced developmental toxicity in mice.
Toxicology 1993; 79(2): 149-56.
Bosque MA, Domingo JL, Llobet JM, Corbella J. Embryotoxicity and teratogenicity of uranium in
mice following subcutaneous administration of uranyl acetate. Biol Trace Elem Res 1993; 36(2):
109-18.
Domingo JL. Reproductive and developmental toxicity of natural and depleted uranium: a review.
Reprod Toxicol 2001; 15(6): 603-9.
Domingo JL, Ortega A, Paternain JL, Corbella J. Evaluation of the perinatal and postnatal effects of
uranium in mice upon oral administration. Arch Environ Health 1989; 44(6): 395-8.
References                                                                                            33
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<pre>0 Domingo JL, Paternain JL, Llobet JM, Corbella J. The developmental toxicity of uranium in mice.
  Toxicology 1989; 55(1-2): 143-152.
1 ECHA (website). Registered substances. European Chemicals Agency (ECHA). Internet.
  http://echa.europa.eu/information-on-chemical, consulted: 16-3-2016.
2 European Commission. Technical Guidance Document on Risk Assessment, Part I. Ispra, Italy:
  European Commission Joint Research Centre; 2003: Publication no EUR 20418 EN/1. Internet:
  https://echa.europa.eu/documents/10162/16960216/tgdpart1_2ed_en.pdf, consulted 16-3-2016.
3 Gilman AP, Villeneuve DC, Secours VE, Yagminas AP, Tracy BL, Quinn JM e.a. Uranyl nitrate:
  91-day toxicity studies in the New Zealand white rabbit. Toxicol Sci 1998; 41(1): 129-137.
4 Gilman AP, Villeneuve DC, Secours VE, Yagminas AP, Tracy BL, Quinn JM e.a. Uranyl nitrate:
  28-day and 91-day toxicity studies in the Sprague-Dawley rat. Toxicol Sci 1998; 41(1): 117-128.
5 Hazardous Substances Data Bank (HSDB). Internet. http://toxnet.nlm.nih.gov/cgi-bin/sis/
  htmlgen?HSDB, consulted: 16-3-2016.
6 Health Council of the Netherlands. Health risks of exposure to depleted uranium. The Hague: Health
  Council of the Netherlands; 2001: publication no. 2001/13E. Revised version 5 February 2002.
7 International Commission on Radiological Protection (ICRP). Human Respiratory Tract Model for
  Radiological Protection. ICRP Publication 66. Annals of the ICRP 1994; 24(1-3).
8 International Commission on Radiological Protection (ICRP). Age Dependent Doses to Members of
  the Public from Intake of Radionclides: Part 4. Inhalation Dose Coefficients. ICRP Publication 71.
  Annals of the ICRP 1995; 25(3-4).
9 International Commission on Radiological Protection (ICRP). Annals of the ICRP. A report of: doses
  to infants from ingestion of radionuclides in mothers' milk. Ann ICRP 2004; 34(3-4): iii, 15-iii, 80.
0 International Union of Pure and Applied Chemistry (IUPAC). Inorganic Chemistry Division,
  Commission on Atomic Weights and Isotopic abundances, Subcommittee for Isotopic Abundance
  Measurements. Isotopic compositions of the elements 1997. Pure & Appl Chem 1998; 70(1):
  217-235.
1 IUCLID. IUCLID dataset for Uranium. 2000.
2 Linares V, Albina ML, Belles M, Mayayo E, Sanchez DJ, Domingo JL. Combined action of uranium
  and stress in the rat. II. Effects on male reproduction. Toxicol Lett 2005; 158(3): 186-95.
3 Llobet JM, Sirvent JJ, Ortega A, Domingo JL. Influence of chronic exposure to uranium on male
  reproduction in mice. Fundam Appl Toxicol 1991; 16(4): 821-9.
4 Malenchenko AF, Barkun NA, Guseva GF. Effect of uranium on the induction and course of
  experimental autoimmune orchitis and thyroiditis. J Hyg Epidemiol Microbiol Immunol 1978; 22(3):
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5 Maynard EA, Randall C, Hodge HC, Scott JK. Effects of feeding uranium nitrate hexahydrate in the
  diets of breeding white rats. J Pharmacol Exp Ther 1949; 95 P(4): 421-428.
6 McDiarmid MA, Engelhardt SM, Dorsey CD, Oliver M, Gucer P, Wilson PD e.a. Surveillance results
  of depleted uranium-exposed Gulf War I veterans: sixteen years of follow-up. J Toxicol Environ
  Health A 2009; 72(1): 14-29.
4 Uranium and its compounds
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<pre>7 McDiarmid MA, Squibb K, Engelhardt S, Oliver M, Gucer P, Wilson PD et al. Surveillance of
  depleted uranium exposed Gulf War veterans: health effects observed in an enlarged “friendly fire”
  cohort. J Occup Environ Med 2001; 43(12): 991-1000.
8 Muller C, Ruzicka L, Bakstein J. The sex ratio in the offsprings of uranium miners. Acta Universitatis
  Carolinae Medica 1967; 13(7): 599-603.
9 Niesink R, de Vries J, Hoolinger M. Toxicology principles and applications. Boca Raton, FL, USA:
  CRC Press; 1995.
0 Sanchez DJ, Belles M, Albina ML, Gomez M, Linares V, Domingo JL. Exposure of pregnant rats to
  uranium and restraint stress: effects on postnatal development and behavior of the offspring.
  Toxicology 2006; 228(2-3): 323-32.
1 Sumanovic-Glamuzina D, Saraga-Karacic V, Roncevic Z, Milanov A, Bozic T, Boranic M. Incidence
  of major congenital malformations in a region of Bosnia and Herzegovina allegedly polluted with
  depleted uranium. Croat Med J 2003; 44(5): 579-584.
2 The Merck Index, 14th edition. An Encyclopedia of Chemicals, Drugs, and Biologicals. Wiley &
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3 U.S.Nuclear Regulatory Commission. Contribution of maternal radionuclide burdens to prenatal
  radiation doses. Washington DC, USA: U.S. Nuclear Regulatory Commission; 1996: NUREG/CR-
  5631, PNL-7445, Rev.2.
4 Wappelhorst O, Kuhn I, Heidenreich H, Markert B. Transfer of selected elements from food into
  human milk. Nutrition 2002; 18(4): 316-322.
5 Zaire R, Notter M, Riedel W, Thiel E. Unexpected rates of chromosomal instabilities and alterations
  of hormone levels in Namibian uranium miners. Radiat Res 1997; 147(5): 579-84.
  Literature used but not cited
  Abu-Qare AW, Abou-Donia MB. Depleted uranium--the growing concern. J Appl Toxicol 2002;
  22(3):149-52.
  Arfsten DP, Bekkedal M, Wilfong ER, Rossi J, III, Grasman KA, Healey LB et al. Study of the
  reproductive effects in rats surgically implanted with depleted uranium for up to 90 days. J Toxicol
  Environ Health A 2005; 68(11-12): 967-97.
  Arfsten DP, Schaeffer DJ, Johnson EW, Robert Cunningham J, Still KR, Wilfong ER. Evaluation of
  the effect of implanted depleted uranium on male reproductive success, sperm concentration, and
  sperm velocity. Environ Res 2006; 100(2): 205-15.
  Arfsten DP, Still KR, Ritchie GD. A review of the effects of uranium and depleted uranium exposure
  on reproduction and fetal development. Toxicol Ind Health 2001; 17(5-10): 180-91.
  Arfsten DP, Still KR, Wilfong ER, Johnson EW, McInturf SM, Eggers JS et al. Two-generation
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  References                                                                                             35
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<pre>  Arfsten DP, Wilfong ER, Bekkedal MY, Johnson EW, McInturf SM, Eggers JS et al. Evaluation of
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  Toxicol Environ Health A 2007; 70(23):1995-2010.
  Bosque MA, Domingo JL, Corbella J. Embryofetotoxicity of uranium in mice: Variability with the
  day of exposure: Embriofetotoxicidad del uranio en ratones:Variabilidad con el dia de exposicion.
  Revista de Toxicologia 1992; 9(3): 107-10.
  Brugge D, Buchner V. Health effects of uranium: new research findings. Rev Environ Health 2011;
  26(4): 231-249.
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  chemical and radiological toxicity of natural uranium: a review. Rev Environ Health 2005;
  20(3):177-93.
  Craft ES, Abu-Qare AW, Flaherty MM, Garofolo MC, Rincavage HL, Abou-Donia MB. Depleted
  and natural uranium: Chemistry and toxicological effects. Journal of Toxicology and Environmental
  Health - Part B: Critical Reviews 2004; 7(4):297-317.
  Domingo JL. Reproductive and developmental toxicity of natural and depleted uranium: a review.
  Reprod Toxicol 2001; 15(6): 603-9.
  Domingo JL, Ortega A, Llobet JM, Paternain JL, Corbella J. The effects of repeated parenteral
  administration of chelating agents on the distribution and excretion of uranium. Res Commun Chem
  Pathol Pharmacol 1989; 64(1):161-4.
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  with special reference to Mosul and possible effects on cancer and birth defect rates. Med Confl
  Surviv 2013; 29(1): 7-25.
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  epidemiological perspective. Environ Health 2005; 4:17.
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  uranyl fluoride by alkaline elution. Radiat Environ Biophys 1990; 29(3):161-7.
  Jadon A, Mathur R. Gametogenic count and histopathological effect of thorium nitrate and uranyl
  nitrate on mice testes. Andrologia 1983; 15(1): 40-3.
  Kundt M, Ubios AM, Cabrini RL. Effects of uranium poisoning on cultured preimplantation
  embryos. Biol Trace Elem Res 2000; 75(1-3): 235-44.
  Lin RH, Wu LJ, Lee CH, Lin Shiau SY. Cytogenetic toxicity of uranyl nitrate in Chinese hamster
  ovary cells. Mutat Res 1993; 319(3): 197-203.
  Linares V, Belles M, Albina ML, Sirvent JJ, Sanchez DJ, Domingo JL. Assessment of the pro-oxidant
  activity of uranium in kidney and testis of rats. Toxicol Lett 2006; 167(2): 152-61.
  Marshall AC. Gulf war depleted uranium risks. J Expo Sci Environ Epidemiol 2008; 18(1):95-108.
  McClain DE, Benson KA, Dalton TK, Ejnik J, Emond CA, Hodge SJ et al. Health effects of
  embedded depleted uranium. Mil Med 2002; 167(2 Suppl):117-9.
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<pre>Mirderikvand N, Mohammadzadeh AB, Naserzadeh P, Shaki F, Shokrzadeh M, Pourahmad J.
Embryo toxic effects of depleted uranium on the morphology of the mouse fetus. Iran J Pharm Res
2014; 13(1): 199-206.
Paternain JL, Domingo JL, Ortega A, Llobet JM. The effects of uranium on reproduction, gestation,
and postnatal survival in mice. Ecotoxicol Environ Saf 1989; 17(3): 291-6.
Pellmar TC, Fuciarelli AF, Ejnik JW, Hamilton M, Hogan J, Strocko S et al. Distribution of uranium
in rats implanted with depleted uranium pellets. Toxicol Sci 1999; 49(1):29-39.
Risica S, Fattibene P, Mazzei F, Nuccetelli C and Rogani A. Radionuclides in pregnancy and breast-
feeding. Microchem J 2002; 73:251-64.
Shawky S. Depleted uranium: an overview of its properties and health effects. East Mediterr Health J
2002; 8(2-3):432-39.
Shawky S. Causes of death in the Eastern Mediterranean Region during the years 1998-2000. Saudi
Med J 2003; 24(4):380-7.
Shields LM, Wiese WH, Skipper BJ, Charley B, Benally L. Navajo birth outcomes in the Shiprock
uranium mining area. Health Phys 1992; 63(5):542-51.
Squibb KS, McDiarmid MA. Depleted uranium exposure and health effects in Gulf War veterans.
Philos Trans R Soc Lond B Biol Sci 2006; 361(1468):639-48.
Steinhardt G, Salinas Madrigal L, Phillips R, DeMello D. Fetal nephrotoxicity. J Urol 1992;
148(2 Pt 2):760-3.
Szakmary E, Tatrai E, Naray M, Hudak A, Ungvary G. Embryotoxic and teratogenic effects of “low-
radiation” uranium. Egeszsegtudomany 2001; 45(3):272-82 (abstract only).
Wiese WH, Skipper BJ. Survey of reproductive outcomes in uranium and potash mine workers.
Results of first analysis. Ann. Am. Conf. Gov. Ind. Hyg. 1986; 14:187-12.
References                                                                                           37
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<pre>8 Uranium and its compounds</pre>

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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
                                                         39
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<pre>0 Uranium and its compounds</pre>

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<pre>nnex A
     The Committee
     •  D. Lindhout, chairman
        Professor of Medical Genetics, Paediatrician (not practising), Clinical
        Geneticist, University Medical Centre, Utrecht
     •  N. Roeleveld
        Reproductive Epidemiologist, Radboud university medical centre, Nijmegen
     •  J.G. Theuns-van Vliet
        Reproductive Toxicologist, Triskelion BV, Zeist
     •  T.G.M. Vrijkotte
        Epidemiologist, AMC, Amsterdam (from Februari 1, 2016)
     •  D.H. Waalkens-Berendsen
        Reproductive Toxicologist, Zeist
     •  P.J.J.M. Weterings
        Toxicologist, Weterings Consultancy BV, Rosmalen
     •  A.H. Piersma, structurally consulted expert
        Professor of Reproductive and Developmental Toxicology, Utrecht
        University, Utrecht and National Institute of Public Health and the
        Environment, Bilthoven
     •  P.W. van Vliet, scientific secretary
        Health Council of the Netherlands, Den Haag
     The Committee                                                               41
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<pre>  The first draft of the present document was prepared by Dr. B. Tiesjema, from
  the National Institute of Public Health and the Environment (RIVM) in
  Bilthoven, 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, persons 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 Health Council to assess
  whether or not someone can become a member. An expert who has no financial
  but another clearly definable interest, can become a member under the restriction
  that he will not be involved in the debate on the subject to which his interest
  relates. If a person’s interest is not clearly definable, he can sometimes be
  consulted as an expert. Experts working for a ministry or governmental
  organisation can be structurally consulted. During the inaugural meeting the
  declarations issued are discussed, so that all members of the Committee are
  aware of each other’s possible interests.
2 Uranium and its compounds
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<pre>nnex B
     The submission letter (in English)
     Subject           : Submission of the advisory report Uranium and its compounds
     Your reference    : DGV/BMO/U-932542
     Our reference     : U-962581/EvV/jh/543-F16
     Enclosure(s)      :1
     Date              : May 18, 2016
     Dear Minister,
     I hereby submit the advisory report on the effects of uranium and its 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. It concerns
     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 Substances. The advisory report was consequently reviewed
     by the Health Council’s Standing Committee on Public Health.
     The submission letter (in English)                                                  43
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<pre>  Today I sent copies of this advisory report to the Minister of Health, Welfare and
  Sport and tot the State Secretary of Infrastructure and the Environment, for their
  information.
  Yours sincerely,
  (signed)
  Professor J.L. Severens
  Vice President
4 Uranium and its compounds
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<pre>nnex C
     Comments on the public draft
     A draft of the present report was released in 2015 for public review. The
     following persons and organisations have commented on the draft document:
     • T.P. Kuipers, on behalf of the Military Healthcare & Occupational Health
         Expertise Co-ordination Centre, Support Command, Ministry of Defence,
         Doorn, The Netherlands
     • T.J. Lentz, J. Anderson, C. Johnson. National Institute for Occupational
         Safety and Health (NIOSH), Cincinnati, OH, USA.
     The comments received, and the reply by the Committee can be found on the
     website of the Health Council.
     Comments on the public draft                                               45
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<pre>6 Uranium and its 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                                                      47
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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.
8 Uranium and its 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                                                        49
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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                                                         51
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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.
2 Uranium and its compounds
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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                                                       53
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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
4 Uranium and its 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.
Regulation (EC) 1272/2008 of the European Community                                                       55
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<pre>  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
  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.
6 Uranium and its compounds
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<pre> 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.
              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                                                                 57
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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
 8            Uranium and its 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 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:
     • If there is sufficient evidence to establish a causal relationship between
         human exposure to the substance and impaired fertility or subsequent
         developmental toxic effects in the offspring, the compound will be classified
         in category 1A, irrespective of the general toxic effects (see Annex D,
         3.7.2.2.1.).
     • Adverse effects in a reproductive study, occurring without reporting 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
         general toxicity studies.
     • Clear adverse reproductive effects will not be disregarded on the basis of
         reversibility per se.
     Additional considerations to Regulation (EC) 1272/2008                              59
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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.
0 Uranium and its compounds
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<pre> nnex        F
             Fertility and developmental toxicity
             studies
 able 1 Fertility studies (oral) in animals.
uthors          compound        species      experimental    dose and route    general toxicity     effects on reproductive
                                             period/design                                          organs and reproduction
Maynard         uranium         rats         195 days,       oral              mortality: In the    testicular lesions,
t al., 1949     nitrate                      followed by a   administration in first 30 days, 4     including degeneration
                hexahydrate                  recovery period diet, at 0 or 2%  females and 5        and atrophic changes
                                             of 170 days     UO2(NO3)2*        males from the       (tubuli with loss of
                                                             6H2O (200-300     uranium group;       spermatozoa, absence of
                                                             mg/rat/day)       10% of controls      spermatids, loss of
                                                                               and 17% of the       primary spermatocytes,
                                                                               uranium group in     presence of
                                                                               the remainder of     multinucleated cells).
                                                                               the year. Reduction  Irregular oestrus cycles
                                                                               of body weight gain  (14/44) compared to 2/45
                                                                               in males and         in control rats; irregular
                                                                               females (after 7     (1/44 vs 0/45 in controls)
                                                                               months males and     or no (17/44 vs 4/45 in
                                                                               females weighed 65   controls) matings;
                                                                               and 60 grams less    reduction in females that
                                                                               than controls).      had at least one litter
                                                                               Degeneration of the  (44/45 in control group
                                                                               kidneys in the first compared to 30/44 in the
                                                                               week; between        uranium group); reduced
                                                                               weeks 8 and 14       number of litters per
                                                                               tubular atrophy; no  female. In the recovery
                                                                               renal abnormality    period, the amount of
                                                                               after the recovery   litters in the uranium
                                                                               period.              group returned to normal.
                                                                                                    No statistics mentioned
             Fertility and developmental toxicity studies                                                                    61
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<pre>Maynard          uranyl nitrate rats       12 or 24 months oral adminis-        not reported         severe degeneration in
 t al., 1953     hexahydrate                                tration in diet, at                      the testes, depletion of
                                                            dose levels of 331                       germ cells (males)
 ited in                                                    mg U/kg bw/day                           reduced litter sizes
  TSDR, 2013                                                (males) and 664                          (females)
 nd Domingo,                                                mg U/kg bw/day                           [no dose-response data
 001                                                        (females)                                available]
Malenchenko uranyl nitrate male            4 months         administration in   Spleen weight and    decreased testes weight
 t al., 1978     hexahydrate Wistar rats                    drinking water at   spleen index were    (p<0.05), testicular
                                                            0.1% UO2(NO5)*      increased (p<0.05)   lesions, and necrosis of
                                                            6H2O (~50           and morphological    spermatocytes and
                                                            mg/kg bw)           changes in the       spermatogonia
                                                                                thyroid gland were
                                                                                observed (not
                                                                                further analyzed)
  lobet et al.,  uranyl acetate male Swiss 64 days (before  oral adminis-       no clinical signs of non-dose-related
 991             dihydrate      mice       mating to        tration in drinking toxicity were        decrease in pregnancy
                                           untreated female water resulting in  observed, except     rate (25-35% in uranium
                                           mice)            doses of 10, 20,    for a reduced body   treated animals vs. 81%
                                                            40, and 80 mg       weight at the        in the control group,
                                                            UO2(CH3COO)2*       highest dose         p<0.01 or p<0.05). No
                                                            2H2O/kg bw/day      (p<0.05)             statistically significant
                                                                                                     differences in total
                                                                                                     implantations, early and
                                                                                                     late resorptions, or
                                                                                                     number of live and dead
                                                                                                     foetuses. Normal testes
                                                                                                     and epididymis weights,
                                                                                                     normal spermatogenesis.
                                                                                                     Increase in Leydig cells
                                                                                                     vacuolization at 80
                                                                                                     mg/kg/day (p<0.05)
Gilman et al., uranyl nitrate Sprague-     28 days          oral adminis-       no general toxicity  no statistically significant
 998a            hexahydrate Dawley                         tration in drinking observed             changes in reproductive
                                rats                        water at doses of                        organ weights in
                                (10/sex/                    < 0.001, 0.96, 4.8,                      epididymis, testes, ovary
                                group)                      24, 120 and 600                          or uterus
                                                            mg UO2(NO3)2*
                                                            6H2O /L (up to
                                                            35.3 mg/kg
                                                            bw/day (males)
                                                            and 40.0 mg/kg
                                                            bw/day (females)
  2             Uranium and its compounds
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<pre>Gilman et al., uranyl nitrate Sprague-  91 days         oral administra-   in all dose groups,   no statistically significant
 998a           hexahydrate Dawley                      tion in drinking   males and females:    changes in reproductive
                               rats                     water at doses of  histopathological     organ weights in
                               (15/sex/                 0, 0.96, 4.8, 24,  lesions in the        epididymis, testes, ovary
                               group)                   120, or 600 mg     kidney and liver,     or uterus
                                                        UO2(NO3)2*         renal lesions of
                                                        6H2O /L (up to     tubules (apical
                                                        36.73 mg/kg bw/d   nuclear
                                                        (males) and 53.56  displacement and
                                                        mg/kg bw/d         vesiculation,
                                                        (females))         cytoplasmic
                                                                           vacuolation, and
                                                                           dilation), glomeruli
                                                                           (capsular sclerosis),
                                                                           and interstitium
                                                                           (reticulin sclerosis
                                                                           and lymphoid
                                                                           cuffing) (p<0.001,
                                                                           p<0.01 or p<0.05)
Gilman et al., uranyl nitrate New       for 91 days     oral administra-   changes in renal      no statistically significant
 998b           hexahydrate Zealand                     tion in drinking   tubules (LOAEL        histopathological or
                               White                    water at doses of  males 0.05 mg         organ weight changes in
                               rabbits                  0, 0.96, 4.8, 24,  U/kg bw/day,          epididymis, testes, ovary
                                                        120, or 600 mg     females 0.49 mg       or uterus
                                                        UO2(NO3)2*         U/kg bw/day)
                                                        6H2O /L (up to
                                                        28.70 mg/kg
                                                        bw/day) in males
                                                        and 0, 4.8, 24,
                                                        or 600 mg UN/L
                                                        (up to 43.02
                                                        mg/kg bw/day)
                                                        in females
Albina et al.,  uranyl acetate male     males were      0, 10, 20 or 40 mg no effects on body    decrease in pregnancy
 005            dihydrate      Sprague  exposed for 3   UO2(CH3COO)2*      weight gain of the    rate at 20 mg/kg bw/day
                               Dawley   months and then 2H2O /kg bw in     dams, maternal        (p<0.05) (no dose-effect
                               rats     mated to        drinking water     toxicity not further  relationship); no effects
                                        untreated                          analyzed              on number of implants,
                                        females                                                  number of viable
                                                                                                 implants and number of
                                                                                                 dead foetuses per litter
               Fertility and developmental toxicity studies                                                               63
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<pre>  inares et al., uranyl acetate male      males were        0, 10, 20 or 40 mg No deaths or        at 20 mg/kg bw/day:
 005             dihydrate      Sprague   exposed for 3     UO2(CH3COO)2*      clinical signs of   decrease in pregnancy
                                Dawley    months and then   2H2O /kg bw in     toxicity, including rate (p<0.05) (9/12, 6/8,
                                rats      mated to          drinking water     body weight gain at 4/8 and 6/8 in females
                                (8/group) untreated                            any dose            mated to males exposed
                                          females                                                  to 0, 10, 20 and 40 mg/kg
                                                                                                   bw/day respectively); no
                                                                                                   statistically significant
                                                                                                   differences in number of
                                                                                                   total implants and
                                                                                                   number of viable and
                                                                                                   nonviable implants per
                                                                                                   litter; decreased
                                                                                                   spermatid number/testis
                                                                                                   at 20 and 40 mg/kg bw/
                                                                                                   day (p<0.05).
                                                                                                   Histopathological
                                                                                                   examination testes after
                                                                                                   3 months revealed few
                                                                                                   differences in the tubule
                                                                                                   and interstitial alterations
                                                                                                   (progressive but not
                                                                                                   statistically significant
                                                                                                   cellular loss, Sertoli cells
                                                                                                   or germinal cells, with
                                                                                                   cytoplasmic
                                                                                                   vacuolization) between
                                                                                                   control and uranium-
                                                                                                   exposed animals
 ánchez et al., uranyl acetate adult      for 4 weeks       at doses of 0, 40 no relevant effects  no effects on number of
 006             dihydrate      female    before mating     and 80 mg          on maternal body    litters or number of
                                Sprague   with untreated    UO2(CH3COO)2* weight gain              implants (total, viable
                                Dawley    males, as well as 2H2O /kg bw/day                        and non viable)/litter
                                rats      during            in the drinking
                                          pregnancy and     water
                                          lactation
Arneault         uranyl nitrate female    group 1: 15       5, 50 or 400       no effects on body  dams first group and
 t al., 2008                    C57Bl×CB weeks, directly    mg/L               weight, kidney      female pups: fewer
                                A mice    followed by       UO2(NO3)2*         weight and          large antral follicles
                                          analysis.         6H2O in drinking   behavior            (Ø >200µm) than
                                          group 2: 15       water (~ 1.25,                         controls (p<0.05). Dams
                                          weeks, just       12.5 and 100 mg                        second group: more
                                          before gestation  U/kg bw/day)                           secondary and early pre-
                                          Analysis after 3                                         antral follicles
                                          months                                                   (Ø 70-110µm) than
                                                                                                   controls (p<0.05)
 w=body weight(s); gd=gestational day(s); pnd=post-natal day(s); U=uranium; UN=uranyl nitrate hexahydrate.
  4            Uranium and its compounds
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<pre> able 2 Developmental studies (oral) in animals.
 uthors       compound       species     experimental       dose and route   general toxicity   effects on reproductive
                                         period/design                                          organs and reproduction
Domingo       uranyl acetate pregnant    dosed on gd 6-15   0, 5, 10, 25     at all doses:      dose-related
 t al. 1989a dihydrate       Swiss mice and sacrificed on   or 50 mg         reduced weight     foetotoxicity, manifested
                             (20/group) gd 18               UO2(CH3COO)2*    gain and food      as reduced foetal body
                                                            2H2O /kg bw/day  consumption,       weight and length,
                                                            by gavage        increased relative increased incidence of
                                                                             liver weight       stunted foetuses and
                                                                             (p<0.001, p<0.01 external and skeletal
                                                                             or p<0.05)         malformations, and
                                                                                                developmental variations
                                                                                                (p<0.001, p<0.01 or
                                                                                                p<0.05). External
                                                                                                malformations included
                                                                                                an increase in the
                                                                                                incidence of cleft palate
                                                                                                (at 10 mg/kg bw/day and
                                                                                                higher doses, (p<0.01)
                                                                                                and hematomas (p<0.05
                                                                                                at 5 and 50 mg/kg
                                                                                                bw/day). In the 5 and 25
                                                                                                mg/kg bw/day groups:
                                                                                                undeveloped renal
                                                                                                papillae. Increased
                                                                                                incidence of skeletal
                                                                                                abnormalities (bipartite
                                                                                                sternebrae and reduced
                                                                                                or delayed ossification of
                                                                                                the hind limb, fore limb,
                                                                                                skull, and tail) in the 25
                                                                                                and 50 mg/kg bw/day
                                                                                                groups (p<0.001, p<0.01
                                                                                                or p<0.05) Embryol-
                                                                                                ethality was not found
Domingo       uranyl acetate pregnant    from gd 13 through 0, 0.05, 0.5, 5  effects on body    number of litters or litter
 t al., 1989b dihydrate      Swiss mice pnd 21              or 50 mg         weight or food     size not affected on
                             (20/group)                     UO2(CH3COO)2 *   intake were not    postnatal day 0, but
                                                            2H2O /kg         observed. Two      decreased litter size at
                                                            bw/day by gavage dams in the        postnatal day 21 at 50
                                                                             5 mg/kg bw/day     mg/kg bw/day (5.5 vs.
                                                                             group and 2 dams   8.8 in controls) (p<0.05);
                                                                             in the 50 mg/kg    decreased viability index
                                                                             bw/day group died  (number of pups viable
                                                                             during lactation   at day 21/number of pups
                                                                                                born) and the lactation
                                                                                                index (number of pups
                                                                                                viable at day 21/number
                                                                                                of pups retained at day 4)
                                                                                                at 50 mg/kg bw/day
              Fertility and developmental toxicity studies                                                               65
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<pre>                                                                                                  (p<0.05); reduction in
                                                                                                  liver weight in pups of
                                                                                                  all dose groups (p<0.01
                                                                                                  or p<0.05); no
                                                                                                  differences in pup weight
                                                                                                  or body length; no
                                                                                                  significant differences in
                                                                                                  developmental signs
                                                                                                  (pinnae unfolding, lower
                                                                                                  incisor eruption, eye
                                                                                                  opening)
 ánchez      uranyl acetate adult      for 4 weeks before at doses of 0,      no statistically    no statistically
 t al., 2006 dihydrate      female     mating with         40 and 80 mg       significant effects significant effects on
                            Sprague    untreated males, as UO2(CH3COO)2*      on maternal body    number of implants
                            Dawley     well as during      2H2O /kg bw/day in weight gain         (total, viable and non
                            rats       pregnancy and       the drinking water                     viable)/litter. No
                                       lactation                                                  statistically significant
                                                                                                  effects on body weight
                                                                                                  pups at postnatal day 1,
                                                                                                  decrease in body weight
                                                                                                  pups (male and female)
                                                                                                  on postnatal day 4 (at 40
                                                                                                  mg/kg bw/day, p<0.05),
                                                                                                  12 and 21 (at 40 and 80
                                                                                                  mg/kg bw/day, p<0.05)
Arneault     uranyl nitrate female     group 1: 15         5, 50 or 400 mg/L  no effects on body  female pups: fewer large
 t al., 2008                C57Bl×CB weeks, directly       UO2(NO3)2*6H2O     weight, kidney      antral follicles
                            A mice     followed by         in drinking water  weight and          (Ø >200µm) than
                                       analysis            (~ 1.25, 12.5 and  behavior            controls (p<0.05).
                                       group 2: 15         100 mg U/kg                            No monotone dose-
                                       weeks, just before  bw/day)                                response relationship.
                                       gestation.                                                 Normal amount of
                                       Analysis after                                             secondary and early
                                       3 months                                                   preantral follicles
                                                                                                  (Ø 70-110 µm)
 w=body weight(s); gd=gestational day(s); pnd=post-natal day(s); U=uranium; UN=uranyl nitrate hexahydrate.
  6          Uranium and its compounds
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<pre>able 3 Developmental studies (other) in animals.
uthors       compound       species     experimental  dose and route    general toxicity    effects on reproductive
                                        period/design                                       organs and reproduction
 osque       uranyl acetate Swiss mice gd 6-15        SC injections at dose-related deaths at ≥ 0.5 mg/kg bw/day:
t al., 1993a dihydrate      (16-22                    dose levels of 0, (0, 1, 2, and 7     increased percentage of
                            dams/                     0.5, 1, and 2 mg deaths at 0, 0.5,    early resorptions
                            group)                    UO2(CH3COO)2* 1 and 2 mg/kg           (p<0.05) and post-
                                                      2H2O /kg bw/day bw/day,               implantation loss
                                                                        respectively) and (p<0.01); reduction in
                                                                        decreased weight foetal body weight at 1
                                                                        gain during         and 2 mg/kg bw/day and
                                                                        gestation (at all   by a dose-dependent
                                                                        dose levels,        increase in the number of
                                                                        (p<0.001, p<0.01 total internal (renal
                                                                        or p<0.05) and      hypoplasia) and total
                                                                        decreased body      skeletal (decreased
                                                                        weight at           ossification) defects,
                                                                        termination (1 and (statistically significant
                                                                        2 mg/kg bw/day,     at all doses: p<0.001,
                                                                        p<0.01 and          p<0.01 or p<0.05).
                                                                        p<0.001,            increase in
                                                                        respectively);      malformations (cleft
                                                                        maternal liver      palate and bipartite
                                                                        weight (absolute    sternebrae) at 1 and 2
                                                                        and relative) and   mg/kg bw/day (p<0.001,
                                                                        kidney weight       p<0.01 or p<0.05).
                                                                        (absolute) were
                                                                        decreased in the
                                                                        1and 2 mg/kg
                                                                        bw/day dose
                                                                        groups (p<0.001
                                                                        or p<0.05)
 osque       uranyl acetate Swiss mice gd 10          single SC         death (20%,         significantly increased
t al., 1993b dihydrate      (12 dams/                 injection of      compared to 0% in   percentage of resorptions
                            group)                    4 mg              controls), lethargy and dead foetuses
                                                      UO2(CH3COO)2*     and reduced body    (together 36.3 vs 2.21%,
                                                      2H2O /kg bw       weight gain         p<0.001); decreases in
                                                                        (p<0.01)            foetal body weight
                                                                                            (p<0.001) and increases
                                                                                            in the percentage of
                                                                                            skeletal anomalies
                                                                                            (78.6 vs 10.7% foetuses
                                                                                            affected in treated vs
                                                                                            control group, p<0.05);
                                                                                            skeletal alterations
                                                                                            including reduced
                                                                                            ossifications, wavy
                                                                                            ribs and dorsal
                                                                                            hyperkyphosis
             Fertility and developmental toxicity studies                                                           67
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<pre>Albina et al., uranyl acetate Sprague  gd 6-15. Cesarean    SC injections    at 0.830 mg/kg      at 0.415 and 0.830
 003           dihydrate      Dawley   sections on gd 20    of 0.415 and     bw/day: decreased   mg/kg/day by reductions
                              rats                          0.830 mg         body weight gain,   in foetal body weight
                              (11-12/                       UO2(CH3COO)2*    decreased gravid    (dose-dependent,
                              group)                        2H2O /kg bw/day  uterine weight,     p<0.05) and increases in
                                                                             decreased absolute  the percentage of
                                                                             and relative kidney skeletally affected
                                                                             weight (p<0.05)     foetuses (16, 55 and 88%
                                                                                                 in controls, at 0.415 and
                                                                                                 at 0.830 mg/kg/day,
                                                                                                 respectively (p<0.003)).
                                                                                                 The skeletal
                                                                                                 abnormalities observed
                                                                                                 were delayed
                                                                                                 ossifications.
 w=body weight(s); gd=gestational day(s); pnd=post-natal day(s); U=uranium; UN=uranyl nitrate hexahydrate.
 8             Uranium and its compounds
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<pre>Health Council of the Netherlands
Advisory Reports
The Health Council’s task is to       In addition, the Health Council
advise ministers and parliament on    issues unsolicited advice that
issues in the field of public health. has an ‘alerting’ function. In some
Most of the advisory opinions that    cases, such an alerting report
the Council produces every year       leads to a minister requesting
are prepared at the request of one    further advice on the subject.
of the ministers.
Areas of activity
Optimum healthcare                    Prevention                          Healthy nutrition
What is the optimum                   Which forms of                      Which foods promote
result of cure and care               prevention can help                 good health and
in view of the risks                  realise significant                 which carry certain
and opportunities?                    health benefits?                    health risks?
Environmental                         Healthy working                     Innovation and
health                                conditions                          the knowledge
Which environmental                   How can employees                   infrastructure
influences could have                 be protected against                Before we can harvest
a positive or negative                working conditions                  knowledge in the
effect on health?                     that could harm their               field of healthcare,
                                      health?                             we first need to
                                                                          ensure that the right
                                                                          seeds are sown.
www.healthcouncil.nl
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