<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
          Molybdenum and molybdenum
          compounds
            Health-based recommended occupational exposure limit
2013/30
</pre>

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<pre>Molybdenum and molybdenum
compounds
    Health-based recommended occupational exposure limit
</pre>

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<pre></pre>

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<pre>Aan de minister van Sociale Zaken en Werkgelegenheid
Onderwerp              : aanbieding advies Molybdenum and molybdenum compounds
Uw kenmerk             : DGV/MBO/U-932342
Ons kenmerk            : U-7988/JR/fs/459-B69
Bijlagen               :1
Datum                  : 11 december 2013
Geachte minister,
Graag bied ik u hierbij aan het advies over de gevolgen van beroepsmatige blootstelling aan
molybdeen en molybdeenverbindingen.
Dit advies maakt deel uit van een uitgebreide reeks, waarin gezondheidskundige advies-
waarden worden afgeleid voor concentraties van stoffen op de werkplek. De conclusies van
het genoemde advies zijn opgesteld door de Commissie Gezondheid en beroepsmatige
blootstelling aan stoffen (GBBS) van de Gezondheidsraad en beoordeeld door de Beraads-
groep Gezondheid en omgeving.
Ik heb dit advies vandaag ter kennisname toegezonden aan de staatssecretaris van Infra-
structuur en Milieu en aan de minister van Volksgezondheid, Welzijn en Sport.
Met vriendelijke groet,
prof. dr. W.A. van Gool,
voorzitter
Bezoekadres                                                        Postadres
Rijnstraat 50                                                      Postbus 16052
2515 XP Den Haag                                                   2500 BB Den Haag
E - m a il : jm .r i j n ke ls @ g r.n l                           w w w. g r. n l
Te l e f o o n ( 0 7 0 ) 3 4 0 6 6 3 1
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<pre></pre>

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<pre>Molybdenum and molybdenum
compounds
Health-based recommended occupational exposure limit
Dutch Expert Committee on Occupational Safety,
a Committee of the Health Council of the Netherlands
to:
the Minister of Social Affairs and Employment
No. 2013/30, The Hague, November 11, 2013
</pre>

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<pre>The Health Council of the Netherlands, established in 1902, is an independent
scientific advisory body. Its remit is “to advise the government and Parliament on
the current level of knowledge with respect to public health issues and health
(services) research...” (Section 22, Health Act).
     The Health Council receives most requests for advice from the Ministers of
Health, Welfare & Sport, Infrastructure & the Environment, Social Affairs &
Employment, Economic Affairs, and Education, Culture & Science. The Council
can publish advisory reports on its own initiative. It usually does this in order to
ask attention for developments or trends that are thought to be relevant to
government policy.
     Most Health Council reports are prepared by multidisciplinary committees of
Dutch or, sometimes, foreign experts, appointed in a personal capacity. The
reports are available to the public.
                 The Health Council of the Netherlands is a member of the European
                 Science Advisory Network for Health (EuSANH), a network of science
                 advisory bodies in Europe.
This report can be downloaded from www.healthcouncil.nl.
Preferred citation:
Health Council of the Netherlands. Molybdenum and molybdenum compounds -
Health-based recommended occupational exposure limit. The Hague: Health
Council of the Netherlands, 2013; publication no. 2013/30.
all rights reserved
ISBN: 978-90-5549-980-9
</pre>

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<pre>   Contents
   Samenvatting 11
   Executive summary 19
   Scope 27
.1 Background 27
.2 Committee and procedure 28
.3 Data 28
   Identification, properties and monitoring 29
.1 Chemical identification 29
.2 Physical and chemical properties 29
.3 EU classification and labelling 31
.4 Analytical methods 31
   Sources 33
.1 Natural occurrence 33
.2 Man-made sources 33
   Contents                                     7
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<pre>   Exposure 35
.1 General population 35
.2 Working population 36
   Kinetics 39
.1 Absorption 39
.2 Distribution 41
.3 Biotransformation and metabolism 41
.4 Elimination 42
.5 Biological monitoring 42
   Mechanism of action 43
.1 Copper deficiency 43
.2 Gout 44
   Effects 45
.1 Observations in humans 45
.2 Effects in laboratory animals 49
.3 Summary 70
   Existing guidelines, standards and evaluations 73
.1 General population 73
.2 Working population 74
.3 Carcinogenic classification 75
   Hazard assessment 77
.1 Hazard identification 77
.2 Quantitative hazard assessment 80
.3 Groups at extra risk 84
.4 Health-based recommended occupational exposure limits and classifications 85
0  Recommendations for research 87
   References 89
   Molybdenum and molybdenum compounds
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<pre>  Annexes 97
A Request for advice 99
B The Committee 101
C The submission letter (in English) 103
D Comments on the public review draft 105
E Evaluation by the Subcommittee on the classification of carcinogenic substances 107
F Classification of substances with respect to carcinogenicity 109
G Evaluation by the Subcommittee on the Classification of
  reproductive toxic substances 111
H BMD-analysis: inhalation study on pathological respiratory tract effects
  by molybdenum trioxide 117
  BMD-analysis: diet study on body weight effects by sodium molybdate 119
  Contents                                                                            9
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<pre>0 Molybdenum and molybdenum compounds</pre>

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<pre>Samenvatting
Vraagstelling
Op verzoek van de minister van Sociale Zaken en Werkgelegenheid leidt de
Commissie Gezondheid en Beroepsmatige Blootstelling aan Stoffen (GBBS) van
de Gezondheidsraad gezondheidskundige advieswaarden af voor stoffen in de
lucht waaraan mensen tijdens hun beroepsuitoefening blootgesteld kunnen wor-
den. Deze advieswaarden vormen vervolgens de basis voor de grenswaarden, die
de minister vaststelt om de gezondheid van werknemers te beschermen.
     In dit advies bespreekt de commissie de gevolgen van blootstelling aan
molybdeen en molybdeenverbindingen* en stelt zij een gezondheidskundige
advieswaarde vast. De conclusies van de commissie zijn gebaseerd op weten-
schappelijke publicaties die vóór oktober 2013 zijn verschenen.
Fysische en chemische eigenschappen
Puur molybdeen is een natuurlijk voorkomend zilverachtig metaal dat in ver-
schillende oxidatietoestanden kan voorkomen, waarvan molybdeen(IV) en
molybdeen(VI) de stabielste vormen zijn. In de natuur wordt molybdeen vooral
 De in dit advies geëvalueerde molybdeenverbindingen zijn metallisch molybdeen, molybdeniet,
molybdeenchloride, molybdeentrioxide, ammoniummolybdaat, ammoniumparamolybdaat, calcium-
molybdaat en natriummolybdaat.
Samenvatting                                                                                 11
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<pre>  aangetroffen als molybdaat, dat vervolgens een verscheidenheid aan molybdeen-
  verbindingen kan vormen. Sommige molybdeenverbindingen lossen bij 20°C
  goed op in water, zoals ammoniummolybdaat, ammoniumparamolybdaat en
  natriummolybdaat; andere lossen minder goed op, zoals molybdeentrioxide, of
  lossen niet op in water, zoals metallisch molybdeen, molybdeniet en molybdeen-
  chloride.
       Molybdeen wordt gebruikt in de metaalproducerende en -verwerkende indus-
  trie.
  Monitoring
  In Nederland wordt de ISO-methode (ISO 15202) gebruikt voor het kwantifice-
  ren en identificeren van metalen in de lucht op de werkvloer. Molybdeen in stof
  (totaal, inhaleerbaar of respirabele fractie in stof) kan gemeten worden met
  atoom-absorptie-spectroscopie of atoom-emissie-spectroscopie.
  Grenswaarden
  In Nederland zijn voor molybdeen en molybdeenverbindingen geen wettelijke
  grenswaarden vastgesteld. Ook zijn er geen grenswaarden vastgesteld door de
  Europese Commissie. Sommige andere landen hanteren voor oplosbare molyb-
  deenverbindingen grenswaarden (tijdgewogen gemiddelde concentratie over
  acht uur) van 0,5 tot 5 mg molybdeen/m3.* Voor metallisch molybdeen en onop-
  losbare molybdeenverbindingen gelden grenswaarden van 3 tot 15 mg molyb-
  deen/m3. De grenswaarden zijn niet zonder meer vergelijkbaar met elkaar, omdat
  deze gebaseerd zijn op bemonstering van verschillende stoffracties (molybdeen-
  gehalte in totaal, inhaleerbaar of respirabel stof).
  Kinetiek
  Onderzoek heeft aangetoond dat dieren en mensen door inademing en inname
  via voedsel en drinkwater, molybdeen en molybdeenverbindingen opnemen in
  het lichaam. Daarbij hangt de snelheid waar het lichaam deze verbindingen via
  het voedsel opneemt af van de oplosbaarheid van de verbindingen en de voedsel-
  samenstelling. In het algemeen is de opname via het maagdarmstelsel snel en
  vrijwel compleet. Het is niet bekend hoe snel en efficiënt de opname via inade-
  ming is.
  mg/m3: milligram molybdeen per kubieke meter lucht
2 Molybdenum and molybdenum compounds
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<pre>    Molybdeen is een essentieel sporenelement dat mensen en dieren nodig heb-
ben om normale biologische processen goed te laten verlopen. Molybdeen wordt
in lage concentraties aangetroffen in alle lichaamsvloeistoffen en – weefsels. Er
vindt in het lichaam geen noemenswaardige stapeling van molybdeen plaats.
Molybdeen kan de placenta passeren en is aangetroffen in moedermelk.
    Het metabolisme van molybdeen is gekoppeld aan het koper- en zwavelmeta-
bolisme. Uitscheiding via de urine – de belangrijkste route van eliminatie – is
snel en versneld bij voedsel dat rijk is aan koper en sulfaat.
Effecten
Waarnemingen bij mensen
Het beschikbare onderzoek onder mensen die beroepsmatig zijn blootgesteld aan
molybdeen(verbindingen) heeft een beperkte waarde voor de afleiding van een
gezondheidskundige advieswaarde, omdat betrouwbare blootstellinggegevens
ontbreken. Daarnaast is sprake van gelijktijdige blootstelling aan andere potenti-
eel toxische stoffen, en zijn de onderzoeken niet goed beschreven. Mensen die
beroepshalve blootstonden aan in ieder geval molybdeentrioxide klaagden over
gewrichtspijn, rugpijn, hoofdpijn, moeilijke ademhaling, borstpijn en vermoeid-
heid. De laatste klachten kunnen wijzen op milde obstructieve longziekten. Ook
werden verhoogde gehaltes aan urinezuur in het bloed aangetroffen. De bloot-
stellingsniveaus waarbij dergelijke klachten optraden, varieerden van 1,6 mg/m3
(molybdeen in respirabel stof in een molybdeenverwerkende ‘roostfabriek’) tot
600 mg/m3 in stof van mijnen.
    Bij Armeense dorpsbewoners werden jichtachtige verschijnselen waargeno-
men en verhoogde gehaltes urinezuur in het bloed. Zij hadden een gemiddelde
dagelijkse inname van 10 tot 15 milligram molybdeen via het voedsel (en 5 tot
10 milligram koper). De gemiddelde dagelijkse inname ligt normaal tussen de
0,1 en 0,3 milligram. In een Amerikaanse drinkwateronderzoek zijn geen effec-
ten op de gezondheid geconstateerd; het drinkwater bevatte tenminste 200 micro-
gram molybdeen per liter water (normaalwaarden: tussen de 10 en 60
microgram).
    Gegevens over mogelijke kankerverwekkendheid van molybdeen(verbindin-
gen) voor de mens zijn beperkt. In een bevolkingsonderzoek naar sterftegevallen
door kanker is een zwakke correlatie van longkanker gevonden onder mensen die
beroepshalve langdurig blootstonden aan molybdeen; in een ander onderzoek
onder vrouwen in Japan werd een positieve correlatie gevonden met kanker in de
alvleesklier. Door gebrek aan betrouwbare blootstellingniveaus, en doordat
Samenvatting                                                                       13
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<pre>  mogelijke andere factoren aanwezig waren die kanker kunnen hebben veroor-
  zaakt in de onderzochte populaties, vallen uit deze onderzoeken geen conclusies
  te trekken.
       In een klinische studie werden afwijkingen in spermakwaliteit en spiegels
  van mannelijke geslachtshormonen waargenomen. Voor zover bekend zijn er
  geen andere onderzoeken uitgevoerd waarin is nagegaan of molybdeen en
  molybdeenverbindingen de vruchtbaarheid bij de mens kunnen verminderen en
  de ontwikkeling van het nageslacht kunnen aantasten.
  Waarnemingen bij dieren
  Bepaalde molybdeenverbindingen, met name de wateroplosbare, bleken irritatie
  te geven aan neus, ogen en luchtwegen.
  Inademing
  Blootstelling tot aan 100 mg molybdeentrioxide/m3 (in aerosolen) gedurende
  dertien weken veroorzaakte geen nadelige gezondheidseffecten en geen patholo-
  gische afwijkingen in weefsels van ratten en muizen. Cavia’s die vijf dagen ach-
  ter elkaar werden blootgesteld aan meer dan 300 mg/m3 (concentratie molybdeen
  in totaal stof in de lucht ), vertoonden irritatie aan de luchtwegen, verloren eetlust
  en gewicht, en hadden last van diarree, ongecoördineerde spieractiviteiten en
  haaruitval.
       Inademing van 10 tot 100 mg molybdeentrioxide/m3 (in aerosolen) voor zes
  uur per dag, vijf dagen per week gedurende twee jaar, veroorzaakte in ratten en
  muizen, vergeleken met een niet-blootgestelde groep, een statistisch significante
  toename van hyalinedegeneratie in het neusweefsel, metaplasie en hyperplasie in
  het strotklepje, en chronische ontstekingsverschijnselen in de longen. In het-
  zelfde onderzoek is ook bekeken of molybdeentrioxide kanker veroorzaakte,
  maar dat leverde tweeslachtige resultaten op. Er werden in geen enkel orgaan in
  het lichaam van ratten en muizen tumoren gevonden, behalve longtumoren in
  muizen, maar het aantal muizen met tumoren vertoonde geen verband met de
  mate van de blootstelling.
       Uitslagen van tests die kunnen aangeven of stoffen het DNA kunnen bescha-
  digen en daardoor kanker kunnen veroorzaken, geven aan dat de geëvalueerde
  molybdeentrioxide, ammoniummolybdaat en natriummolybdaat waarschijnlijk
  niet het DNA beschadigen.
       Er zijn verder geen duidelijke aanwijzingen gevonden dat inademing van
  molybdeentrioxide (tot 100 mg/m3, de hoogst geteste concentratie, gedurende
  dertien weken) de fertiliteit van mannelijke muizen en ratten aantast.
4 Molybdenum and molybdenum compounds
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<pre>Orale inname
In een dieronderzoek werd een statistisch significante afname van het absolute
lichaamsgewicht waargenomen in mannelijke ratten bij de hoogste dosering aan
natriummolybdaat (60 mg molybdeen/kg lichaamsgewicht). De dieren kregen de
stof via de voeding toegediend gedurende 90 dagen. Ook bij vrouwlijke ratten
werd een afname van het absolute lichaamsgewicht geconstateerd ten opzichte
van niet blootgestelde dieren. Er werden in hetzelfde onderzoek geen andere dui-
delijk aan molybdeen gerelateerde effecten gevonden. Er zijn ook andere kortdu-
rende dieronderzoeken uitgevoerd maar daaruit kunnen geen conclusies worden
getrokken. De reden daarvan is dat de onderzoeken met te weinig dieren waren
uitgevoerd. Er zijn geen drinkwater- of dieetstudies uitgevoerd naar mogelijke
kankerverwekkende eigenschappen van molybdeenverbindingen.
    Wel zijn er dierexperimenten uitgevoerd naar vruchtbaarheids- en ontwikke-
lingseffecten. Daaruit komen aanwijzingen dat bepaalde molybdeenverbindingen
wellicht schade aan de vruchtbaarheid van mannelijke dieren (en mogelijk ook
aan vrouwlijke dieren) kunnen veroorzaken. In een onderzoek werd bijvoorbeeld
een statistisch significante afname van spermabeweeglijkheid en het aantal sper-
macellen waargenomen in ratten, die gedurende 60 dagen en vijfmaal per week
natriummolybdaat via een maagsonde kregen toegediend (dosis 30 en 50 mg
natriummolybdaat/kg lichaamsgewicht per dag). Bij deze doseringen zijn geen
andere effecten gerapporteerd. Veel van deze experimenten zijn echter slecht
gerapporteerd. Ook het hierboven beschreven onderzoek is slecht gerapporteerd.
In andere dierexperimenten werden geen effecten op de vruchtbaarheid waarge-
nomen.
Evaluatie
De commissie vindt de gegevens van epidemiologische onderzoeken onvol-
doende om een gezondheidskundige advieswaarde te kunnen afleiden, vanwege
factoren als gecombineerde blootstelling en gebrek aan details over blootstelling
en karakteristieken van de onderzochte groepen. Er zijn wel gegevens van enkele
dierexperimentele onderzoeken beschikbaar, die als basis voor een gezondheids-
kundige advieswaarde zouden kunnen dienen. Voor het afleiden van een gezond-
heidskundige advieswaarde gebruikt de commissie de benchmarkdosis (BMD)
software van de Amerikaanse Environmental Protection Agency, waarmee het
best passende model voor een blootstellingsresponsrelatie kan worden bepaald.
Dit model is vervolgens gebruikt om een blootstellingsniveau af te leiden (de
BMDL, de onderste concentratie van het 95 procent betrouwbaarheidsinterval
Samenvatting                                                                      15
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<pre>  van de BMD), dat als vertrekpunt dient voor het afleiden van een gezondheids-
  kundige advieswaarde.
  Molybdeentrioxide
  Wat molybdeentrioxide betreft vormt volgens de commissie het tweejarig dier-
  experimenteel onderzoek, waarin ratten en muizen van beide geslachten aeroso-
  len van molybdeentrioxide inhaleerden met een concentratie oplopend tot 100
  mg/m3 het beste uitgangspunt. De meest relevante effecten die in dit onderzoek
  naar voren kwamen waren: metaplasie in het strottenklepje in beide diersoorten
  en in beide geslachten; hyalinedegeneratie in het neusweefsel, en chronische ont-
  steking en metaplasie in longweefsel. Deze laatste effecten waren minder consis-
  tent en beperkten zich tot slechts één diersoort en/of geslacht. Alle effecten in
  deze dieren beschouwt de commissie als relevant voor de mens. Uit de BMD-
  analyse werd een BMDL van 0,29 mg molybdeentrioxide/m3 afgeleid (metapla-
  sie in het strottenklepje), dat overeenkomt met een 10 procent extra risico op dit
  effect vergeleken met het achtergrondrisico*.
       Voor het vaststellen van een gezondheidskundige advieswaarde wordt nog
  rekening gehouden met verschillende onzekerheden. Zo zijn er verschillen tussen
  diersoorten. De commissie acht het echter niet nodig om daarvoor te compense-
  ren, omdat sprake is van oppervlakkige lokale effecten. Een andere onzekerheid
  is dat mensen onderling verschillend kunnen reageren op blootstelling. Daarvoor
  past de commissie een onzekerheidsfactor van drie toe. Toepassing van deze fac-
  tor levert een gezondheidskundige advieswaarde voor molybdeentrioxide op van
  0,1 mg molybdeentrioxide/m3. Deze waarde is gebaseerd op inhaleerbare stof-
  blootstelling en is gemiddeld over een achturige werkdag.
       Aangaande de kankerverwekkendheid beveelt de commissie verder aan
  molybdeentrioxide te classificeren in categorie 2 (verdacht kankerverwekkend
  voor de mens)**. Door een gebrek aan gegevens is het niet mogelijk de stof te
  classificeren voor effecten op de vruchtbaarheid en de ontwikkeling, en effecten
  tijdens lactatie.
  Natriummolybdaat
  Voor natriummolybdaat zijn twee dierexperimenten beschikbaar waarin bloot-
  stellingsresponsrelaties zijn bestudeerd. De eerste is die waarin duidelijke effec-
  De commissie kiest standaard voor dichotome (kwantale) diergegevens een extra risico van 10%. Zij
  kan hiervan afwijken als daar gegronde wetenschappelijke redenen voor zijn.
* Zie bijlage F voor het classificatiesysteem.
6 Molybdenum and molybdenum compounds
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<pre>ten zijn gevonden in de testis van ratten die via een maagsonde de stof kregen
toegediend (bij 30 en 50 mg natriummolybdaat/kg lichaamsgewicht per dag, vijf
dagen per week, gedurende 60 dagen). De andere is het dierexperiment waarin
een duidelijke gewichtsafname was te zien in vooral mannelijke ratten, die de
stof via de voeding kregen toegediend bij een dosis van 60 mg molybdeen/kg
lichaamsgewicht gedurende 90 dagen.
     Wat de eerste studie betreft is de commissie bezorgd over het optreden van
vruchtbaarheidseffecten. Dat die kunnen optreden lijkt te worden bevestigd door
andere dierexperimentele studies en door een humane studie, wat het relevant
maakt voor de mens. Daar staat tegenover dat de commissie constateert dat de
betreffende studie slecht gerapporteerd is en daardoor de vraag oproept hoe
betrouwbaar de gegevens zijn voor een kwantitatieve risicoanalyse.
     De studie waarin gewichtsafname is beschreven is goed uitgevoerd en gerap-
porteerd. Dit was ook de studie waarin geen andere noemenswaardige effecten
optraden. Op basis van deze studie heeft de commissie een BMDL berekend
van 10,9 mg molybdeen/kg lichaamsgewicht, die correspondeert met een 10 pro-
cents afname van lichaamsgewicht door blootstelling ten opzichte van het
lichaamsgewicht in niet-blootgestelde dieren*. Omdat het een orale dosis betreft
en de gezondheidskundige advieswaarde gebaseerd is op een concentratie in de
lucht is deze omgerekend. Dit levert een inhalatoire BMDL op van 41,20 mg
molybdeen/m3.
     Voor het vaststellen van een gezondheidskundige advieswaarde wordt nog
rekening gehouden met verschillende onzekerheden, zoals verschillen tussen
diersoorten. Omdat het gaat om systemische effecten hanteert de commissie een
factor drie om te compenseren voor verschillen tussen diersoorten. De commissie
hanteert verder ook nog een factor drie om te compenseren voor verschillen tus-
sen mensen onderling. Toepassing van deze twee factoren levert een gezond-
heidskundige advieswaarde voor natriummolybdaat op van 4,6 mg molybdeen/
m3 (afgerond). Deze waarde is gebaseerd op inhaleerbare stofblootstelling en is
gemiddeld over een achturige werkdag.
     Door een gebrek aan gegevens is het niet mogelijk de stof te classificeren
voor kankerverwekkendheid. De commissie beveelt wel aan molybdaten te clas-
sificeren voor effecten op de vruchtbaarheid, namelijk in categorie 2 (‘wordt
ervan verdacht de vruchtbaarheid te schaden’). Door een gebrek aan gegevens is
het niet mogelijk de stof te classificeren voor effecten op de ontwikkeling en
effecten tijdens lactatie.
De commissie kiest standaard een 10 procents toe- of afname in gewicht als respons voor de bereke-
ning van een BMDL.
Samenvatting                                                                                       17
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<pre>  Metallisch molybdeen en alle andere molybdeenverbindingen
  Door een gebrek aan gegevens kan de commissie voor deze stoffen geen gezond-
  heidskundige advieswaarde afleiden. Door een gebrek aan gegevens is het voor
  de commissie verder niet mogelijk voorstellen te doen voor classificatie wat
  betreft mogelijke kankerverwekkendheid, vruchtbaarheidseffecten, ontwikke-
  lingseffecten en effecten tijdens lactatie.
  Aanbevelingen
  Gezondheidskundige advieswaarden
  De Commissie GBBS van de Gezondheidsraad stelt de volgende gezondheids-
  kundige advieswaarden voor bij beroepsmatige blootstelling van:
  • Molybdeentrioxide, te weten 0,1 mg molybdeentrioxide/m3 (= 0,07 mg
       molybdeen/m3).
  • Natriummolybdaat, te weten 9,9 mg natriummolybdaat/m3 (= 4,6 mg molyb-
       deen/m3).
  gebaseerd op inhaleerbare aerosol of stofblootstelling, gemiddeld over een acht-
  urige werkdag. De beschikbare gegevens voor metallisch molybdeen en andere
  molybdeen-verbindingen zijn onvoldoende om een voorstel voor een gezond-
  heidskundige advieswaarde te kunnen doen.
  Classificaties
  Wat de kankerverwekkendheid betreft beveelt de commissie aan om molybdeen-
  trioxide te classificeren in categorie 2 (‘verdacht kankerverwekkend voor de
  mens’)*. De gegevens van andere molybdeenverbindingen zijn onvoldoende om
  een voorstel tot classificatie te kunnen doen.
  Wat de effecten op de vruchtbaarheid betreft, stelt de commissie voor molybda-
  ten te classificeren in categorie 2 (‘wordt ervan verdacht de vruchtbaarheid te
  schaden’). Voor de andere molybdeenverbindingen kan geen voorstel worden
  gedaan in verband met een gebrek aan gegevens. Door dat gebrek aan gegevens
  is voor geen enkele molybdeenverbinding een evaluatie mogelijk op ontwikke-
  lingseffecten en effecten tijdens lactatie.
  Zie bijlage F voor het classificatiesysteem.
8 Molybdenum and molybdenum compounds
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<pre>Executive summary
Scope
At request of the Minister of Social Affairs and Employment, the Dutch Expert
Committee on Occupational Safety (DECOS), a committee of the Health
Council, proposes health-based recommended occupational exposure limits
(HBR-OELs) for chemical substances in the air in the workplace. These
recommendations serve as a basis in setting legally binding occupational
exposure limits by the minister.
     In this report, the Committee discusses the consequences of occupational
exposure to molybdenum and molybdenum compounds*, and recommends a
health-based occupational exposure limit. The Committee's conclusions are
based on scientific papers published before October 2013.
Physical and chemical properties
Pure molybdenum is a naturally occurring silvery white metal that has several
oxidation states, the most stable being molybdenum(IV) and molybdenum(VI).
In nature, molybdenum occurs predominantly as molybdate, which may form a
The evaluated molybdenum compounds in this report are: metallic molybdenum, molybdenite;
molybdenum chloride; molybdenum trioxide; ammonium molybdate; ammonium paramolybdate;
calcium molybdate; and, sodium molybdate.
Executive summary                                                                        19
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<pre>  wide variety of molybdenum compounds. At 20°C, some molybdenum
  compounds dissolve in water, such as ammonium molybdate, ammonium
  paramolybdate, and sodium molybdate; others are less soluble, such as
  molybdenum trioxide; or, insoluble, such as, metallic molybdenum,
  molybdenite, and molybdenum chloride.
      Molybdenum is used in the metal producing and processing industry.
  Monitoring
  In the Netherlands, the ISO method (ISO 15202) for identifying metals in
  workplace air is used. Molybdenum in dust (total, inhalable or respirable dust
  fraction) can be measured using atomic absorption spectroscopy or atomic
  emission spectroscopy.
  Current limit values
  Neither in the Netherlands nor in the European Commission, legally binding
  occupational exposure limits have been set for molybdenum and molybdenum
  compounds. In some other countries, occupational exposure limits (8h-TWA)
  have been set for soluble molybdenum compounds, namely 0.5 up to 5 mg
  molybdenum per m3; and, for metallic molybdenum and insoluble molybdenum
  compounds, 3 to 15 mg molybdenum per m3. The limits cannot be compared just
  like that, because they are based on samples taken from different particulate dust
  fractions (content of molybdenum in total, inhalable or respirable dust).
  Kinetics
  As shown by various animal studies and a few human studies, molybdenum and
  molybdenum compounds are taken up by the body through inhalation, and
  consumption of food and drinking water. The absorption rate after oral intake
  depends on the solubility of the compounds and composition of the diet. Overall,
  absorption via the gastro-intestinal tract is rapid and almost complete. It is not
  known how fast and efficient absorption via inhalation is.
      For humans and animals, molybdenum is an essential trace element that is
  needed for normal biological processes. It is present in low concentrations in all
  body fluids and tissue. There is no apparent bioaccumulation of molybdenum in
  the body. Molybdenum compounds can cross the placental barriers and
  molybdenum is found in human milk.
0 Molybdenum and molybdenum compounds
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<pre>     The metabolism of molybdenum compounds is related to copper and sulphur
metabolism. Excretion via the urine – the main route of elimination – is rapid,
and enhanced by the presence of high dietary levels of copper and sulphate.
Effects
Observations in humans
Studies on people, who were occupationally exposed to molybdenum
(compounds), are of limited value in deriving health-based occupational
exposure limits, because of a lack of reliable exposure data, concomitant
exposure to other potentially toxic compounds, and poor descriptions of the
studies. Overall, workers who were at least exposed to molybdenum trioxide
reported complaints, such as joint pain (gout-like symptoms), back pain,
headache, and mild obstructive lung disease (including breathing difficulties,
chest pain and fatigue). Also increased levels of uric acid and ceruloplasmin have
been reported compared to non-exposed workers. Exposure levels to
molybdenum at which symptoms occurred were found to be as low as 1.6 mg/m3
(molybdenum in respirable dust in a molybdenum roasting plant) to 600 mg/m3
(dust in mines).
     Among Armenian villagers, gout-like symptoms and increased blood levels
of uric acid have been observed. They had an average dietary intake of
molybdenum of 10 to 15 mg per day (and of copper of 5 to 10 mg per day). The
average normal daily intake varies between 0.1 and 0.3 mg molybdenum per day.
In an American drinking-water study, no adverse health effects were found by
consumption of drinking water that contained at least 200 µg molybdenum per
litre water (normal mean values: between 10 and 60 µg).
     Data on carcinogenic activity in humans are limited. Positive but weak
correlations were found for lung cancer among molybdenum-exposed workers
with a long exposure history, and for pancreas cancer in females in a Japanese
population. However, due to a lack of reliable exposure and intake levels, and the
presence of other potentially carcinogenic factors in the investigated populations,
no conclusions can be drawn from these studies.
     In a clinical study, lowered semen quality and changes in male reproductive
hormone level were observed. No other investigations have been performed in
which adverse effects of molybdenum and molybdenum compounds on fertility,
and development of progeny, in humans was examined.
Executive summary                                                                   21
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<pre>  Animal experiments
  Depending on the molybdenum compound, in particular soluble compounds
  showed to be irritating the nose, eyes, and respiratory tract.
  Inhalation
  In rats and mice exposed to up to 100 mg molybdenum trioxide/m3 (in aerosol)
  for thirteen weeks, no adverse health effects or pathological lesions were found.
  Guinea pigs exposed to very high levels of molybdenum trioxide (> 300 mg/m3;
  concentration molybdenum in total dust in air) for five weeks, showed signs of
  respiratory irritation, loss of appetite and weight, diarrhea, muscular
  incoordination, and loss of hair.
      Groups of rats and mice were exposed to molybdenum trioxide for two years.
  Animals were exposed to the compound at concentrations of 0 (control), 10, 30
  or 100 mg molybdenum trioxide/m3 (in aerosol) for 6 hours per day, five days
  per week, for 106 weeks. In the respiratory tract of exposed animals the
  following effects were observed: hyaline degeneration in the respiratory and
  olfactory epithelium of the nose; laryngeal squamous metaplasia in the epiglottis,
  and laryngeal hyperplasia; and, chronic inflammation of the lungs. Some of these
  effects were statistically significantly increased compared to non-exposed groups
  at 10 mg/m3 onwards. In the same study, also carcinogenicity of the compound
  was investigated with equivocal results, in that no exposure-related increases in
  tumour development was found in any organ in rats and mice, except for lung
  tumours in mice, and that the findings in mice were not dose-related.
      Based on the limited evidence available, the Committee is of the opinion that
  molybdenum trioxide, ammonium molybdate and sodium molybdate are
  probably not genotoxic.
      No significant signs of adverse effects on fertility have been found in male
  rats and mice exposed to molybdenum trioxide at a concentration of up to 100
  mg/m3 (higher concentrations not tested) for thirteen weeks.
  Oral intake
  In male rats which were given sodium molybdate in the diet, a statistically
  significantly decrease in absolute body weight (and body weight gain) was
  observed at the highest dose (60 molybdenum mg/kg bw). Also in female rats a
  reduction of the absolute body weight was observed when compared to non-
  exposed animals. In the same study, no other effects were found which could be
  related to molybdate exposure. Other short- and mid-term animal studies have
  been performed, but from none of these a clear conclusion on the adverse effects
2 Molybdenum and molybdenum compounds
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<pre>could be made. The reason for this is that the studies used a low number of
animals. Furthermore, there are no animal carcinogenicity studies performed in
which molybdenum compounds have been given via the diet or drinking water.
    A number of animal studies have been published on fertility and
developmental effects. These studies indicate that certain molybdenum
compounds may reduce the fertility in male rats (and possibly also in females).
For instance, in one study, a statistically significant reduction of sperm motility
and total sperm count in rats has been reported. The rats received sodium
molybdate by gavage at a concentration of 30 and 50 mg sodium molybdate/kg
bw/day, for five days a week during 60 days. At these exposure levels no other
adverse effects have been described. However, many of the reproduction toxicity
studies have been poorly reported. This also applies for the study described in
more detail. Furthermore, in some animal studies no reproduction toxicity have
been observed at all.
Evaluation
Overall, the Committee considers the current epidemiological data insufficient
for quantitative hazard assessment, because of the presence of confounding
factors, such as concomitant exposure, and missing details on exposure and
population characteristics. However, the results of a few animal studies could
serve as starting point in deriving health-based recommended occupational
exposure limits (HBR-OELs). For this purpose. DECOS used the benchmark
dose (BMD) software from the US Environmental Protection Agency to assess
the best fitting model of the exposure- response relationships. This model was
then used to derive an exposure level, the BMDL (the lowest concentration of the
95% confidence interval of the benchmark dose), that could serve as point of
departure in estimating an HBR-OEL.
Molybdenum trioxide
Regarding molybdenum trioxide, according to the Committee, the two-year
inhalation study, in which rats and mice of both sexes inhaled molybdenum
trioxide aerosols at concentrations of up to 100 mg molybdenum trioxide/m3, is
the best point of departure. The most relevant effects in this study included:
squamous metaplasia in the epiglottis (larynx) in both species and in both sexes;
and, hyaline degeneration in the nose, and chronic inflammation and metaplasia
in the lungs. The latter effects were less consistent among the animal species and
sexes. All these respiratory effects are considered relevant for humans. BMD-
analysis revealed a BMDL of 0.29 mg molybdenum trioxide/m3 (squamous
Executive summary                                                                   23
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<pre>  metaplasia in the laryngeal epiglottis), which corresponds to an extra 10% risk
  compared to background risk levels*.
      For the assessment of the HBR-OEL, several aspects and uncertainties were
  considered. For instance, interspecies differences should be taken into account.
  However, the Committee noticed that the effects were local effects and,
  therefore, no additional extrapolation for interspecies differences is needed.
  However, differences among people should be taken into account. The
  Committee used a factor of three to compensate for this. Consequently, the
  Committee recommends an HBR-OEL for molybdenum trioxide of 0.1 mg
  molybdenum trioxide/m3, based on personal inhalable dust exposure, as an eight-
  hour time weighted average concentration.
      Based on the available carcinogenicity data, the Committee recommends,
  furthermore, classifying molybdenum trioxide in category 2 (suspected
  carcinogen to man)**. Due to a lack of data, no classifications on fertility,
  developmental toxicity or lactation can be proposed.
  Sodium molybdate
  For sodium molybdate two animal studies are available, in which concentration-
  response relationships have been studied. The first, is a study in which clear
  fertility effects are observed in male rats, which received the compound by
  gavage (30 and 50 mg sodium molybdate/kg bw/day, five days during 60 days).
  The other one is a study in which a clear reduction in body weight and body
  weight gain is observed, in particular in male rats, which received the compound
  via the diet at a concentration of 60 mg molybdenum/kg bw for 90 days.
      Regarding the first study, the Committee is concerned about the occurrence
  of fertility effects. That these effects may occur appears to be confirmed by other
  animal studies, and by a human study, which makes it relevant for humans. On
  the other hand, the Committee noted that the study is poorly reported, raising the
  question how reliable the data are for quantitative risk-analysis.
      The study in which reduced body weight and body weight gain have been
  described is well-performed. This was also the study in which no other notable
  adverse health effects were observed. Based on this study, the Committee
  calculated a BMDL of 10.9 mg molybdenum/kg bw, which corresponds to a
  decrease in body weight of 10% due to exposure, compared to the body weight in
  The Committee uses 10% extra risk as a default for dichotomous (quantal) animal data. The default
  may be modified based on scientific considerations.
* See Annex F for the classification system.
4 Molybdenum and molybdenum compounds
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<pre>non-exposed animals*. Since this concerns an oral dose and the health-based
recommended occupational exposure level should be based on a concentration in
the air, the BMDL is converted. This results in a inhalation BMDL of 41.20 mg
molybdenum/m3.
    For the assessment of the HBR-OEL, several aspects and uncertainties were
considered. For instance, interspecies differences should be taken into account.
Since the effects were systemic, the Committee proposes to adjust for
interspecies differences with a factor of three. Furthermore, for differences
between people, the Committee uses another uncertainty factor of three.
Consequently, the Committee recommends an HBR-OEL for sodium molybdate
of 4.6 mg molybdenum/m3 (rounded off), based on personal inhalable dust
exposure, as an eight-hour time weighted average concentration.
    Due to a lack of data, no classification on carcinogenicity can be proposed
for sodium molybdate. However, the Committee recommends a classification in
category 2 for effects on fertility (‘suspected human reproductive toxicant’) of all
molybdates. Due to a lack of data, no classifications on developmental toxicity or
lactation can be proposed.
Metallic molybdenum and any other molybdenum compounds
Due to insufficient data, the Committee is not able to propose an HBR-OEL for
metallic molybdenum and any other molybdenum compounds. It is also not able
to propose an HBR-OEL for soluble molybdenum compounds as a group, or for
insoluble molybdenum compounds as a group.
    Due to a lack of data, no classification on carcinogenicity, fertility,
developmental toxicity or lactation can be proposed for metallic molybdenum or
any other molybdenum compounds.
Recommendations
Health-based recommended occupational exposure limits
The Committee recommends a health-based occupational exposure limit for:
• molybdenum trioxide, namely of 0.1 mg molybdenum trioxide/m3
    (= 0.07 mg molybdenum/m3)
• sodium molybdate, namely of 9,9 mg sodium molybdate/m3
    (= 4,6 mg molybdenum/m3).
The Committee uses a de- or increase in body weight of 10% as a default response for calculating a
BMDL.
Executive summary                                                                                  25
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<pre>  based on personal inhalable aerosol or dust exposure, measured as an eight-hour
  time weighted average concentration. The available data are insufficient to
  recommend an HBR-OEL for metallic molybdenum and any other molybdenum
  compounds.
  Classifications
  Regarding carcinogenicity, the Committee recommends classifying molybdenum
  trioxide in category 2 (‘suspected carcinogen to man’)*. The available data are
  insufficient to evaluate the carcinogenic properties of metallic molybdenum and
  other molybdenum compounds.
  Regarding reproduction toxicity, the Committee recommends classifying sodium
  molybdate and other molybdates in fertility category 2 (‘suspected human
  reproductive toxicant’). The available data on metallic molybdenum or any other
  molybdenum compounds are insufficient to evaluate fertility effects. For the
  same reason, data on molybdenum or any molybdenum compounds are
  insufficient to evaluate developmental toxicity and effects on lactation.
   See Annex F for the classification system.
6 Molybdenum and molybdenum compounds
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<pre> hapter 1
        Scope
1.1     Background
        At request of the Minister of Social Affairs and Employment (Annex A), the
        Dutch Expert Committee on Occupational Safety (DECOS), a committee of the
        Health Council of the Netherlands, performs scientific evaluations on the toxicity
        of chemical substances that are used in the workplace. The purpose of these
        evaluations is to recommend a health-based occupational exposure limit for
        concentrations in the air, provided the database allows derivation of such a value.
        In the Netherlands, these recommendations serve as a basis in setting public
        occupational exposure limits by the minister.
        In this advisory report, such an evaluation is made for molybdenum and
        molybdenum compounds:
        • (Metallic) molybdenum                            •  Ammonium molybdate
        • Ammonium paramolybdate                           •  Calcium molybdate
        • Molybdenite                                      •  Molybdenum chloride
        • Molybdenum trioxide                              •  Sodium molybdate
        Scope                                                                               27
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<pre>1.2 Committee and procedure
    This document contains the assessment of DECOS, hereafter called the
    Committee. The members of the Committee are listed in Annex B. The
    submission letter (in English) to the state secretary can be found in Annex C.
        In 2010 and in 2013 the President of the Health Council released a draft of
    the report for public review. The individuals and organisations that commented
    on the draft are listed in Annex D. The Committee has taken these comments into
    account in deciding on the final version of the report.
1.3 Data
    The Committee’s recommendations on the health-based occupational exposure
    limit of molybdenum and molybdenum compounds have been based on publicly
    available scientific data. Data were obtained from the online databases Toxline
    and Medline (PubMed), using “molybd? OR CAS 7439-98-7” in combination
    with “toxic? OR epidemio? OR occupational?” as key words. The final search, in
    Medline (PubMed), was performed in October 2013.
 8  Molybdenum and molybdenum compounds
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<pre> hapter 2
        Identification, properties and
        monitoring
2.1     Chemical identification
        Pure molybdenum (Mo) is a naturally occurring silvery white metal that has
        several oxidation states, the most stable being +4 (Mo(IV)), and +6 (Mo(VI)).1
        In soil and natural water, molybdenum occurs predominantly as the molybdate
        anion (MoO42-), which may form a wide variety of complex polymolybdate
        compounds, such as ammonium paramolybdate. Table 1 shows the chemical
        identification of the evaluated molybdenum compounds.2,3,4
2.2     Physical and chemical properties
        The physical and chemical properties of the evaluated molybdenum compounds
        are shown in Table 2.2,3,4,1 Molybdenum and molybdenum compounds show
        differences in water solubility:
        • soluble molybdenum compounds (at around 20°C): sodium molybdate,
            ammonium molybdate, and ammonium paramolybdate
        • low solubility in water (at around 20°C): molybdenum trioxide
        • insoluble molybdenum compounds (at around 20°C): metallic molybdenum,
            molybdenite, calcium molybdate, and molybdenum chloride.
        At room temperature, the molybdate anion (MoO42-) is soluble and will form
        upon contact of molybdenum-containing minerals with oxygen and water.
        Identification, properties and monitoring                                      29
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<pre> able 1 Identification of the evaluated molybdenum compounds.
                               Molecular formula       Synonyms                    CAS#            EINECS#        RTECS#
Molybdenum                     Mo                      Metallic molybdenum         7439-98-7       231-107-2      QA4680000
Molybdenite                    MoS2                    Molybdenum (IV) sulfide,    1317-33-5       215-263-9      QA4697000
                                                       molybdenum disulfide
Molybdenum chloride            MoCl5                   Molybdenum (V) chloride     10241-05-1      233-575-3      Not
                                                                                                                  specified
Molybdenum trioxide            MoO3                    Molybdenum (VI) oxide,      1313-27-5       215-204-7      QA4725000
                                                       Molybdenum peroxide
Ammonium molybdate             (NH4)2MoO4              Ammonium molybdate (VI),    13106-76-8      236-031-3      QA4900000
                                                       Diammonium molybdate
Ammonium paramolybdate (NH4)6Mo7O24⋅4H2O Ammonium molybdate (IV)                   12054-85-2      Not specified Not
                                                       tetrahydrate                                               specified
 alcium molybdate              CaMoO4                  Calcium molybdate (VI),     7789-82-4       232-192-9      EW2975000
                                                       Powellite
 odium molybdate               Na2MoO4                 Sodium molybdate (VI),      7631-95-0       231-551-7      QA5075000
                                                       Disodium molybdate
 able 2 Chemical and physical properties of the evaluated molybdenum compounds.
                          Molybdenum                 Molybdenite              Molybdenum chloride        Molybdenum trioxide
Molecular weight          95.94                      160.07                   273.20                     143.94
 hysical form             Gray-black or silver-      Black powder or crystals Grey-black crystals;       White-yellow
                          white metal                                         hygroscopic                crystals
Melting point (˚C)        2,623                      2,375                    194                        801
 oiling point (˚C)        4,639                      Not specified            268                        1,155 sublimates
Density (g/cm3)           10.2                       5.06                     2.93                       4.70
 apour pressure           3.47 Pa (2,617 ˚C)         Not specified            Not specified              Not specified
 olubility                Insoluble in water; dilute Insoluble in water;      Insoluble in water;        Solubility in water:
                          in acid and alkaline       soluble in concentrated  soluble in ethanol and     0.1- 0.5 g/100 mL
                          solutions                  acid solutions           ethyl ether                at 20 °C; soluble in
                                                                                                         concentrated acid and
                                                                                                         alkali solutions
                          Ammonium molybdate         Ammonium                 Calcium molybdate          Sodium molybdate
                                                     paramolybdate
Molecular weight          196.04                     1,235.86                 200.02                     205.92
 hysical form             White to off-white         Colourless or green-     White crystals             Colourless crystals
                          powder                     yellow crystals
Melting point (˚C)        Decomposes                 Decomposes               965; decomposes            687
Boiling point (˚C)        Not specified              Not specified            Not specified              Not specified
Density (g/cm3)           2.28                       2.50                     4.35                       ≈3.5
 apour pressure           Not applicable             Not applicable           Not applicable             Not applicable
 olubility                Soluble in water, acids    Solubility in water,     Solubility in water, 9.5   Solubility in water,
                          and alkaline solutions     43 g/100 mL at 20°C;     mg/100 mL at 20°C;         44 g/100 mL at 20°C;
                                                     insoluble in ethanol     soluble in conc. acid      Solubility of sodium
                                                                              solutions                  molybdate dihydrate,
                                                                                                         65 g/100 mL at 20°C
 0           Molybdenum and molybdenum compounds
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<pre>2.3 EU classification and labelling
    Based on Regulation (EC) No 790/2009, which is an adaption of Regulation
    (EC) No 1272/2008 of the European Parliament, and of the Council on
    Classification, labelling and packaging of substances and mixtures (16 December
    2008), molybdenum trioxide was given the hazard statement codes:
    • H319: causes serious eye irritation
    • H335: may cause respiratory irritation
    • H351: suspected of causing cancer.
    According to the same regulation molybdenum trioxide is classified in
    carcinogenic category 2 (“suspected human carcinogen”).
         No hazard statement codes or classifications have been assessed by the
    European Commission, regarding other molybdenum compounds evaluated in
    this report.
2.4 Analytical methods
    In the Netherlands, a method for monitoring and identifying metals in workplace
    air is used according to ISO 15202 (International Organization for
    Standardization).5 In the United States of America, both the National Institute for
    Occupational Safety and Health (NIOSH), and the Occupational Safety and
    Health Administration have described methods for sampling soluble or insoluble
    molybdenum compounds. This includes the use of a 0.8 µm mixed cellulose ester
    filter, or a low tare weight ash polyvinyl chloride filter, respectively, to be used in
    a 37-mm cassette filter holder estimating the ‘total dust’ fraction. Within Europe,
    size fractions for measurement of airborne particles in workplace atmospheres
    have been standardized (reference: EN 481: Workplace atmospheres – size
    fraction definitions for measurement of airborne particles, 1993, Brussels, CEN).
    In this standard, three fractions have been defined (inhalable, thoracic, and
    respirable fraction).
         In general, molybdenum is identified using atomic absorption spectroscopy,
    or inductively coupled argon plasma – atomic emission spectroscopy (ICP-AES).
    The latter method is also proposed by NIOSH for identifying metals in biological
    samples, such as in the urine, blood and tissue. Identification of molybdenum in
    air or biological samples can also be done by using instrumental neutron
    activation analysis.6
    Identification, properties and monitoring                                               31
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<pre>2 Molybdenum and molybdenum compounds</pre>

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<pre> hapter 3
        Sources
3.1     Natural occurrence
        Molybdenum is found in the earth’s crust as a natural element. The compound is
        contained in various minerals, the most important being molybdenite.
        Molybdenite can occur as the sole mineral in an ore body, but is often found as a
        by-product of other ores, such as copper and tungsten ores. Molybdenite is
        principally obtained from its natural resources by mining, the largest producers
        being found in the United States.
            Since molybdenum minerals are present everywhere in soil and natural water
        resources – although in low levels –, secondary natural sources of exposure may
        be the consumption of certain vegetables and drinking water. Also combustion of
        coal and municipal sewage sludge may pose a source of exposure.1,3
3.2     Man-made sources
3.2.1   Extraction and processing*
        Molybdenite ores and other ores containing molybdenite are recovered by
        mining in open pits or underground mining. The extracted rocks containing the
        ores of interest are then crushed and ground into powder. Using flotation, the
        Source: International Molybdenum Association (IMOA), www.imoa.info.
        Sources                                                                           33
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<pre>      molybdenite minerals are separated from gangue, reaching a molybdenite
      concentration of between 85% and 92%. If necessary, also acid leaching is used
      to remove copper and lead impurities.
          In the next process molybdenite is roasted into technical grade molybdenum
      trioxide. Part of the technical grade molybdenum trioxide is then further
      processed into pure molybdenite (using sublimation), or into a wide range of
      pure molybdenum chemicals, such as molybdates (using wet chemical
      processes). Metallic molybdenum is produced by hydrogen reduction of pure
      molybdenum trioxide or ammonium molybdate.3
3.2.2 Use*
      The vast majority of molybdenum is used in metallurgical applications, such as
      stainless steel and cast iron alloys. The addition of molybdenum to steel alloys
      improves the strength and thermal resistance of the alloy, and reduces the
      corrosive potential. Furthermore, metallic molybdenum enhances the adherence
      of siliceous material to metals and is, therefore, useful in metal-ceramic
      composites. Molybdenum trioxide is used as a corrosion inhibitor, and as a blue
      dye for ceramic glazes and enamels. Molybdenite is applied in dry lubricants and
      chemical catalysts. Molybdenum salts are used in fertilizers (2-6 ppm
      molybdenum) for leguminous plants. Ammonium tetrathiomolybdate is a
      chelating agent used in patients having elevated concentrations of copper
      (Wilson’s disease).1
      Source: International Molybdenum Association (IMOA), www.imoa.info.
 4    Molybdenum and molybdenum compounds
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<pre> hapter 4
        Exposure
4.1     General population
        The major source of exposure to the general population is consumption of plant-
        based foods and drinking water. The molybdenum content in the plant-based
        foods depends on the content of the soil in which the plants are grown, and the
        type of plants. Certain legumes, grain products, and nuts are the major
        contributors of dietary molybdenum, whereas animal products, fruits, and many
        other vegetables are generally low in molybdenum.7,8
        • Urban air. Minimal concentrations of molybdenum of 0.01 to 0.03 µg/m3
            have been reported in urban air.9
        • Surface and drinking water. In US surface waters, concentrations of
            molybdenum have been reported ranging from 0.002 to 1.50 mg/L (mean
            0.06 mg/L).7 Molybdenum concentrations in drinking water are worldwide
            typically less than 0.01 mg/L, although in areas near mining sites, the
            molybdenum concentrations may reach up to 0.20 mg/L.8,9
        • Food products. Highest levels of molybdenum have been reported to be: 0.96
            mg/kg fresh weight in nuts; 0.31 mg/kg fresh weight for canned vegetables;
            and, 0.23 mg/kg fresh weight for cereals.8,10
        • Average daily intake. From household food surveys, it is estimated that the
            average daily intake ranges between 0.09 and 0.28 mg per day.11-13
        Exposure                                                                        35
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<pre>                   Note: Molybdenum is an essential trace element, which acts in human and animal
                   metabolism as a cofactor for several enzymes, such as sulfite oxidase, xanthine
                   oxidase, and aldehyde oxidase, and as an electron transport agent.8,9,14,15 These
                   enzymes catalyze basic metabolic reactions in the carbon, sulphur and nitrogen
                   cycles. The American Institute of Medicine set an estimated average requirement
                   at 0.034 mg per day for adults.8
4.2                Working population
                   Table 3 summarizes exposure levels in the workplace of various industries.
                   Overall, data are limited and sometimes incomplete. As shown in the table
                   exposure levels differ considerably, depending on industry and sampling
                   characteristics.
 able 3 Occupational exposure levels.
 ource of exposure Job activities                                   Sampling characteristics        Exposure levels
                                                                                                    (in µg/m3)
  ussian steel foundry Production of steel containing               Molybdenum content in
Goljakova 1971 [in Russian];    • 4% molybdenum                     • air samples                   • 1,390 (average)
ited in 16)                     • 17% molybdenum                    • air samples                   • 5,400 (average)
                                • Not specified                     • air samples within breathing  • 220 (average; with peaks up to
                                                                       zone of workers                  500)
                                                                    Note: Exposure and sampling
                                                                    characteristics not further
                                                                    specified.
Russia (Moglevskaya 1963 Workers (N=19) exposed to                  Concentration molybdenum in     1,000-19,000
 n Russian]; cited in 14,16-18) molybdenum and molybdenum           workplace air. No further
                                trioxide. No further specifications specifications given.
                                given.
Russian mining and Miners and metallurgy workers. Molybdenum and molybdenum                         60,000-600,000
metallurgy industry No further specifications given. trioxide. Exposure and sampling
Eolajan 1965 [in Russian];                                          characteristics not specified.
ited in 16,18)
US molybde-num                  N = 25 workers:                     Molybdenum content in:
 oasting plant where • Base of the roaster                          • respirable dust, area sample  • 1,020
molybdenum sulphide • 7.3 m away from roaster                       • respirable dust, area sample  • 1,580
s converted to                  • 13.4 m away from roaster          • respirable dust, area sample  • 4,490
molybdenum oxides;
Colorado19                      • Base of the roaster               • total dust, area sample       • 3,040
                                • 7.3 m away from roaster           • total dust, area sample       • 9,110
                                • 13.4 m away from roaster          • total dust, area sample       • 33,280
                                                                    • Soluble molybdenum in total • 9,470
                                                                       dust (8-hr TWA), area sample
  6                Molybdenum and molybdenum compounds
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<pre>  wedish industrial      Processing of sintered and           Molybdenum content in total dust:
 acuum furnace           laminated molybdenum sheet
 roduction factory15 metal:
                         • grinding                           • Personal (N=1), 200 minutes      • 1,500 – 2,000
                                                                 sampling time
                         • grinding, cutting, heating         • Personal (N=1), 70 minutes       • 7,900
                                                                 sampling time
                         • area sampling                      • Stationary air sampling, 300     •    700
                                                                 minutes sampling time
  roduction of           • Welding                            • Personal; total suspended        • 0.27-9.7
 tainless steel vessels,                                         particulate matter (N=15)          (median 1.45)
Czech Republic6          • Polishers                          • Personal; total suspended        • 0.03-4.2
                                                                 particulate matter (N=9)           median 0.82)
                         • Others                             • Personal; total suspended        • 0.14-0.60
                                                                 particulate matter (N=15)          (median 0.32)
                         • All                                • Area; particle equivalent        • 0.02-0.09
                                                                 aerodynamic diameter 2-10µm        (median 0.03)
                         • All                                • Area; particle equivalent        • 0.09-0.50
                                                                 aerodynamic diameter <2µm         (median 0.15)
                         Exposure to welding fumes and
                         airborne particulate matter          Note: workers involved in
                         originating from various activities  polishing were equipped with
                         in the production of stainless steel respirators, while welders did not
                         vessels, mainly polishing and        use them. Welding and polishing
                         shaving.                             workplaces were equipped with
                                                              local exhausts.
  innish stainless steel In a melting shop ferrochrome was • Personal sampling                   • 0.3 median; 2.3 maximum
melting shop20           combined with alloying materials, • Stationary area sampling            • 0.6 median; 4.0 maximum
                         such as nickel and molybdenum.
                                                              Sampling characteristics of
                                                              molybdenum not further specified.
               Exposure                                                                                                    37
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<pre>8 Molybdenum and molybdenum compounds</pre>

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<pre> hapter 5
        Kinetics
5.1     Absorption
        Overall, reports suggest that soluble molybdenum compounds are readily
        absorbed, whereas insoluble compounds are not. A brief summary is given
        below.
5.1.1   Inhalation
        No human data are available on inhalation exposure.
             In one animal study published in 1945, guinea pigs were used for a short-
        term inhalation study to test for tissue distribution and gross pathology.21 The
        animals (24-25 animals per group) inhaled high amounts of dust containing
        molybdenum trioxide (average concentration of 205 mg molybdenum/m3,
        corresponding to 310 mg molybdenum trioxide/m3), molybdenite (286 mg
        molybdenum/m3, corresponding to 607 mg molybdenite/m3), or calcium
        molybdate (159 mg molybdenum/m3, corresponding to 388 mg calcium
        molybdate/m3). Exposure was performed for one hour per day, five days per
        week for a total of five weeks. At the end of the exposure period half of the
        animals were killed for analysis of molybdenum content in various tissues organs
        (i.e., the liver, kidneys, lungs, spleen and bones). The other half of the animals
        were allowed to live for two weeks longer, with no molybdenum exposure,
        Kinetics                                                                           39
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<pre>      before they were also sacrificed. Data were compared with non-exposed
      controls.
           After exposure, molybdenum trioxide dust was found in all tissues examined
      (the highest amounts in the kidneys and bones). Calcium molybdate was mainly
      found in the lungs, the kidneys and bones. Molybdenite dust gave merely
      negative results (according to the authors, no data presented). The authors also
      reported on exposure to molybdenum sulphide. High levels of molybdenum
      sulphide were found in the lungs, but levels of molybdenum in the liver, kidneys,
      spleen and bones did not exceed the levels found in non-exposed animals. The
      authors considered molybdenum sulphide as a very insoluble compound, and
      molybdenum trioxide dust (and fume) as soluble compounds. No quantitative
      data or further details were presented on how much of the molybdenum
      compounds were actually absorbed by the lungs.
5.1.2 Oral intake
      Giussani et al. (2006) investigated the intestinal absorption of molybdenum in
      seven healthy volunteers by simultaneous oral administration (water, tea or
      composite meals), and intravenous injection, of stable isotopes of
      molybdenum.22 For this, isotopic solutions were prepared using metal
      molybdenum powders enriched in 95Mo and 96Mo, respectively. Their results
      indicated that molybdenum ingested in orally (in liquid form) was rapidly and
      totally absorbed into the circulation. The rate and extent of absorption depended
      on the composition of the meals. A comparable result was reported by Werner et
      al. (1998).23
           Turnlund et al. (1995) investigated molybdenum absorption, excretion and
      retention with stable isotopes, in four healthy volunteers.24 They were given a
      low-molybdenum diet (22 µg/day) for 102 days, followed by the same diet
      supplemented with molybdenum (ammonium paramolybdate dissolved in
      deionized water) to contain 467 µg/day for another eighteen days. The stable
      isotopes 100Mo (prepared for diet), 97Mo (prepared for intravenous injections)
      and 94Mo (used as an isotopic diluents) were used as tracers. The isotopes were
      purchased as metal powders. The oral absorption of 100Mo averaged 88% in the
      low-molybdenum diet, and 93% in the high-molybdenum diet. Turnlund also
      studied molybdenum kinetics after consumption. Using a comparable design as
      the previous study, and using compartmental kinetic models, it was estimated
      that the residence time for molybdenum in the gastro-intestinal tract was at 1.7
      ± 0.4 days; in plasma molybdenum retention time averaged 22 ± 4 minutes,
 0    Molybdenum and molybdenum compounds
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<pre>      whereas slow-turn-over tissue (possibly hepatic) retention averaged 58 ± 16
      days.25
          In various animal species (e.g., guinea pigs, rabbits) absorption of ingested
      soluble and insoluble molybdenum compounds was reported, the absorption
      being dependent on solubility and diet composition, and varying between 40 and
      85%.10,14,21,26
5.1.3 Dermal uptake
      Sodium molybdate dihydrate was tested in vitro for dermal absorption using skin
      membranes according to OECD guideline 428*. Doses applied to the skin were
      105 and 542 µg/cm2. The percentage of the doses absorbed by the skin, including
      stratum corneum were 0.21 and 0.16% (after eight hours of exposure and 16
      hours post-exposure monitoring). No other human or animal data available.
5.2   Distribution
      In humans and various animal species, molybdenum is present in low
      concentrations in all the fluids and tissues in the body; in plasma, molybdenum is
      bound to α2-macroglobulin in the form of molybdate.1 The greatest amounts are
      found in the kidneys, liver, and the bones; with smaller levels in the adrenal
      glands.10,14,21,26
          Overall, substantial individual variation in the molybdenum blood level
      occurs, because plasma molybdenum reflects molybdenum intake by food and
      water products.13 Average plasma concentrations range between 0.3 to 1.1 µg/L
      (3 to 11 nmol/L).1,3,9,13 This level may increase up to 400 µg/L in persons near
      areas rich in molybdenum or near molybdenum mining centers.9
          There is no apparent bioaccumulation of molybdenum in human or animal
      tissue, and when exposure is withdrawn, the tissue concentrations quickly return
      to normal.9
          Molybdenum can cross the placental barriers, and is furthermore found in
      human milk, with a concentration in the milk ranging from 1 to 35 µg/L.1,7,10,27-29
5.3   Biotransformation and metabolism
      No data are available on the biotransformation of molybdenum compounds.
      Data obtained from the European Chemicals Agency: //echa.europa.eu/.
      Kinetics                                                                            41
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<pre>        The metabolism of molybdenum is related to copper and sulphur meta-
    bolism; molybdenum salts are capable of inhibiting absorption of copper in the
    intestines through yet partly unknown mechanisms.9
5.4 Elimination
    Under normal exposure conditions, molybdenum intake and excretion are
    balanced in humans and animals. The excretion is rapid, and is enhanced by the
    presence of high dietary levels of copper and sulphate, and, furthermore, by
    increased exposure to the compound itself.9,3 Taking these factors into account,
    in humans, percentages of urinary excretion ranged between 17 and 80% of the
    dose.9,21 Referring to the study by Turnland et al. (1995; see Section 5.1.2), of the
    dose molybdenum fed during intake of the low-molybdenum diet (in the form of
    100Mo), in a twelve day period, 20% was excreted in the urine, 12% in the feces,
    and 68% remained in the body.24 The excretion percentages of 100Mo in the
    group fed high-molybdenum diet, were 71% (in the urine) and 7.3% (in the
    feces); the percentage retention in the body was 21%. In animals percentages of
    urinary excretion of between 36 and 90% have been reported.9,21 The kidneys are
    the main route of excretion. Furthermore, kinetic modelling suggested that low
    intake resulted in adaptation to conserve body molybdenum, whereas high intake
    results in increased elimination of molybdenum.30,31
        The blood half-life for molybdenum may vary from several hours in
    laboratory animals up to several weeks in humans.1,9
5.5 Biological monitoring
    NIOSH has described methods for the identification of metals in urine, blood and
    tissue, using inductively coupled argon plasma – atomic emission spectroscopy
    (ICP-AES). The identification of molybdenum in biological material can also
    been done using instrumental neutron activation analysis (INAA).6
 2  Molybdenum and molybdenum compounds
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<pre> hapter 6
        Mechanism of action
        Several reviews have been published in which the mechanisms of toxic actions
        of molybdenum are discussed.1,3,9,16,32,33 Overall, the available data are limited,
        and it is not always clear whether humans or animals have been studied. It is
        known that ruminants (e.g., cattle, goats, sheep) are more sensitive in developing
        symptoms of toxicity than non-ruminant monogastric animals (e.g., humans,
        rodents, poultry). This is probably due to a higher dietary copper requirement in
        ruminants. A summary of the main findings in the reviews is given below.
6.1     Copper deficiency
        In ruminants, excess molybdenum intake can induce secondary copper
        deficiency, which may be enhanced by high dietary sulphate intake. In the
        gastro-intestinal tract micro-organisms convert sulphate in sulphide, which on its
        turn forms insoluble complexes with molybdenum (thiomolybdates). Next, these
        thiomolybdates form insoluble complexes with copper, thus leading to reduced
        absorption of copper. The absorption of copper may be further reduced by the
        fact that high levels of sulphide may form insoluble complexes with copper
        itself.
            When copper is absorbed, it is transported through the blood to all body parts
        by binding to ceruloplasmin, a plasma α-globulin. Smaller amounts are bound to
        albumin, but the copper bound to this plasma protein is not bioavailable.
        Thiomolybdates bind also to albumin, and this new formed complex has a high
        Mechanism of action                                                                 43
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<pre>    affinity for copper. The consequence is that less copper is bound to
    ceruloplasmin, resulting in reduced bioavailability, and a higher risk of copper
    deficiency.
        Copper deficiency in humans is rare. However, in one Russian study,
    investigators reported liver dysfunction with hyperbilirubinemia among workers,
    who were chronically exposed to molybdenum, which was explained by the rise
    of free α-globulins (e.g., ceruloplasmin).3 Furthermore, Walravens et al. (1979)
    showed that free plasma ceruloplasmin levels (and uric acid levels) were higher
    in workers exposed to soluble molybdenum compounds (including molybdenum
    trioxide), compared to unexposed controls.19 The workers were exposed to
    airborne concentration of molybdenum of 9.5 mg/m3 (8h-TWA). However,
    urinary copper levels were normal. That molybdenum can increase free plasma
    ceruloplasmin was also demonstrated in patients having Wilson’s disease. The
    disease is characterized by decreased free ceruloplasmin. Treatment with
    tetrathiomolybdate successfully increased free plasma levels of ceruloplasmin.
        Molybdenum is an essential cofactor for several enzymes, such as sulphite
    oxidase.1,34,35 The enzyme oxidizes sulphite into sulphate. Therefore, it is
    conceivable that excess intake of molybdenum may increase the formation of
    sulphate. Sulphate has a double role in molybdenum induced copper deficiency,
    in that it inhibits gastrointestinal absorption of molybdenum by blocking its
    carrier proteins, and – after absorption – accelerates excretion of molybdenum by
    inhibiting tubular resorption of molybdenum from the kidneys (at least in
    animals, such as rats, rabbits and poultry).1,34,35
        Molybdenum can inhibit sulphide oxidase (present in the liver), resulting in
    higher levels of sulphide in tissue. These sulphides can form insoluble copper-
    sulphide complexes, and, therefore, may induce copper deficiency.1,34,35
6.2 Gout
    Molybdenum is also an essential cofactor in the enzyme xanthine oxidase.
    Excess intake of molybdenum may stimulate the activity of this enzyme.
    Xanthine oxidase converts xanthine into uric acid (by oxidation), which is
    excreted as urate in urine. High amounts of uric acid may crystallize in the
    joint, which can result in gout-like diseases and other bone/joint disorders.
    Higher levels of uric acids have been reported after airborne exposure to soluble
    molybdenum compounds in workers, who were exposed to 9.5 mg molyb-
    denum/m3 (8h-TWA).19 In another study, no change in uric acid excretion was
    found when people took up to 1.54 mg molybdenum per day by diet.36
 4  Molybdenum and molybdenum compounds
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<pre> hapter 7
        Effects
7.1     Observations in humans
        Few data are available on human toxicity due to excess exposure to molybdenum
        and molybdenum compounds.
7.1.1   Irritation and sensitization
        Dueva and Stepanian (1989) reported that approximately twenty percent of 352
        Russian workers, who were engaged in molybdenum productions, showed signs
        of work-related dermatoses.37 The study was published in Russian, and no
        further details in English were available.
7.1.2   Acute and short-term toxicity
        No relevant data available.
7.1.3   Non-carcinogenic long-term toxicity
        Several studies have been presented on the working and general population
        without information on exposure data, and lacking non-exposed groups as
        controls. Furthermore, not always simultaneous exposure to other potentially
        toxic compounds could be excluded. A number of these studies were published
        Effects                                                                       45
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<pre>             in Russian, of which a brief English description was found only in reviews. For
             completeness, a brief summary of these limited studies is given in Table 4.
                   In two studies, non-exposed control groups were included, and clear
             descriptions were given on exposure and/or effect measurements. The first is
             Walravens et al. (1979), who examined twenty-five male workers from a
             molybdenum roasting plant, and twenty-four controls, who were not exposed.19
             Respirable particles mainly consisted of molybdenum trioxide and other
             undefined soluble oxides of molybdenum. The 8-hour TWA, measured as
             molybdenum in respirable dust, was 1.6 mg/m3, and measured as molybdenum in
             total dust, 9.5 mg/m3 (stationary sampling). Medical complaints were reviewed
             by medical questionnaires. Seven workers had no complaints. The others
             reported joint pain, back pain, headache, diarrhea, and/or nonspecific hair or skin
             changes. Pulmonary lung function tests revealed a mild decrease in FEV1 in
             three workers (72-76% of control), and a marked decrease in two workers
             (67-68% of control), indicative of mild obstructive lung disease. No evidence for
             molybdenum-induced gout was found.
 able 4 Summary of the epidemiological studies on molybdenum-related adverse health effects, with limitations in design or
 escriptions of the results.
 tudy population                    Findings                                                          Reference
General population
Adult Armenian villagers             Gout-like symptoms (pain, swelling, inflammation and joint        Kovalskii et al. (1961);
 ) 10-15 mg molybdenum/day,          deformities), and increased blood uric acid levels were           cited in 1,3,7,9,14,16-18,
 -10 mg copper/day; n=184            observed in 57/184 subjects (31%) and in 14/78 control            summarized in 38
 ) 1-2 mg molybdenum /day,           subjects (18%). Both plasma molybdenum and plasma
 0-15 mg Cu/day; n=78.               xanthine oxidase activity were positively correlated with
                                     plasma uric acid levels. Increasing urinary copper excretion
                                     was positively related to increasing plasma molybdenum
                                     levels.
Working population
  ussian workers from a copper-      Increased levels of uric acid in the blood, and symptoms of       Akopian et al. (1964);
molybdenum processing plant.         arthralgia. No quantitative data on the workers and the           cited in 3,14,17
                                     exposure available.
  ussian miners (n=500) exposed to   In many miners, non-specific symptoms such as weakness,           Eolian (1965);
 ust with 60-600 mg molybdenum/m3, fatigue, anorexia, headaches, pains in the joints and muscles, cited in 14,16,18
 nd unknown levels of copper.        tremor of hands and general central nervous system effects
                                     were noted. Symptoms may be caused by co-exposure to other
                                     potentially toxic substances.
  ussian workers (n=19):             All workers were symptomatic and 3 out of 19 had X-ray            Mogilevskaya (1967);
man: 6-19 mg molybdenum/m3 and       findings indicative of pneumoconiosis. The symptoms               cited in 9,14,16-18,39
molybdenum trioxide for 4-7 yrs;     included breathing difficulties, chest pain and general fatigue.
women: 1-3 mg molybdenum/m3 and The information and findings of this study are however
molybdenum trioxide for 5 yrs.       insufficient to conclude that the condition of the three workers
                                     was due to their work environment or that molybdenum was
                                     the causative agent.
 6           Molybdenum and molybdenum compounds
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<pre> innish steel melting shop workers.  The molybdenum levels were considered to be low. The           Huvinen et al. (2002)20
 ersonal: median 0.3 µg molybdenum/  authors concluded that an average exposure time of 23 years in
m3 (maximum 2.3 µg/m3); Area:        modern ferrochromium and stainless steel production, with
median 0.6 µg molybdenum/m3          low exposure to dusts and fumes containing hexavalent and
maximum 4.0 µg/m3).                  trivalent chromium, nickel and molybdenum, did not lead to
                                     respiratory changes detectable by lung function tests or
                                     radiography. Note: co-exposure to other potentially toxic
                                     substances is likely.
One Swedish industrial furnace maker Subject had symptoms of acute arthritis with high plasma uric Seldén et al. (2005)15
age 36).                             acid (564 µmol/L) levels. Gout was treated but nausea and
 ersonal: 1.5-7.9 mg molybdenum/m3. hyperhydrosis stayed. Subject did not improve after cessation
Area: 0.7 mg molybdenum/m3           of the occupational molybdenum exposure. The authors stated
                                     that the association between molybdenum exposure and gout
                                     may be circumstantial.
              Plasma levels of molybdenum ranged between 9 and 365 ng/mL in workers, and
              between <5 to 34 ng/mL in controls; also plasma uric acid and ceruloplasmin
              levels were on average higher in workers than in controls (workers versus
              controls: uric acid, 59 versus 50 mg/mL, p<0.025; ceruloplasmin, 505 versus
              305 mg/mL, p<0.005). In urine, molybdenum levels were elevated in workers
              (workers versus controls: 120-11,000 versus 4-347 µg/L), but copper levels were
              normal (<40 µg/L). The authors remarked that variations in plasma and urine
              levels could be explained by differences in collection time among the workers.
              Also they noted the high turnover rate of the workers, which rendered
              epidemiological study difficult.
                  The second is Ott et al. (2004), who investigated respiratory symptoms and
              bronchoalveolar lavage abnormalities (BAL) among 43 Austrian workers from a
              metal plant, of which 33 suffered from respiratory symptoms.40 The study also
              included 23 non-exposed controls. No exposure measurements were performed,
              but the authors stated that all the workers were exposed to a similar level of
              molybdenum trioxide particles in air. The most common symptoms reported,
              included chest pain, dyspnoea, and cough. None of the exposed workers showed
              firm radiological signs of interstitial lung disease. In lung function testing,
              symptomatic and asymptomatic workers did not significantly differ; both groups
              showed a higher FEV1 and FVC than the control group (p<0.05). In BAL
              cytology of exposed symptomatic workers, higher counts of lymphocytes
              (p<0.001) and neutrophils (p<0.01); lower counts of alveolar macrophages
              (p<0.01); and a higher CD4/CD8 positive T-lymphocytes ratio (p<0.05) were
              found, compared with asymptomatic and control workers. This finding may
              represent a molybdenum trioxide-induced subclinical alveolitis.
              Effects                                                                                                   47
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<pre>      In a two-year drinking-water study among residents from two Colorado cities
      (Denver and Golden), Chappell et al. (1979) evaluated the effects of ingestion of
      (unspecified) molybdenum.34 The Denver residents (n=42) consumed 2 to 50 µg
      molybdenum per litre drinking water, whereas the Golden residents (n=13)
      consumed at least 200 µg per litre drinking water. No adverse health effects were
      observed that could be related to molybdenum exposure in any of the residents.
      Plasma molybdenum levels were within the normal range; however, mean free
      plasma ceruloplasmin levels and urinary molybdenum levels were higher among
      the Golden residents than the Denver residents (ceruloplasmin, 403 versus 304
      mg/L; urinary molybdenum, 187 versus 87 µg/day).
7.1.4 Carcinogenicity
      Droste et al. (1999) investigated the relationship between lung cancer and
      exposure to occupational carcinogens in a general case-control study in an
      industrial region of Belgium.41 A total of 478 lung cancer patients and 536
      controls were interviewed. Based on job task exposure, the investigators reported
      52 cases with an association between occupational exposure to molybdenum and
      lung cancer, with an adjusted odds ratio of 2.1 (95% confidence interval,
      1.2-3.7). Dividing the 52 cases in four groups by duration of exposure, only the
      persons who had been exposed for more than 21 years to molybdenum (n=19)
      showed significantly elevated odds ratios (3.3; 95% confidence interval, 1.3-8.3).
      It is, however, difficult to relate lung cancer cases to molybdenum exposure,
      because of concomitant exposure to other potentially carcinogenic substances
      and metals.
           In a population-based study, Nakadaira et al. (1995) tried to correlate
      selenium and molybdenum exposure to cancer mortality in the general
      population.42 Although they found a positive correlation with female cancer
      mortality of the pancreas, and inverse correlations with female cancer mortality
      of the oesophagus and rectum, no clear conclusion can be drawn from this study.
      This is due to a lack of reliable information on daily intake, and unknown other
      sources of cancer risk.
           Suggestions have been made that oesophageal cancer in South Africa, China,
      and Russia, could be attributed to a low intake of molybdenum.43 However, in at
      least one study, no such an association could be made.43
 8    Molybdenum and molybdenum compounds
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<pre>7.1.5 Genotoxicity
      Cytogenetic damage, measured as chromosome aberrations and sister-chromatid
      exchanges, was increased in lymphocytes of workers in a metallurgical plant,
      with more than 10 years of occupational exposure to molybdenum, molybdenite,
      and molybdenum trioxide (Babaian et al. 1980; Bobyleva et al. 1993; cited
      in39).44,45 The Committee noted that most likely the workers were exposed to
      several other potentially harmful metals.
7.1.6 Reproduction toxicity
      In 2008, Meeker et al. reported on semen quality (sperm count, sperm
      concentration, percent motile sperm, and sperm morphology), and metals in
      blood among men recruited through fertility clinics (N=219).46 They found
      molybdenum-dependent decreases in sperm concentration and normal
      morphology, when adjusted for age, current smoking, and the impact of
      multiple metals on semen quality simultaneously (odds ratios (OR) for sperm
      concentration: metal percentile 70-85th, 2.2 (95% confidence interval (CI),
      0.7-7.6); metal percentile >85th, 6.26 (95% CI, 1.6-25.0). OR for sperm
      morphology: metal percentile 70-85th, 0.9 (95% CI, 0.4-2.2); metal percentile
      >85th, 3.4 (95% CI, 1.2-9.7)).
          Two years later, Meeker et al. reported on reproductive hormone levels
      (serum FSH, LH, inhibin B, testosterone, and SHBG) among the same group of
      men.47 The authors found a significant inverse trend between molybdenum
      concentrations in blood and testosterone levels, also when correcting for
      exposure to other metals. They also found an interaction between high
      molybdenum levels and low zinc levels. In addition, 37% of men with a low zinc
      level had a reduction in testosterone levels.
          No other investigations have been presented in which adverse effects of
      molybdenum and molybdenum compounds on fertility, and development of
      progeny, in humans was examined.
7.2   Effects in laboratory animals
7.2.1 Mortality after single exposure
      In Table 5, data on mortality are shown of animals exposed once-only to metallic
      molybdenum compounds.
      Effects                                                                          49
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<pre> able 5 Data on mortality in animals after a single exposure to molybdenum or molybdenum compounds.
 ompound              Route of     Animal          Mortality           Concentration         Exposure design Source
                      exposure     species                             (mg molybdenum
                                                                       per m3 or kg bw)
Molybdenum            Inhalation Rat               0% (at 4 weeks)     12,000 - 15,000       Single exposure ACGIH 200348
rioxide dust                                                           mg/m3                 for one hour
Ammonium              Inhalation Rat               0% (at 4 weeks)     3,000 - 5,000         Single exposure ACGIH 200348
 aramolybdate dust                                                     mg/m3                 for one hour
Molybdenum            ip           Guinea pig 75% (at day 4)           Approx. 400           N=8; single     Fairhall 194521
rioxidea                                           75% (at 4 weeks)    mg/kg bw              injection
                                                   75% (at 4 months)
Ammonium              ip           Guinea pig 100% (at 4 days)         Approx. 800 mg/kg N=12; single        Fairhall 194521
molybdatea                                         100% (at 4 weeks) bw                      injection
                                                   100% (at 4 months)
 odium molybdate      ip           Rat             100%                114-117 mg/kg bw Single injection     Maresh et al.
                                                                                                             1940 (source
                                                                                                             ACGIH
                                                                                                             2003)48
Metallic              Inhalation   Rat             0% (at 4 weeks)     25,000 to 30,000      Single exposure ACGIH 200348
molybdenum dust                                                        mg/m3                 of one hour
Molybdenitea          ip           Guinea pig      17% (at 4 days)     Approx. 800           N=12; single    Fairhall 194521
                                                   17% (at 4 weeks)    mg/kg bw              injection
                                                   25% (at 4 months)
 alcium molybdatea ip              Guinea pig      0% (at 4 days)0%    Approx. 400           N=6; single     Fairhall 194521
                                                   (at 4 weeks)        mg/kg bw              injection
                                                   17% (at 4 months)
    Data from one and the same experiment, intraperitoneal (ip) injection, guinea pigs (Fairhall 1945).
7.2.2        Irritation and sensitization
             Exposure to sodium molybdate causes skin and eye irritation. Molybdenum
             trioxide also irritates the respiratory tract. No skin or eye irritation was observed
             upon exposure to calcium and zinc molybdate.14,49,50 No data are available on
             irritation of the respiratory tract after inhalation of molybdenum or molybdenum
             compounds.
                  Molybdenum chloride was identified as sensitizer in the Guinea Pig
             Maximization Test.49 At the highest challenge concentration that did not cause
             erythema in non-sensitized animals, 13 out of 20 sensitized animals showed
             reactions at 24 hours after challenge, and 10 out of 20 sensitized animals at 48
             hours after challenge.
                  The results of a study by Abdouh et al. (1995) were in line with this
             finding.51 Using the auricular lymph node assay in C57B1/6 mice, in which the
             compound was applied topically on the dorsum of both ears at different
             concentrations (0.1-5.0%), for three consecutive days, statistically significant
 0           Molybdenum and molybdenum compounds
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<pre>           and dose-related increases in the weight, and cellularity of the draining auricular
           lymph node weight were noted. The authors argued that the increase in the cell
           numbers and weight of the auricular lymph nodes may have been nonspecific,
           because they did not observe T-cell activation. However, it should be noted that
           the lymph node test performed by Abdouh et al. was not according the current
           guidelines for performing the Local Lymph Node Assay, and in addition, that a
           shift in T-cell activation in the lymph node is not a criterion for the identification
           of sensitizers.
                No data are available on (specific/nonspecific) sensitization of molybdenum
           or molybdenum compounds after inhalation.
 able 6 Summary of data on mortality in animals after short-term repeated exposure to molybdenum or molybdenum
 ompounds.
Compound               Route of   Animal         Mortality         mg molybdenum       Exposure design   Source
                       exposure   species                          per m3 or kg bw
Molybdenum trioxide Inhalation Rat                  0%             Up to 300 mg/m3     N=5/sex;          NTP 199743
 erosola                                                                               6 hrs/day,
                                                                                       5x/week,14 days
Molybdenum trioxide Inhalation Rat                  0%             Up to 100 mg/m3     N=10/sex;         NTP 199743
 erosola                                                                               6.5 hrs/day,
                                                                                       5x/ week,13 weeks
Molybdenum trioxide Inhalation Mouse                0%             Up to 300 mg/m3     N=5/sex;          NTP 199743
 erosola                                                                               6 hrs/day,
                                                                                       5x/week,14 days
Molybdenum trioxide Inhalation Mouse                0%             Up to 100 mg/m3     N=10/sex;         NTP 199743
 erosola                                                                               6.5 hrs/day,
                                                                                       5x/ week,13 weeks
Molybdenum trioxide Inhalation Guinea pig         51%              Approx. 205 mg/m3 N=24;               Fairhall 194521
 ustb                                                                                  1 hr/day,
                                                                                       5x/week, five
                                                                                       weeks.
Molybdenum trioxide Inhalation Guinea pig          8.3%            Approx. 191 mg/m3 N=25;               Fairhall 194521
umeb                                                                                   1 hr/day,
                                                                                       5x/week, five
                                                                                       weeks.
Ammonium               Inhalation Rat            100% (at 30       500 - 2,500 mg/m3 One hour daily for Mogilevskaya
 aramolybdate aerosolc                           days)                                 30 days           1967 (Source
                                                                                                         ACGIH 2003)48
Molybdenum trioxided Oral         Rat             50% (at 120      Approx.             N=8; daily        Fairhall 194521
                                                 days)             125 mg/kg bw        ingestion
Molybdenum trioxidee Oral         Guinea pig 100% (at 27           Approx.             N=8; daily        Fairhall 194521
                                                 days)             330 mg/kg bw        ingestion
Ammonium               Oral       Rat            100% (at 13       Approx. 660-1,250 N=8; daily          Fairhall 194521
molybdateb                                       days)             mg/kg bw/day        ingestion
Ammonium               Oral       Rat            25% (at 232       Approx. 66-125      N=8; daily        Fairhall 194521
molybdateb                                       days)             mg/kg bw/day        ingestion
           Effects                                                                                                    51
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<pre>Metallic molybdenum    Inhalation  Rat               0% (at 30      12,000 tot 15,000 One hour daily for Mogilevskaya
 erosolc                                          days)             mg/m3             30 days             1967 (Source
                                                                                                          ACGIH 2003)48
Molybdenite dustb      Inhalation  Guinea pig      4.2%             Approx. 286 mg/m3 N=25;               Fairhall 194521
                                                                                      1 hr/day,
                                                                                      5x/week,
                                                                                      five weeks
 alcium molybdate      Inhalation  Guinea pig      0.8%             Approx.           N=24; 1 hr/day, 5x/ Fairhall 194521
 ustb                                                               159 mg/m3         week,
                                                                                      five weeks
Molybdenited           Oral        Rat            0% (at 44 days) Approx.             N=8; daily          Fairhall 194521
                                                                    3,300 - 6,250     ingestion
                                                                    mg/kg bw
 alcium molybdated     Oral        Rat            50% (at 137       Approx.           N=10; daily         Fairhall 194521
                                                  days)             101 mg/kg         ingestion
                                                                    bw/day
 alcium molybdated     Oral        Rat            100% (at 128      Approx.           N=10; daily         Fairhall 194521
                                                  days)             232 mg/kg bw/day ingestion
 alcium molybdatee     Oral        Guinea pig     25% (at 95        Approx.           N=8; daily          Fairhall 194521
                                                  days)             280-420 mg/kg bw ingestion
    Data from one and the same experiment, inhalation, rats and mice (NTP 1997).
    Data from one and the same experiment, inhalation, guinea pigs (Fairhall 1945).
    Data from one and the same experiment, inhalation, rats (Mogilevskaya 1967).
    Data from one and the same experiment, oral, rats (Fairhall 1945).
    Data from one and the same experiment, oral, guinea pigs (Fairhall 1945).
7.2.3       Short-term toxicity
            Mortality
            In Table 6, a summary of data on mortality is given, which were obtained from
            short-term animal studies. Symptoms included diarrhea, coma, and death from
            cardiac failure.43
                In a short-term study, rats were fed daily molybdenum compounds at various
            doses for up to 232 days.21 A computation of the relative toxicities of the
            compounds revealed oral LD50 values of approximately 125, 101, and 333 mg
            molybdenum/kg bw, for molybdenum trioxide (after approx. 120 days in test),
            calcium molybdate (after approx. 135 days in test), and ammonium molybdate
            (no data given), respectively.
            Inhalation exposure
            The US National Toxicology Program performed a series of inhalation studies on
            molybdenum trioxide, using F344/N rats and B6C3F1 mice of both sexes.43
 2          Molybdenum and molybdenum compounds
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<pre>    In a first study, the animals (N=5/group/sex) were exposed to the compound
at a concentration of 0, 3, 10, 30, 100, and 300 mg molybdenum trioxide/m3 (in
aerosol) for six hours a day, five days a week for a total of two weeks.
Statistically significant weight loss was observed in all animals, which were
exposed to 300 mg/m3, and in male rats exposed to 100 mg/m3. No local or
systemic toxicity was observed. Haematology and clinical chemistry were not
investigated.
    In a second study, the animals (N=10/group/sex) were exposed to the
compound at a concentration of 0, 1, 3, 10, 30, and 100 mg molybdenum
trioxide/m3 (in aerosol) for six and a half hours a day, five days a week for a total
of thirteen weeks. No effects on body weight (gain) were observed. No mortality
and no clinical findings or pathological lesions related to molybdenum exposure
were observed. No significant differences in absolute or relative organ weights,
haematology or clinical chemistry parameters were observed either.
    Fairhall et al. (1945) exposed guinea pigs (N=24-26/group) to dusts of
molybdenum trioxide (205 mg molybdenum/m3, corresponding to 311 mg
molybdenum trioxide/m3), molybdenite (286 mg molybdenum/m3, corres-
ponding to 608 mg molybdenite/m3), and calcium molybdate (159 mg
molybdenum/m3, corresponding to 389 mg calcium molybdate/m3) for one
hour a day, five days a week for a total of five weeks.21 Molybdenum trioxide
exposure caused respiratory irritation, loss of appetite and weight, diarrhea,
muscular incoordination, and loss of hair. Daily exposure to molybdenite dust
induced increased respiration during exposure, whereas calcium molybdate did
not cause any clinical signs of toxicity.
    See also Table 8 for a brief summary of animal inhalation studies on non-
carcinogenic effects.
Oral exposure
The International Molybdenum Association (IMOA) commissioned two separate
animal experiments, in which Sprague-Dawley CD rats were given sodium
molybdate dihydrate by gavage or via the diet.52 In one experiment, the animals
(5 animals/sex/ group) were given the compound by gavage (once daily) or in
their diet (ad libitum), for 28 consecutive days. Doses administered were 0, 4
or 20 mg molybdenum/kg bw/day. Also one group of animals received the
compound by gavage twice daily (10 mg/kg bw/administration for a total of
20 mg/kg bw/day). At the end of the treatment, all animals were killed and
postmortem examinations, including microscopic pathology, were performed.
Analysis of blood samples revealed that molybdenum was present in the system.
Effects                                                                               53
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<pre>  The investigators did not find exposure-related adverse effects on any in-life
  parameters (survival, body and organ weights, food consumption).
       In the other experiment, the animals (10 or 20 animals/sex/group) were fed
  sodium molybdenum dihydrate at doses of 0, 5, 17, and 60 mg molybdenum/kg
  bw/day, for 91 or 92 days.53 At the end of the treatment ten animals of each
  group were killed for postmortem examinations. The remaining ten animals (in
  groups administered 0 or 60 mg molybdenum/kg bw/day) were allowed to
  recover for a further 60 days, before they were also killed for postmortem
  examinations. In males and females, the mean body weight changes from
  baseline were statistically significantly decreased at the highest dose level (see
  Table 7). Furthermore, a statistically significant decrease in absolute body weight
  was observed among male animals from the highest dosed group. These
  reductions were partially explained by lower food intake. Furthermore,
  microscopic examinations revealed slight diffuse hyperplasia of the proximal
  tubules in the kidneys of two female rats fed 60 mg molybdenum/kg bw/day.
  Table 7 Summary of body weight and body weight gain in rats given sodium molybdate in the diet
  for 90 days.53
                                 0 mg/kg bw     5 mg/kg bw       17 mg/kg bw   60 mg/kg bw
  Mean body weight (grams ± SD)
     Malesa                      587.1 ± 50.3   583.9 ± 41.4     576.3 ± 47.9  498.5 ± 32.9b*
     Femalesa                    296.1 ± 20.5   313.2 ± 32.8     313.2 ± 32.8  279.5 ± 25.2
  Mean body weight changes from baseline (grams ± SD)
     Malesa                      246.3 ± 38.9   242.6 ± 37.6     240.1 ±33.9   164.4 ± 30.1b*
     Femalesa                    69.4 ± 15.1b   81.2 ± 21.6      82.9 ± 19.4   49.2 ±20.3*
  * p<0.001. Dose concerns mg molybdenum/kg bw. With permission of IMOA.
  a     n=20 in groups 0 and 60 mg/kg bw; n=10 in groups 5 and 17 mg/kg bw.
  b     n=19 in animals in group.
  Bompart et al. (1990) investigated the effect of ammonium paramolybdate on
  renal function.54 Male Sprague-Dawley rats (N=7/group) received the compound
  by gavage at doses of 0, 40, or 80 mg molybdenum/kg bw/day for a total of eight
  weeks (60 days). Once every two weeks the animals were housed in metabolism
  cages to collect urine over 24 hours. Statistically significant changes in renal
  function were only observed in the highest-dose group. The changes included: a
  lower body weight and absolute kidney weight; a higher relative kidney weight;
  a reduced urinary creatinine clearance; and, an increased urinary kallikrein
  excretion (at day 60 only). However, no changes in activity or effects were
  observed in any of the groups regarding blood pressure, and proximal brush-
  border enzymes (alanine aminopeptidase, γ-glutamyltransferase). Based on the
4 Molybdenum and molybdenum compounds
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<pre>           results, the authors concluded that the glomerulus and the distal tubule were
           more sensitive to chronic molybdenum exposure than the proximal tubule.
               Groups of eight to ten male white rats received molybdenite, molybdenum
           trioxide, calcium molybdate or ammonium molybdate added in the diet at levels
           of 10 to 500 mg per animal (corresponds to approximately 100 to 5,000 mg
           molybdenum/kg bw, based on an animal weight of 100 gram), for up to 232
           days.21 No signs of toxicity were apparent in rats ingesting molybdenite.
           However, in rats receiving molybdenum trioxide, calcium molybdate or
           ammonium molybdate, loss of appetite, weight loss, a rough fur, and a tendency
           to become quiet and listless, were observed. The Committee noted the high
           mortality rate of 25% (ammonium molybdate) to 50% (molybdenum trioxide,
           calcium molybdate) in the lowest-dose groups, up to 100% (all three compounds)
           in the highest-dose groups. No mortality was observed in the groups receiving
           molybdenite.
           In a limited study, adult and weanling rabbits received sodium molybdate in their
           diet for up to 4 gram per kg diet (highest dose corresponds to approximately to
           120-160 mg molybdenum/kg bw, assuming that a rabbit on average ingests 30 to
           40 gram of food per kg bw). They developed anaemia, anorexia, loss of weight,
           alopecia, slight dermatosis, and defects in the skeletal system.55 Early mortality
           in the highest two dose groups (2 and 4 gram molybdenum/kg diet) reached
           100%. The Committee noted the very low number of animals per dose group
           (N=2). It was not possible to recalculate the dose in mg molybdenum/kg bw per
           day.
               See also Table 8 for a brief summary of oral animal studies on non-
           carcinogenic effects.
 able 8 Summary of studies on non-carcinogenic effects in animals, which were exposed to molybdenum and molybdenum
 ompounds.
Compound              Level                   Animal species        Exposure design         Health effects
                      (mg/m3 as
                      molybdenum)
 nhalation
Molybdenum trioxide 0, 3, 10, 30, 100, or 300 Rats and mice         6 hrs/day, 5 days/week, No local or systemic toxicity
 erosol               (in mg molybdenum       (n= 5/group /sex)     two weeks               found (NTP1997)43
                      trioxide/m3)
Molybdenum trioxide 0, 3, 10, 30, or 100      Rats and mice         6.5 hrs/day, 5 days/    No local or systemic toxicity
 erosol               (in mg molybdenum       (n= 10/group/ sex) week, thirteen weeks       found (NTP 1997)43
                      trioxide/m3)
Molybdenum trioxide 0, 10, 30, or 100         Rats and mice         6 hrs/day, 5 days/week, Signs of pathological
 erosol                                       (n= 50/group/ sex) 106 weeks                  respiratory tract effects
                                                                                            observed from 10 mg/m3
                                                                                            onwards (NTP 1997)43
           Effects                                                                                                      55
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<pre>Molybdenum trioxide 205                Guinea pigs         1 hr/day, 5 days/week,    Respiratory irritation, loss of
 ust                                   (n=24-26/group)     five weeks                appetite and weight, diarrhea,
                                                                                     muscular oncoordination, and
                                                                                     loss of hair (Fairhall 1945)21
  alcium molybdate  159                Guinea pigs         1 hr/day, 5 days/week,    No clinical signs of toxicity
 ust                                   (n=24-26/group)     five weeks                found (Fairhall 1945)21
Molybdenite dust    286                Guinea pigs         1 hr/day, 5 days/week,    Increased respiration (Fairhall
                                       (n=24-26/group)     five weeks                1945)21
Oral intake
Molybdenum trioxide 100 to 5,000       Rats (n=8-10/group) In diet for up to 232     Loss of appetite, weight loss, a
                                                           days                      rough fur, tendency to become
                                                                                     quiet and listless; 50%
                                                                                     mortality in lowest dose group,
                                                                                     100% in highest dose group
                                                                                     (Fairhall 1945)21
Ammonium molybdate 100 to 5,000        Rats (n=8-10/group) In diet for up to 232     Loss of appetite, weight loss, a
                                                           days                      rough fur, tendency to become
                                                                                     quiet and listless; 25%
                                                                                     mortality in lowest dose group,
                                                                                     100% in highest dose group
                                                                                     (Fairhall 1945)21
 odium molybdate    0, 4, or 20 mg     Rats (n=5/group/    By gavage (once daily), No exposure-related adverse
 ihydrate           molybdenum/kg bw   sex)                or in diet, for 28 days health effects found (IMOA,
                                                                                     2011)52
 odium molybdate    0, 5, 17, or 60 mg Rats (n=10 or 20/   In diet for 90 days; part At 60 mg/kg bw: statistically
 ihydrate           molybdenum /kg bw  group/sex)          of animals had recovery lowered body weight (males),
                                                           period of 60 days         and body weight gain (males
                                                                                     and females). No other clear
                                                                                     exposure-related effects
                                                                                     observed53
Ammonium            0, 40 or 80        Rats (n=7/group)    By gavage/daily for       Lowered body weight and
 aramolybdate                                              eight weeks               absolute kidney weight; higher
                                                                                     relative kidney weight; reduced
                                                                                     urinary creatinine clearance;
                                                                                     increased urinary kallikrein
                                                                                     excretion in the highest-dose
                                                                                     group only (Bompart et al.
                                                                                     1990)54
  alcium molybdate  100 to 5,000       Rats (n=8-10/group) In diet for up to 232     Loss of appetite, weight loss, a
                                                           days                      rough fur, tendency to become
                                                                                     quiet and listless; 50%
                                                                                     mortality in lowest dose group,
                                                                                     100% in highest dose group
                                                                                     (Fairhall 1945)21
Molybdenite         100 to 5,000       Rats (n=8-10/group) In diet for up to 232     No signs of toxicity found; no
                                                           days                      mortality (Fairhall 1945)21
 6          Molybdenum and molybdenum compounds
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<pre>7.2.4 Long-term toxicity and carcinogenicity
      Regarding carcinogenicity, the data were evaluated by the Subcommittee on the
      classification of carcinogenic substances of the DECOS. A summary of the
      findings and the conclusion of the Subcommittee are given in Annex E in this
      report.
      In an inhalation study performed by the US National Toxicology Program, F344/
      N rats and B6C3F1 mice of both sexes (N=50/group/sex) were exposed to
      molybdenum trioxide at concentrations of 0, 10, 30 and 100 mg molybdenum
      trioxide/m3 (in aerosol), six hours per day, five days per week for a total of 106
      weeks.43,56 On all animals a complete necropsy was performed, followed by
      microscopic evaluations.
          Survival rates of exposed rats were similar to those of the control groups.
      Also mean body weights were similar throughout the study. Furthermore, no
      clinical findings related to exposure were observed, and no significant
      differences in bone density or curvature between exposed and control animals.
      There was a significant dose-dependent increase in blood molybdenum levels in
      exposed animals. Comparable results were found for mice, except for a slightly
      lower survival rate of males exposed to 30 mg/m3, and a higher mean body
      weight of exposed females (from week 11 onwards), compared to controls.
          Respiratory tract effects: The most relevant findings on respiratory
      nonneoplastic and neoplastic lesions are summarized in Table 9. In summary, in
      exposed animals, nonneoplastic effects included: hyaline degeneration in the
      respiratory epithelium of the nose; hyaline degeneration in the olfactory
      epithelium of the nose (female rats, male and female mice); laryngeal squamous
      metaplasia in the epiglottis; laryngeal hyperplasia (mice only); chronic
      inflammation in the alveoli of the lungs (male and female rats); alveolar
      epithelium metaplasia (mice only); and, cellular histiocyte infiltration in the
      lungs (male mice only). Most of these effects were statistically significantly
      increased at an exposure concentration of 10 mg/m3 onwards compared to non-
      exposed controls, despite the fact that some effects also occurred in non-exposed
      controls at relatively high incidence (olfactory epithelium hyaline degeneration
      in the nose, and chronic inflammation in the lungs of female rats; olfactory and
      respiratory epithelium hyaline degeneration in the nose of female mice; and,
      respiratory epithelium hyaline degeneration in the nose and lung adenomas in
      male mice).
      Effects                                                                            57
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<pre> able 9 Occurrence of respiratory tract effects by molybdenum trioxide in a two-year carcinogenicity study
 sing rats and mice.43,56
                                                               0 mg/m3          10 mg/m3       30 mg/m3    100 mg/m3
Male F344/N rats
   Lung: alveolus chronic inflammation                           2/50            3/50          25/50**     47/50**
   Lung: alveolar/bronchiolar adenoma                            0/50            0/50           0/50        3/50
   Lung: carcinoma                                               0/50            1/50           1/50        1/50
   Lung: adenoma/carcinoma                                       0/50            1/50           1/50        4/50
   Nose: respiratory epithel. hyaline degeneration               2/50            7/49          48/49**     49/50**
   Larynx: epiglottis, squamous metaplasia                       0/49           11/48**        16/49**     39/49**
 emale F344/N rats
   Lung: alveolus chronic inflammation                         14/50            13/50          43/50**     49/50**
   Lung: alveolar/bronchiolar adenoma                            0/50            1/50           0/50        2/50
   Lung: carcinoma                                               0/50            1/50           0/50        0/50
   Lung: adenoma/carcinoma                                       0/50            2/50           0/50        2/50
   Lung: squamous cell carcinoma                                 1/50            0/50           0/50        0/50
   Nose: olfactory epithelium hyaline degeneration             39/48            47/49*         50/50**     50/50**
   Nose: respiratory epithel. hyaline degeneration               1/48           13/49**        50/50**     50/50**
   Larynx: epiglottis, squamous metaplasia                       0/49           18/49**        29/49**     49/50**
Male B6C3F1 mice
   Lung: alveolar epithelium hyperplasia                         2/50            1/50           6/49        2/50
   Lung: alveolar/bronchiolar epithelium metaplasia              0/50           32/50**        36/49**     49/50**
   Lung: adenoma                                                 9/50           14/50          10/49        9/50
   Lung: carcinoma                                               2/50           16/50**        14/49**     10/50*
   Lung: adenoma/carcinoma                                     11/50            27/50**        21/49**     18/50
   Nose: inflammation suppurative                                2/50            6/50          10/49        8/50*
   Nose: olfactory epithelium atrophy                            3/50            5/50           3/49       10/50*
   Nose: resp. epithelium degeneration hyaline                 11/50            13/50          11/49       41/50**
   Larynx: hyperplasia                                           1/50            3/49           6/48       41/50**
   Larynx: epiglottis, squamous metaplasia                       0/50           26/49**        37/48**     49/50**
 emale B6C3F1 mice
   Lung: alveolar epithelium hyperplasia                         1/50            3/50           3/49        6/49
   Lung: alveolar/bronchiolar epithelium metaplasia              2/50           26/50**        39/49**     46/49**
   Lung: adenoma                                                 1/50            4/50           8/49*       9/49*
   Lung: carcinoma                                               2/50            2/50           0/49        6/49
   Lung: adenoma/carcinoma                                       3/50            6/50           8/49       15/49**
   Nose: olfactory epithelium degeneration hyaline             22/49            14/50          14/49       36/49**
   Nose: resp. epithelium degeneration hyaline                 26/49            23/50          28/49       48/49**
   Larynx: hyperplasia                                           1/49            1/50           7/49       35/50**
   Larynx: epiglottis, squamous metaplasia                       1/49           36/50**        43/49**     49/50**
  p<0.05; ** p<0.01.
 8            Molybdenum and molybdenum compounds
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<pre>No significant neoplastic respiratory effects were found in exposed rats.
However, some evidence of carcinogenic activity was found in exposed mice: a
statistically significantly increased incidence of alveolar/bronchiolar adenoma or
carcinoma was observed compared to controls, with the notion that in the control
group of male mice also cases of lung tumours were observed.
    Overall, the investigators of the NTP-study considered the evidence for
respiratory carcinogenicity of molybdenum trioxide in this study equivocal.
    Non-respiratory tract effects: Neoplastic lesions were observed in some
exposure groups, including: clitoral gland adenomas/carcinomas (female rats);
mammary gland fibroadenomas, adenomas and carcinomas (female rats);
hepatocellular carcinomas (male mice); and, hepatocellular adenomas and skin
sarcomas (non-significant increase in female mice). Also a decrease in lesions
were observed in exposed animals, such as a decrease of thyroid gland (C-cell)
carcinomas (male rats), and of adrenal medulla pheochromocytoma (female
rats). However, due to a lack of dose- related responses, a non-significant
increase/decrease, or questions on relevance of certain lesions for humans, the
investigators could not relate any of these effects to exposure to molybdenum
trioxide.
    Stoner et al. (1976) and Shimkin et al. (1977) reported on a study, in which
inbred strain A/Strong mice (N=20/group) were exposed to molybdenum
trioxide by repeated intraperitoneal injections (a total of 19 injections, thrice
weekly).57,58 The total doses applied were 0, 950, 2,375 and 4,750 mg
molybdenum/kg bw (maximum tolerated dose). The animals were killed 30
weeks after the first injection. A statistically significant increase in the average
number of lung tumours per mouse was observed in the highest-dose group
compared to controls (1.13±0.2 versus 0.42±0.1 in exposed versus control,
respectively). All the responses were however weak, and no distinction was
made between the type of tumours. No differences were found concerning
number of animals with tumours (10 versus 9 of twenty animals in each group,
exposed versus control). The Committee noted the short duration of the study,
that the route of exposure is not relevant to human exposure, and that the mice
were highly susceptible to lung tumour development. This makes it difficult to
make a final conclusion on the relevance for humans.
In three separate initiation-promotion carcinogenicity studies using rats, sodium
molybdate was applied in drinking water or diet, in combination with treatment
with the tumour initiators N-nitroso-N-methylurea, N-nitrososarcosine ethyl
ester, or N-methyl-N-benzylnitrosamine.59-61 The presence of sodium molybdate
reduced the incidences of oesophageal, fore stomach and mammary gland
Effects                                                                              59
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<pre>      tumours, compared to tumour initiator-treated controls. No groups were included
      receiving sodium molybdate only.
7.2.5 Mutagenicity and genotoxicity
      In vitro assays
      Molybdenum trioxide: The compound scored negative in an Ames test with
      Salmonella typhimurium strains TA97, TA98, TA100, TA1535 and TA1537, and
      in Escherichia coli strain WP2P uvrA, both with and without metabolic
      activation.62,63
      Furthermore, no increased incidence of sister chromatid exchanges, and
      chromosome aberrations, were observed in assays with Chinese Hamster
      Ovarian cells, both with and without metabolic activation.43 In addition, in a
      micronucleus assay using primary human lymphocytes, with and without a
      metabolic activation system, the compound did not show any clastogenic or
      aneugenic properties (concentrations added up to 1439 µg/mL, which is the
      maximum that should be tested according to the OECD guidelines).64
      Ammonium molybdate: Ammonium molybdate (10 µM; exposure duration, 24
      hours) induced chromosome aberrations, and sister-chromatid exchanges, in
      human lymphocytes (Bobyleva et al. 1991; in Russian, summarized in English
      in39).45 The Committee noted that the data presented are insufficient to conclude
      whether or not ammonium molybdate showed clastogenic potential.
          In a micronucleus assay using human lymphocytes, a concentration-related
      increase of the number of micronucleated cells was observed for ammonium
      molybdate (dose applied, 0.1-2 mM; viability of the cells ranged between 61%
      and 68%, which is above the minimum of 40 to 50% cell viability according to
      the OECD guidelines).39 The Committee noted that the increase was minimal.
          Armitage (1997) reported on ammonium octamolybdate and did not find
      mutagenic activity when using the Ames test with Salmonella typhimurium
      strains TA98, TA100, TA1535 and TA1537, with and without metabolic
      activation.65
      Sodium molybdate: The compound was tested in the Ames test with Salmonella
      typhimurium strains TA98, TA100, TA102, TA1535 and TA1537, with or
      without metabolic activation (final concentration up to 5,000 µg/plate).66,67
      Using the Microtitre® fluctuation test, sodium molybdate did not induce
 0    Molybdenum and molybdenum compounds
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<pre>      mutation in the tk locus in mouse lymphoma cells (L5178Y) in the absence and
      presence of a metabolic activation system.68 Concentrations tested were up to
      2,060 µg/mL (= 10 mM).
          In a micronucleus assay using human lymphocytes, a minimal (little more
      than twofold over the control level) concentration-related increase of the number
      of micronucleated cells for the compound (0.1-5 mM) was observed (viability of
      the cells ranged between 63% and 73%).39 However, in another micronucleus
      assay using a shorter treatment procedure, sodium molybdate (concentration
      tested up to 10 mM) did not induce concentration-related increase in micronuclei
      using primary human lymphocyte cultures, in the absence or presence of a
      metabolic activation system.69
      In vivo assays
      Sodium molybdate: In a micronucleus test, male C57BL/6J mice (Ntotal, 15;
      Ngroup, not given) were intraperitoneally injected with 0, 200 or 400 mg sodium
      molybdate per kg bw for two consecutive days.39 The femoral bone marrow cells
      were harvested 48 hours after the final injection. A statistically significant
      (p<0.05) increase in micronuclei frequency in polychromatic erythrocytes was
      observed at both doses tested, compared with the negative control. The
      Committee noted that the increase, although it was statistically significant, was
      small, and that it was not dose-related. The first observation might be explained
      by the fact that cells were harvested 48 hours after the final injection and not
      after 6 hours, which is recommended according to the OECD guidelines.
7.2.6 Transformation assays
      Molybdenum (in the form of particulates): The C3H10T½ mouse fibroblast cell
      line was used to assess cytotoxicity and neoplastic transformation incidence.70
      Molybdenum showed marked toxicity only at the highest tested concentration of
      500 µg/mL. Molybdenum did not induce transformation.
          Molybdenum trioxide. The compound was tested in the Syrian hamster
      embryo (SHE) cell transformation assay (at reduced pH 6.7); it gave a significant
      increase in morphological transformations after 24 hours of exposure, with
      concentrations of ≥75 µg/mL (cytotoxic concentration, 200 µg/mL).71
          Sodium molybdate. The C3H10T½ mouse fibroblast cell line was used to
      assess cytotoxicity and neoplastic transformation incidence. Significant
      transformation into neoplastic foci was observed at 10 µg/mL sodium molybdate
      (p<0.01). However, the relevance of the positive finding is unclear, because at
      Effects                                                                           61
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<pre>      higher concentrations up to 500 µg/mL, no cellular transformation was
      detected.70
7.2.7 Reproductive toxicity
      Data on reproduction toxicity were evaluated by the Subcommittee on the
      classification of reproductive toxic substances of the DECOS. A summary of the
      findings and the conclusion of the Subcommittee are given in Annex G in this
      report.
      Fertility
      Molybdenum trioxide: In a NTP-study, Fischer 344 rats (N=10/sex/dose) and
      B6C3F1 mice (10/sex/dose) were exposed to 0, 10, 30, and 100 mg molybdenum
      trioxide/m3 (in aerosol) by inhalation, for 6.5 hour per day, 5 days per week for
      thirteen weeks.43 Body and organ weights, clinico-chemical and hematological
      parameters, and histopathological findings were not different from the control
      values.
          In exposed male rats, sperm counts were unaffected. In addition, no
      statistically significant effect was observed on the concentration of epididymal
      spermatozoa. At 10, 30 and 100 mg/m3, rats showed slightly decreased absolute
      epididymis weights (0.48 g, 0.49 g and 0.47 g, respectively) compared to
      unexposed rats (0.50 g). However, these effects were not statistically significant.
          In exposed mice, absolute cauda epididymis weight was slightly increased
      (0.025 g versus 0.018 g in controls) at 10 mg/m3, and absolute testis weight was
      slightly decreased (0.10 g versus 0.12 g in controls) at 100 mg/m3. However,
      these effects were not statistically significant. No statistically significant effects
      were observed on sperm count, and on the concentration and motility of
      epididymal spermatozoa in any of the treatment groups.
          The NTP also performed a long-term carcinogenicity study, in which rats and
      mice were exposed to the same molybdenum trioxide levels as in the thirteen-
      week study (for details on study design see Section 7.2.4). Examination included
      the occurrence of non-neoplastic lesions. No lesions were found in the genital
      system of males and females that could be related to exposure to molybdenum.
      The NTP did not specifically examine sperm pathology.
      Sodium molybdate: In a dose-range finding study, sodium molybdate dihydrate
      was administered in the diet ad libitum to pregnant Sprague-Dawley rats (N=10/
      group) at doses of 0, 1, 5, 10 and 20 mg molybdenum/kg bw/day from 6 to 20
 2    Molybdenum and molybdenum compounds
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<pre>days of gestation.72 At gestation day 20, the animals were sacrificed and gross
necropsy was performed. No molybdenum-related general effects (maternal
body weight, weight gains, organ weights, clinical observations, feed
consumption), and fertility effects (ovarian corpora lutea counts, placental
weight and disposition) were observed.
     Pandey and Singh (2002) administered to groups of 10 adult male Druckery
rats (body weight at start of experiment averaged 120 grams) 0, 10, 30, or 50 mg
sodium molybdate per kg bw by gavage, 5 days/week for 60 days.73 No effects
on body weight or clinical signs that could be related to treatment were observed.
At 50 mg/kg bw, testis, epididymis, seminal vesicles, and prostate gland weights
(absolute and/or relative weights) were statistically significantly decreased, and
an accumulation of molybdenum was seen in these organs. At 30 mg/kg bw,
epididymis weight, absolute weight of seminal vesicles, and relative weight of
the prostate gland were statistically significantly decreased. At both
concentrations, degeneration of the seminiferous tubules in the testis was
observed. The authors derived an NOAEL of 10 mg sodium molybdate/kg bw
from this study. Details of the results for the most relevant effects are given in
Table 10.
     In a separate experiment by the same investigators (Pandey and Singh, 2002),
male Druckery rats (N=20/group) were treated with 0 or 30 mg sodium
molybdate/kg bw, 5 days/week for 12 weeks, and mated with untreated females
during 2 weeks thereafter.73 The fertility index was 60% for treated males and
80% for untreated controls. The pregnant unexposed females were sacrificed on
Table 10 Relevant fertility effects of male Druckery rats, which were orally exposed to sodium
molybdate for 60 days.73
Effect (mean ± SE)        0                 10               30                50
                          mg/kg bw          mg/kg bw         mg/kg bw          mg/kg bw
Absolute organ weight (gram):
   Testis                 2.5±0.08          2.50±0.03        2.40±0.05         2.40±0.03
   Epididymis             0.81±0.01         0.78±0.02        0.50±0.02*        0.49±0.02
   Seminal vesicle        0.18±0.01         0.17±0.02        0.09±0.012*       0.08±0.01*
   Prostate gland         0.11±0.01         0.11±0.006       0.09±0.004        0.05±0.01*
Relative organ weight (organ to whole animal; gram):
   Testis                 1.20±0.03         1.20±0.03        1.15±0.03         1.15±0.03*
   Epididymis             0.38±0.01         0.37±0.01        0.30±0.02*        0.32±0.02*
   Seminal vesicle        0.08±0.001        0.08±0.01        0.05±0.01         0.05±0.008*
   Prostate gland         0.05±0.006        0.05±0.004       0.04±0.002*       0.03±0.005*
Sperm motility (%)        86.0±2.3          85.0±0.08        65.0±1.2*         49.1±1.3*
Total epididymal sperm 8.0±0.17             8.2±0.08         6.0±0.07*         5.0±0.05
count/epididymis (x107)
* p ≤ 0.05
Effects                                                                                        63
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<pre>  day 20 of gestation. The number of implantations, live foetuses and foetal body
  weight were significantly decreased in litters of dams mated with exposed males.
  Implantation loss was statistically significantly increased compared to controls.
  The effects on developmental parameters seemed to be related to an effect of
  sodium molybdate on male fertility.
      The Committee considers the effects observed in male rats in the study by
  Pandey and Singh (2002) relevant for humans. On the other hand, however, the
  study is poorly reported, raising uncertainties about for instance, the duration of
  the study. In addition, it is not clear to the Committee why the reduction of total
  sperm count in the highest exposed group is not statistically significant, whereas
  the data presented in the paper indicate otherwise. Also the authors did not
  indicate from which exposure group data are presented in Table 6 of the
  publication.
      The International Molybdenum Association (IMOA) commissioned two
  separate animal experiments, in which Sprague-Dawley CD rats were given
  sodium molybdate dihydrate by gavage or via the diet.52 See Section 7.2.3, oral
  exposure, for a detailed description of the studies. Regarding the 28-day study,
  histopathology did not reveal abnormalities in the kidneys, testes or epididymis.
  The Committee emphasizes that adverse effects on male fertility could have
  occurred after 28 days, because the spermatogenesis cycle in rats takes
  approximately ten weeks. Furthermore, it is known that, for instance, effects on
  the seminiferous tubuli can develop in the long term. However, in the other
  experiment by IMOA (the 90-day study) also no molybdenum-related adverse
  effects were observed on the gonads, estrous cycles or sperm parameters in any
  of the exposed groups.53
      In a poorly reported study, Jeter et al. (1954) administered doses of <1, 20, 80,
  or 140 ppm molybdenum (approximately <0.04, 0.9, 3.5, 6.2 mg molybdenum/kg
  bw/day*) as disodium molybdate dihydrate in diets containing 5 ppm copper
  (normal copper content 1.8 ppm) to Long-Evans rats** (N=4-8/sex/group) for
  about 20 weeks.74 The growth rates of male rats at 20, 80 or 140 ppm
  molybdenum, and of females at 80 and 140 ppm molybdenum, were statistically
  significantly decreased over the first eleven weeks.
      Depigmentation of the hair and alopecia were observed in some rats fed 20,
  80 or 140 ppm molybdenum. Animals were allowed to mate from eleven weeks
  onwards. At 80 and 140 ppm molybdenum, males were successful in mating in
  Assuming a mean body weight of 425 grams and a food intake of 18.75 grams per day.
* Age and body weights of rats at the start of the study were not given; only average weight gains
  at wk 11.
4 Molybdenum and molybdenum compounds
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<pre>one of four cases. Mating of the treated males with untreated females did not
result in pregnancy. In contrary, mating of females given 80 or 140 ppm
molybdenum with untreated males resulted in pregnancy rates of 100%.
Histopathologic examination of the testes of males treated with 80 and 140 ppm
molybdenum revealed degeneration of the seminiferous tubules.
     Weanling female Sprague-Dawley rats (N=21/group) were given drinking
water with 0, 5, 10, 50 and 100 mg/L molybdenum* as sodium molybdate
dihydrate for 6 weeks (Fungwe et al. 1990).75 Thereafter, rats were exposed
during three oestrus cycles before being mated with untreated males (N=15/
group) or sacrificed (N=6/group). The mated females remained exposed during
gestation until necropsy on day 21. During the first six weeks of the study, no
effects on body weight became apparent. At 10 mg/L and higher, oestrus cycle
lengths were statistically significantly prolonged compared to control females.
Pregnancy rate was not affected by treatment.
     In the dominant lethal assay, C57BL/6J male mice were treated with 0, 200
and 400 mg sodium molybdate per kg bw, and mated with untreated C3H/J
female mice.39 Pregnancy rate was 10% decreased in the highest exposure group
(not significant), and an overall dose-dependent increase in total post-
implantation loss was observed (6.7%, 10.6%, 16.3%, respectively). This
increase was mostly represented by early resorptions (p=0.003) in the first week
after treatment. The authors suggest that sodium molybdate induces dominant
lethality at the post-meiotic stage of spermatogenesis. The Committee noted that
the number of corpera lutea in females, which were mated with males treated at
400 mg/kg bw, was lower than that in controls. This might have affected
pregnancy rate, and thus the post-implantation loss.
Ammonium molybdate: The effect of ammonium molybdate (AM) and
thiomolybdate (TM, presumably ammonium tetrathiomolybdate) in drinking
water on the trace element status, reproductive capacity of guinea pigs was
studied by Howell et al. (1993).76
     Mature female (n=8/dose) and male (12 in total) Hartley albino guinea pigs,
weighing around 500-600 grams were fed ad libitum on a diet containing 212
µmol Cu/kg. When each female entered the third oestrus cycle, males were
introduced twice a day. Females of dose groups A (control), B (261 µmol
AM/L), C (261 µmol TM/L), and D (130 µmol TM/L) received molybdenum
Assuming a mean water intake of 50 to 125 mL/kg bw/day for SD rats, the units in mg/L correspond
to a daily intake of approximately 0.25-0.625 mg/kg bw (5 mg/L), 0.5-1.25 mg/kg bw (10 mg/L),
2.5-6.25 mg/kg bw (50 mg/L), and 5.0-12.5 mg/kg bw (100 mg/L).
Effects                                                                                          65
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<pre>  compounds from the first day of the oestrus cycle onwards, whereas treatment of
  group E (261 µmol TM/L) and F (130 µmol TM/L) females was started
  immediately after mating.*
       Subcutaneous oedema was found only in 1/8 and 4/8 female adult guinea
  pigs of the high TM dose groups, C and E. Upon X-ray examination, an ossified
  ridge in the mid shaft region of the femur was observed in the TM-dose groups
  (frequencies: 3/5, 0/7, 4/5, and 1/7 for groups C, D, E, and F, respectively), but
  not in the AM-treated animals nor in any of the pups. The reason for reporting
  the results for less than eight animals was not given, but it might be that animals
  that died (pregnant or non-pregnant) were excluded from examination**. All
  adult females had oestrus cycles and conception rates were reported to be
  unaffected. Details on developmental effects in dams are described in the
  following section.
  Developmental toxicity
  Sodium molybdate: In a dose-range finding study, sodium molybdate dihydrate
  was administered in the diet ad libitum to pregnant Sprague-Dawley rats (N=10/
  group) at doses of 0, 1, 5, 10 and 20 mg molybdenum/kg bw/day from 6 to 20
  days of gestation.72 At gestation day 20, the animals were sacrificed and gross
  necropsy was performed. No molybdenum-related developmental toxicity (pre-
  and postimplantation loss, fetal numbers, sex ratio, body weights and or fetal
  external malformations) was observed.
       Based on the previous outcome, the study was repeated with higher doses.
  Sodium molybdate dihydrate was given to maternal Sprague Dawley rats (N=25/
  group) via the diet at doses of 0, 3, 10, 20 and 40 mg molybdenum/kg bw/day
  from 6 to 20 days of gestation.77 At gestation day 20, the animals were sacrificed
  and gross necropsy was performed. No treatment-related effects were observed
  on maternal body weight, weight changes, feed consumption, clinical
  observations, pregnancy indices or maternal organ weights. Also no treatment-
  related effects were observed regarding numbers of ovarian corpora lutea, uterine
  implantation sites and losses, number of fetuses, fetal sex ratios, fetal body
  weights, fetal external, visceral or skeletal malformations or variations in the
  fetuses per females. The Committee cannot make a final conclusion on the
  Assuming a mean water intake of 100 to 170 mL/kg bw/day for guinea pigs, the units in µmol/L
  correspond to a daily intake of approximately 8.70 mg AM/kg bw (261 µmol/L), 11.55 mg TM/kg bw
  (261 µmol/L), and 5.75 mg/kg bw (130 µmol/L).
* In the discussion section of the study it is stated that “Of 32 animals receiving TM, eight had changes
  in the shaft of the femur”.
6 Molybdenum and molybdenum compounds
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<pre>  present and the previous study, since a lack of maternal toxicity in combination
  with a lack of developmental effects may indicate that the chosen exposure levels
  were too low to induce adverse health effects. In that case, and according to
  OECD-guideline 414 (prenatal developmental toxicity study), further
  investigations are needed.
       Weanling female Sprague-Dawley rats (N=21/group) were given drinking
  water with 0, 5, 10, 50 and 100 mg/L molybdenum* as sodium molybdate
  dihydrate for 6 weeks (Fungwe et al. 1990).75 Thereafter rats were exposed
  during three oestrus cycles before being mated with untreated males (N=15/
  group) or sacrificed (N=6/group). The mated females remained exposed during
  gestation until necropsy on day 21.
       During the first 6 weeks of the study, no effects on body weight became
  apparent. During gestation, weight gain of the dams was statistically
  significantly decreased at 10, 50 and 100 mg/L, but these changes were attributed
  to reduced foetal weights. The number of resorptions was increased in females
  treated at 10 mg/L and above. Litter size did not differ between treatment groups
  and controls, but foetal weight and length were decreased at 10, 50 and 100
  mg/L. Growth retardation was observed (less mature hepatic structure, delayed
  transfer of foetal haemopoiesis to bone marrow, delayed foetal oesophageal
  development, and myelination in the spinal cord) in the foetuses at 10 mg/L and
  above. Blood and hepatic enzymes of the dams were affected at 5 mg/L and
  above. Plasma ceruloplasmine was statistically significantly increased in all
  gestating dams, but not in dams sacrificed after three oestrus cycles. Hepatic
  xanthine oxidase/dehydrogenase, and sulphite oxidase, were statistically
  significantly increased in all treated females in the study.
       In a poorly reported study by Jeter et al. (1954), Long-Evans rats
  (N=4-8/sex/group) received <1, 20, 80 or 140 ppm molybdenum as sodium
  molybdate (approximately <0.04, 0.9, 3.5, 6.2 mg molybdenum/kg bw/day**) in
  diet containing 5 ppm copper (normal copper content 1.8 ppm) for about 20
  weeks.74 The growth rates of male rats at 20, 80 or 140 ppm molybdenum, and of
  females at 80 and 140 ppm molybdenum, were statistically significantly
  decreased over the first eleven weeks. Depigmentation of the hair and alopecia
  were observed in some rats fed 20, 80 or 140 ppm molybdenum. Animals were
  allowed to mate from eleven weeks onwards.
  Assuming a mean water intake of 50 to 125 mL/kg bw/day for SD rats, the units in mg/L correspond
  to a daily intake of approximately 0.25-0.625 mg/kg bw (5 mg/L), 0.5-1.25 mg/kg bw (10 mg/L),
  2.5-6.25 mg/kg bw (50 mg/L), and 5.0-12.5 mg/kg bw (100 mg/L).
* Assuming a mean body weight of 425 grams and a food intake of 18.75 grams per day.
  Effects                                                                                          67
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<pre>       No effects on pup weight at day zero of lactation were identified. During
  lactation, increased weight loss of the mothers compared to controls was
  observed at 80 and 140 ppm molybdenum, and pup weight gain was decreased at
  the same dose levels. This was attributed to reductions in milk production and
  possible excretion of molybdenum into milk.
  Ammonium molybdate and ammonium tetramolybdate: Howell et al. (1993)
  studied the effect on the trace element status, and reproductive capacity of guinea
  pigs of ammonium molybdate (AM) and thiomolybdate (TM, presumably
  ammonium tetrathiomolybdate) in drinking water.76 Mature female (N=8/dose)
  and male (12 in total) Hartley albino guinea pigs, weighing around 500-600
  grams, were fed ad libitum a diet containing 212 µmol copper/kg diet. When
  each female entered the third oestrus cycle, males were introduced twice a day.
  Females of dose groups A (control), B (261 µmol AM/L), C (261 µmol TM/L),
  and D (130 µmol TM/L) received molybdenum compounds from the first day of
  the oestrus cycle onwards, whereas treatment of group E (261 µmol TM/L) and F
  (130 µmol TM/L) females was started immediately after mating.* Details on
  fertility effects are described in the previous section.
       At birth, two animals of each litter were retained with the mother for a further
  six weeks. All dams and pups were X-rayed after they had been killed. Clinical
  signs observed in several dams of the high TM-dose groups included hair loss,
  transient diarrhoea, subcutaneous oedema, and mortality before or during
  pregnancy. No changes in ossified femur was observed in any of the pups. There
  appeared to be a reduced pregnancy rate in AM-treated females, and an increased
  ‘aborted resorbing’ in high TM-dose females. The mean number of pups born
  alive was reduced in groups B, C, D and E, but not in group F. Pup body weight
  was slightly decreased at birth in the TM-treated groups.
       Six weeks after birth, body weights of group C pups (high TM dose) were
  still reduced. Administration of AM or TM usually resulted in an increase in the
  concentration of molybdenum in the organs examined (the liver, kidneys, femur,
  and brain). This increase was statistically significant in the liver, kidneys, and
  femur at all ages in the group given AM; and, in the liver and kidneys at birth in
  all groups given TM with the exception of the liver in group E. However, the
  concentration of molybdenum was statistically significantly depressed in the
  femur of the pups from group F killed at six weeks.
  Assuming a mean water intake of 100 to 170 mL/kg bw/day for guinea pigs, the units in µmol/L
  correspond to a daily intake of approximately 8.70 mg AM/kg bw (261 µmol/L), 11.55 mg TM/kg bw
  (261 µmol/L), and 5.75 mg/kg bw (130 µmol/L).
8 Molybdenum and molybdenum compounds
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<pre>  Molybdate: Schroeder et al. (1971) exposed five pairs of Charles River CD mice
  to 10 mg/L molybdenum (as molybdate; cation unknown) in deionized drinking
  water for up to six months, while the diet contained 0.45 ppm molybdenum.* The
  study was poorly reported.78 Animals were allowed to breed freely during this
  period. Animals were at random selected from the first three litters to form the
  F1, and allowed to breed to form the F2 (period not indicated). Animals of the
  first two F2 litters were selected to form the F3-generation.
       No mortality was observed in the F0-generation. Molybdenum did not affect
  the growth rate in the F0-generation. Age at first litter and interval between litters
  were similar to control values. No other data on this generation are available. In
  the F1-generation, no differences between treatment group and controls were
  reported for number of litters, litter size and number of runts. Fifteen of the 238
  F1 mice died early (not further specified). In the selected animals of the F1-
  generation, one female died. The interval between the litters was increased (43
  versus 28 days in controls), but the age at first litter was not affected. The
  number of F2 litters, litter size, and dead young were similar to controls. Five of
  the 26 litters were found dead compared to 0 out of 23 in controls. In the selected
  F2, four maternal deaths were reported, and the age at first litter was increased
  from 62 to 79 days. No effect on interval between litters was found. The number
  of litters and litter size were decreased in treated animals. Four litters in the F3
  were found dead. The numbers of runts (11 versus 0 in controls) and dead young
  (34 versus 1 in controls) were increased.
  Lactation
  Sodium molybdate: In a poorly reported study by Jeter et al. (1954), Long-Evans
  rats (N=4-8/sex/group) received <1, 20, 80 or 140 ppm molybdenum as sodium
  molybdate (approximately <0.04, 0.9, 3.5, 6.2 mg Molybdenum/kg bw/day**) in
  diet containing 5 ppm copper (normal copper content 1.8 ppm) for about 20
  weeks.74 During lactation, increased weight loss of the mothers compared to
  controls was observed at 80 and 140 ppm molybdenum, and pup weight gain was
  decreased at the same dose levels. The authors assumed these decreases to be
  explained by reductions in milk production and possible excretion of
  molybdenum into milk.
  Assuming a mean water intake of 167 to 200 mL/kg bw/day and a food intake of 120 to 150 g/kg
  bw/day, the total intake of molybdenum per day approximates 1.7 to 2 mg/kg bw.
* Assuming a mean body weight of 425 grams and a food intake of 18.75 grams per day.
  Effects                                                                                      69
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<pre>7.3   Summary
7.3.1 Observations in humans
      Studies involving the working population with occupational molybdenum
      exposure are of limited value, because of a lack of reliable exposure data,
      concomitant exposure to other potentially toxic compounds, and poor
      descriptions of the studies. Overall, workers who were at least exposed to
      molybdenum trioxide reported complaints, such as joint pain (gout-like
      symptoms), back pain, headache, and mild obstructive lung disease (including
      breathing difficulties, chest pain and fatigue). Also increased levels of uric acid
      and ceruloplasmin have been reported in workers compared to non-exposed
      controls. Exposure levels to molybdenum at which symptoms occurred were
      found to be as low as 1.6-9.5 mg/m3 (molybdenum in respirable-total dust;
      molybdenum roasting plant) to up to 600 mg/m3 (mine dust).
          Among Armenian villagers, gout-like symptoms and increased levels of uric
      acid have been observed. They had an average dietary intake of molybdenum of
      10 to 15 mg per day, and of copper of 5 to 10 mg per day. However, no adverse
      health effects were found in an American study, in which people consumed
      drinking water that contained at least 200 µg molybdenum per litre water.
          Data on carcinogenic activity in humans are limited. Positive but weak
      correlations were found for lung cancer among molybdenum-exposed workers
      with a long exposure history, and for pancreas cancer in females in a Japanese
      population. However, due to a lack of reliable data on exposure and intake levels,
      and the presence of other potentially carcinogenic factors, no conclusions can be
      drawn.
          One study reported on dose-dependent negative trends between serum
      molybdenum levels and sperm concentration, normal sperm morphology, and
      serum testosterone levels. No other studies were found on possible effects of
      molybdenum or molybdenum compounds on fertility, developmental toxicity,
      and lactation in humans.
7.3.2 Animal experiments
      Depending on the molybdenum compound, some of them showed to be irritating
      the nose, eyes, and respiratory tract.
 0    Molybdenum and molybdenum compounds
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<pre>Inhalation exposure
In rats and mice exposed to molybdenum trioxide of up to 100 mg molybdenum
trioxide/m3 (in aerosol) for thirteen weeks, no adverse health effects or
pathological lesions were found. Guinea pigs exposed to very high levels of
molybdenum trioxide (> 300 mg/m3) for five weeks, showed signs of respiratory
irritation, loss of appetite and weight, diarrhea, muscular incoordination, and loss
of hair.
     Groups of rats and mice were exposed to molybdenum trioxide for two years.
Animals were exposed to the compound at concentrations of 0 (control), 10, 30
or 100 mg molybdenum trioxide/m3 (in aerosol) for six hours per day, five days
per week, for 106 weeks. Statistically increased incidence of nonneoplastic
respiratory tract effects in exposed animals included: hyaline degeneration in the
respiratory and olfactory epithelium of the nose; laryngeal squamous metaplasia
in the epiglottis, and laryngeal hyperplasia; and, chronic inflammation of the
lungs. The effects were observed at 10 mg/m3 onwards.
     In the same study, described above, evidence for respiratory carcinogenicity
of molybdenum trioxide was found to be equivocal, because in most animal
groups, no significant neoplastic respiratory tract effects were found, except in
mice. In those animals, a statistically significantly increased incidence in
alveolar/bronchiolar adenomas and carcinomas have been observed, but the
findings were not dose-related. Furthermore, no dose-related carcinogenic effects
in other organs were observed.
     Based on the limited evidence available, the Subcommittee is of the opinion
that molybdenum trioxide, ammonium molybdate and sodium molybdate are
probably not genotoxic.
     No significant signs of adverse effects on fertility have been found in male
rats and mice exposed to molybdenum trioxide at a concentration of up to 100
mg/m3 (highest concentration tested) for thirteen weeks.
Oral exposure
Overall, data on adverse health effects in animal experiments after acute or
subchronic oral exposure are limited, due to low number of animals in study. An
exception is a 90-day study by IMOA, in which a statistically significant
decrease in average body weight and change in body weight gain was observed
in male rats exposed to 60 mg molybdenum/kg bw. At this dose, also the average
body weights of female rats was statistically significantly decreased compared to
Effects                                                                              71
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<pre>  controls. No data were available on non-carcinogenic and carcinogenic long-
  term effects of oral exposure to molybdenum or molybdenum compounds only.
      Reproduction toxicity: In a poorly reported 60-day study by Pandey and
  Singh (2002), oral exposure (by gavage) to sodium molybdate decreased sperm
  motility and total sperm count in male rats, in the absence of general toxicity
  (doses applied up to 50 mg sodium molybdate/kg bw). A number of other poorly
  reported studies support this finding. However, in one well performed 90-day
  study by IMOA, no fertility effects of sodium molybdate have been found in rats
  (another breed of rats than in the study by Pandey and Singh), when given in the
  diet at a dose of up to 60 mg molybdenum/kg bw. Pandey and Singh (2002) also
  found indications that female fertility was affected, but this is not confirmed in
  other studies. In addition, there are indications for developmental toxicity;
  however, the studies reporting on this issue were poorly reported. There are no
  indications to label for effects on lactation.
2 Molybdenum and molybdenum compounds
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<pre> hapter 8
        Existing guidelines, standards and
        evaluations
8.1     General population
        Since molybdenum is considered an essential trace element, shortage of
        molybdenum in the body may induce molybdenum deficiency. Although up to
        now no cases of deficiency have been reported in healthy people under normal
        dietary conditions, several institutions and authorities have suggested Reference
        Daily Intakes (RDI) and Estimated Average Requirements (EAR). Also,
        Tolerable Upper Intake Levels (UL; total uptake from food, water, and
        supplements) have been recommended, based on impaired reproduction and
        growth in animals.8
            For adults, in 2006, the US Institute of Medicine adopted an RDI value of 45
        µg molybdenum per day, an EAR value of 34 µg molybdenum per day, and an
        UL of 2,000 µg molybdenum per day.8 A year earlier, the same values were set in
        Australia and New Zealand. A lower UL was adopted by the European Food
        Safety Authority, namely 600 µg molybdenum per day for adults, which is
        equivalent to approximately 10 µg molybdenum/kg bw/day.35 The US
        Environmental Protection Agency adopted an oral Reference Dose of 5 µg
        molybdenum/kg bw/day.38
            In the guidelines for drinking-water quality, the World Health Organization
        assessed a guideline value for molybdenum in drinking water of 70 µg/litre,
        which represents a concentration of molybdenum that does not result in any
        significant health risk to the consumer over a lifetime of consumption.79
        Existing guidelines, standards and evaluations                                    73
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<pre>                  No guidelines or standards exist for the general population regarding
              exposure to airborne molybdenum or molybdenum compounds.
8.2           Working population
              In the Netherlands, no legally-binding occupational exposure limits exists
              for molybdenum and molybdenum compounds. Also, no exposure limits have
              been set by the European Commission. However, some individual European
              countries and in the United States have assessed exposure limits, dividing the
              soluble from the metal and insoluble molybdenum compounds. A summary is
              shown in Table 11.
 able 11 Occupational exposure limits of molybdenum and molybdenum compounds.
 ountry (Organization) Monitoring                       OEL           TWA        Type of exposure limit a      Valid since
                                                         (mg/m3)
 oluble compounds, measured as molybdenum
Germany (DFG)80         -                                 -b          -          -                             -
UK (HSE)   81           Not specified                     5           8h         OES                           <1999
                        Not specified                   10            15min      OES                           <1999
Denmark82               Not specified                     5           8h         OEL                           <2001
 inland                 Not specified                     0.5         8h         OEL                           2007
 weden83                In total dust                     5           8h         OEL                           1984
USA (ACGIH)48           In respirable particulate         0.5         8h         TLV                           2001
USA (NIOSH)48           -                                 -           -          -                             -
USA (OSHA)48            Not specified                     5c          8h         PEL                           1989
Metal and insoluble compounds, measured as molybdenum
Germany (DFG)80         -                                 -b          -          -                             -
UK (HSE)81              Not specified                   10            8h         OES                           <1999
                        Not specified                   20            15min      OES                           <1999
Denmark82               Not specified                   10            8h         OEL                           <2001
 weden83                In respirable dust                5           8h         OEL                           1984
                        In total dust                   10            8h         OEL                           1984
USA (ACGIH)48           In respirable particulate         3           8h         TLV                           2001
                        In inhalable particulate        10            8h         TLV                           2001
USA (NIOSH)48           -                                 -           -          -                             -
USA (OSHA)48            In total dust                   15c           8h         PEL                           1989
     OEL, occupational exposure limit; OES, occupational exposure standard; PEL, permissible exposure limit; TLV, threshold
     limit value.
     No OEL has been derived due to a lack of information.
     NIOSH considered the proposed PELs by OSHA to be inadequate.
 4            Molybdenum and molybdenum compounds
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<pre>8.3 Carcinogenic classification
    Germany has classified molybdenum trioxide as a category 3B carcinogen.80
    Substances are classified in the category “for which in vitro or animal studies
    have yielded evidence of carcinogenic effects that is not sufficient for
    classification of the substance in one of the other categories. Further studies are
    required before a final decision can be made”.
        The American ACGIH has classified soluble molybdenum compounds as an
    A3 carcinogen, indicating that it is a “confirmed animal carcinogen with
    unknown relevance to humans.48 The agent is carcinogenic in laboratory animals
    at a relatively high dose […] that may not be relevant to worker exposure.
    Available epidemiological studies do not confirm an increased risk of cancer in
    exposed humans. Available evidence does not suggest that the agent is likely to
    cause cancer in humans except under uncommon or unlikely routes or levels of
    exposure”.
    Existing guidelines, standards and evaluations                                      75
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<pre>6 Molybdenum and molybdenum compounds</pre>

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<pre> hapter 9
        Hazard assessment
9.1     Hazard identification
        A few epidemiological studies and laboratory animal studies have been
        performed to identify adverse health effects of certain molybdenum compounds.
        The following paragraphs contain short evaluations on the relevant toxic effects
        of molybdenum and molybdenum compounds after single and repeated exposure
        via food, drinking water, or inhalation.
        Note: Molybdenum and molybdenum compounds are present in low amounts as
        natural elements in the environment. For humans and animals, the compound is
        an essential trace element that can be found in low amounts in all parts of the
        body. It serves as a cofactor of various enzymes involved in natural biochemical
        processes in the body.
        Non-carcinogenic effects (excluding reproduction toxicity)
        Various epidemiologic studies involving the working population, associate
        inhalation of molybdenum to for instance gout-like symptoms in the joints,
        weakness, fatigue, headaches, breathing difficulties, and chest pain.
            Also, increased blood levels of uric acid have been reported. However, due to
        combined exposure to other potentially toxic compounds in most workplaces,
        and missing details on exposure and population characteristics, it is difficult to
        Hazard assessment                                                                  77
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<pre>  conclude whether the observed symptoms are actually caused by molybdenum
  exposure. Exposure levels to molybdenum at which symptoms occurred, were
  found to be as low as 1.6-1.9 mg/m3 (as respirable-total dust; molybdenum
  roasting plant) to up to 600 mg/m3 (as mine dust).
      Signs of short- and long-term clinical and pathological animal toxicity, and
  mortality, have been reported for several molybdenum compounds under various
  exposure and experimental conditions. The symptoms included respiratory tract
  effects after inhalation, and loss of appetite and body weight after oral intake.
  However, other animal studies did not find any clinical or pathological signs of
  toxicity. The studies are difficult to compare, because the choice of animal
  species, the choice of molybdenum compounds in study, and exposure and study
  designs, were mutually very divergent. In addition, the Committee considers part
  of the data insufficient in deriving health-based occupational exposure limits,
  because the number of animals in test was limited, or one dose or concentration
  have been tested only, so that for most animal studies no dose-response
  relationships can be assessed, with a few exceptions.
      The first concerns the subchronic and chronic studies performed by the US
  National Toxicology Program, in which two different animal species are used,
  and a range of inhalation exposure levels of molybdenum trioxide aerosols. In
  particular, the two-year inhalation study with exposure concentrations ranging
  from 10 to 100 mg molybdenum trioxide/m3 revealed pathological, upper
  respiratory tract effects in both rats and mice, of both sexes, such as hyaline
  degeneration in the nose epithelium, squamous metaplasia in the larynx, and
  chronic inflammation of the lungs (the latter in rats only). All these effects were
  statistically significantly increased in exposed animals compared to non-exposed
  controls.
      In the study by Pandey and Singh (2002), statistically significantly reduced
  sperm motility and quality in rats exposed to 30 and 50 mg sodium molybdate/kg
  bw (the two highest dose-groups) were observed. The sodium molybdate was
  given orally by gavage. Another study on sodium molybdate is the subchronic
  study by IMOA, in which male and female rats were given sodium molybdate in
  the diet at doses of up to 60 mg molybdenum/kg bw for 90 days. In the highest
  dosed group a statistically significant decrease in mean body weight was
  observed in both sexes, compared to controls. Also the mean body weight gain
  was statistically significantly reduced, but in males only. Other adverse effects
  (slight diffuse hyperplasia of the proximal tubules in the kidneys of two female
  rats fed 60 mg molybdenum/kg bw/day) were non-significant.
      For metallic molybdenum and other molybdenum compounds, no reliable
  data on dose-response relationships are available.
8 Molybdenum and molybdenum compounds
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<pre>Carcinogenic effects
Data on carcinogenic activity of molybdenum and molybdenum compounds in
humans are limited and give no conclusive information.
    In the two-year inhalation study by the US National Toxicology Program,
rats did not develop molybdenum trioxide-related tumours, whereas in some
mice exposed at a concentration of 10 mg/m3 to up to 100 mg molybdenum
trioxide/m3 (in aerosol), statistically increased incidence of alveolar/bronchiolar
adenomas and carcinomas were found compared to controls (see Table 9). The
investigators of the study did not consider these results dose-related, and stated
that the evidence for respiratory tract carcinogenicity in rats and mice is
equivocal, a reason being that in the male control group, high incidences of lung
tumours have been observed.
    From the available data on carcinogenicity, DECOS’ Subcommittee on the
classification of carcinogenic substances is of the opinion that molybdenum
trioxide is a suspected carcinogen to man, and recommends classifying the
compound in category 2* (see Annex E for further details on the Subcommittee’s
opinion). The available data on other molybdenum compounds and metallic
molybdenum, are insufficient to evaluate the carcinogenic properties.
Reproduction toxicity
One epidemiology study reported on dose-dependent negative trends between
serum molybdenum levels and sperm concentration, normal sperm morphology,
and serum testosterone levels. Animal studies on reproduction toxicity of
molybdenum compounds are limited to oral exposure to mainly (sodium)
molybdates. Effects on male fertility were observed in two poorly reported
studies (Pandey and Singh, 2002; Jeter et al. (1954).84,85 In addition, there are
indications that exposure to molybdates might affect female fertility (prolonged
oestrus cycle) in the study of Fungwe et al. (1990). However, these effects were
not confirmed by others (Howell et al. (1993) and IMOA (2011). Summarizing,
there is weak evidence of fertility effects of molybdates.
    Considering the available human and animal data on reproduction toxicity,
DECOS’ Subcommittee on the classification of reproductive toxic substances
concluded that molybdates causes concern for human fertility (corresponding to
a classification in category 2 for fertility effects), and that a lack of data
precludes the assessment for effects on fertility of molybdenum trioxide (and
See Annex F for the classification system.
Hazard assessment                                                                   79
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<pre>      other molybdenum compounds). Furthermore, due to a lack of data, the
      Subcommittee recommends not to classify molybdates and molybdenum trioxide
      for effects on development, and not to label for effects on lactation (see Annex G
      for further details on the Subcommittee’s opinion).
      Conclusion
      Currently, the Committee considers the epidemiological data insufficient for
      quantitative hazard assessment, because of the presence of confounding factors,
      such as concomitant exposure, and missing details on exposure and population
      characteristics. Taking the whole set of animal data into account, a few studies
      have been performed showing data on exposure-response relationships, which
      are of interest for quantitative risk analyses. It concerns data on exposure to
      molybdenum trioxide and sodium molybdate.
9.2   Quantitative hazard assessment
      In deriving a health-based recommended occupational exposure limit (HBR-
      OEL), the Committee performed benchmark dose-analysis (BMD-analysis).
9.2.1 Recommendation of an HBR-OEL (8-hour TWA) for molybdenum trioxide
      The most clear and evident effects of molybdenum trioxide are found in a two-
      year inhalation study by US National Toxicology Program (1997), in which the
      substance induced non-neoplastic effects in the respiratory tract of rats and mice
      of both sexes.43,56 Rats and mice of both sexes inhaled molybdenum trioxide
      aerosols at concentrations of 0, 10, 30 and 100 mg molybdenum trioxide/m3 (in
      aerosol), six hours per day, five days per week, for a total of 106 weeks. On all
      animals, gross necropsy and microscopic pathology were performed.
          Endpoints of interest. Results on respiratory tract effects are shown in Table 9.
      The most striking outcome is the induction of squamous metaplasia in the
      epiglottis (larynx), in that a statistically significant increase was observed in all
      animal species tested, and in both sexes; the lowest significant increase was found
      in groups that were exposed to 10 mg/m3, whereas in non-exposed controls only
      one case was found (female mouse). The Committee also noted that at that
      concentration molybdenum trioxide induced other effects, such as hyaline
      degeneration in the nose, and chronic inflammation and metaplasia in the lungs,
      but these effects were less consistent, in that they were not observed in both
 0    Molybdenum and molybdenum compounds
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<pre>animal species and in both sexes. Overall, the Committee did not find indications
that the observations in animals would not occur in humans.
    Uncertainties. The Committee notes that some effects occurred at a high
incidence in control animals (e.g., olfactory hyaline degeneration in the nose of
female rats and mice). In addition, some other effects showed hardly any case in
controls, but instead high incidences at the lowest exposure level (e.g., alveolar/
bronchial metaplasia in the lungs of male mice). Although, from a statistical
viewpoint these effects still differed significantly (between controls and exposed
groups), the high background in controls or high incidences in the lowest
exposure groups weakens the strength or power of the data, making them less
useful for quantitative hazard assessment. This has repercussions on BMD-
analysis, in that the models used in the analysis do not fit adequately the data,
and thus for these specific effects no reliable analysis can be performed.
    The Committee prefers to include the degree of a specific pathological lesion,
since it expects that in a low-dose group the effects might be less severe
compared to the same lesion in a high-dose group. Such data on degree of
severity could lower the uncertainty in the set of data for BMD-analysis, but
these are not presented in the NTP-report nor in the scientific publication.43,56
    BMD-analysis. In Annex H, data on effects are shown, from which a BMDL
could be calculated. The BMDL is the 95% lower confidence limit of the BMD
that corresponds with a 10% extra risk*. Because of the limited power of these
carcinogenicity studies, BMD values based on lower percentage of extra risk are
not reliable. The lowest BMDL is used as starting point in deriving an HBR-
OEL; in this case a BMDL of 0.29 mg/m3 (squamous metaplasia in the epiglottis
of female mice).
    HBR-OEL. For the establishment of an HBR-OEL several aspects have to be
considered. One of these aspects is the difference between animals and humans.
The Committee notes that in this case the squamous metaplasia and other
respiratory effects are superficial and local, for which no compensation is
needed. However, due to possible inter-individual differences among people, the
Committee is of the opinion that an uncertainty factor of three is required.
Adjusting the BMDL value of 0.29 mg/m3 by the factor of three, an HBR-OEL
for molybdenum trioxide is proposed of 0.1 mg molybdenum trioxide/m3
(corresponding to 0.07 mg molybdenum/m3). The HBR-OEL is based on
personal inhalable dust exposure, measured as an eight-hour time weighted
average concentration.
The Committee uses 10% extra risk as a default for dichotomous (quantal) animal data. The default
may be modified based on scientific considerations.
Hazard assessment                                                                                 81
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<pre>9.2.2 Recommendation of an HBR-OEL (8-hour TWA) for sodium molybdate
      As written in the previous section, regarding sodium molybdate, two animal
      studies are of interest, one showing reproduction toxicity in male rats (Pandey
      and Singh, 2002), and one showing reduction of body weight and body weight
      gain in male and female rats (IMOA, 2011).
          The Committee considers the effects on the reproduction more sensitive and
      specific than reduction of the body weight. Effects on reproduction toxicity in
      male animals, and in humans, have been described in several studies, and
      therefore the effects found in the Pandey and Singh-study cannot be ignored
      (although none of the other studies can be used for quantitative risk analysis).
      The data of the Pandey-study appear to be consistent, showing comparable
      changes among the different effect parameters on sperm quality and motility.
      Also, the values of the parameters are in line with the values that would be
      expected when such effects occur. On the other hand, the Committee is aware of
      the poor reporting by Pandey and Singh, raising the question as to how the
      experiment was actually performed, and thus how reliable the data are for
      quantitative risk-analysis. It is not clear for instance, what the actual duration of
      the study was; whether the exposure concentration is expressed as molybdenum,
      sodium molybdate or sodium molybdate dihydrate; and, from which exposure
      group the data are presented in Table 6 of the publication. Furthermore, Pandey
      and Singh did not mark ‘total sperm count’ of the highest exposure group as
      statistically significant, whereas data indicate otherwise. It is unknown what the
      sensitivity is of the animal species they used, and, furthermore, the dietary
      composition may have influenced the outcome, but data on composition (in
      particular copper content) are not given.
          Regarding the IMOA-study, it is well-performed but did not show
      reproduction toxicity. It is possible that effects on reproduction might have
      occurred at higher exposure levels, but then it would be difficult to assess
      whether such an effect was caused by the substance or by the occurrence of
      general toxicity, since at the highest exposure levels signs of general toxicity
      (changes in body weight and body weight gain) did occur. Also the study design
      was different from that by Pandey and Singh, since a different rat strain was
      used, and in the IMOA-study sodium molybdate was given in the diet, which
      reflects a more steady exposure, whereas in the Pandey-study the compound was
      given by gavage, which reflects a peak exposure pattern.
          Taking all these considerations and uncertainties into account, the Committee
      decided not to use the data by Pandey and Singh in deriving a health-based
 2    Molybdenum and molybdenum compounds
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<pre>recommended occupational exposure limit. Instead, data of the IMOA-study on
body weight and body weight gain reductions are used.
    BMD-analysis. Data of the IMOA-study on the reduction of body weight and
body weight gain are given in Table 7. In addition, in Annex I, data are shown,
which showed statistically significant differences compared to controls, and from
which a BMDL could be calculated. The BMDL is expressed as the 95% lower
confidence limit of the BMD that corresponds with a decrease in body weight of
10% due to exposure, compared to the body weight in non-exposed animals*.
The lowest BMDL is used as starting point in deriving an HBR-OEL, namely the
BMDL of 10.9 mg molybdenum/kg bw (reduced body weight gain in male rats).
    Adjustment from oral to inhalation exposure. The BMDL-value should be
adjusted for obtaining a value for inhalation exposure. No quantitative data are
available on inhalation bioavailability of sodium molybdate (and other
molybdenum compounds) in humans and animals (see Section 5.1). Regarding
oral bioavailability, absorption of molybdenum might reach 100% in humans.
Therefore, the Committee uses the worst case assumption that 100% will be
taken up, and will be available, after oral intake and inhalation. In addition, the
Committee uses the formula below to adjust from oral to inhalation exposure
concentration:
    X = (x/y) × (L/A) × oral dose
in which X represents the exposure concentration in mg/m3; x the percentage oral
absorption (100%); y the percentage absorption (100%) after inhalation; L the
body weight (the average weight of control animals during the experiment, 0.48
kg); A the breathing volume of the animals in rest (calculated to be 0.127 m3 in 8
hours); and, oral dose represents the BMDL of 10.9 mg molybdenum/kg bw.
Using this formula, the Committee calculated that the oral BMDL corresponds to
an exposure concentration at 41.20 mg molybdenum/m3 after inhalation.
    HBR-OEL. For the establishment of an HBR-OEL several aspects have to be
considered. One of these aspects is the difference between animals and humans.
The Committee noted that in this case the effects were systemic, and, therefore,
an uncertainty factor of three should be applied. In addition, due to possible
inter-individual differences among people, the Committee is of the opinion that
another uncertainty factor of three is required. Adjusting the BMDL value of
41.20 mg molybdenum/m3 by these two factors, an HBR-OEL for sodium
The Committee uses a de- or increase in body weight of 10% as a default response for calculating a
BMDL.
Hazard assessment                                                                                  83
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<pre>      molybdate is derived of 4.6 mg molybdenum/m3 (rounded off; corresponds to 9.9
      mg sodium molybdate/m3). The HBR-OEL is based on personal inhalable dust
      exposure, measured as an eight-hour time weighted average concentration.
9.2.3 Metallic molybdenum and other molybdenum compounds
      No individual HBR-OELs can be established for metallic molybdenum and
      other molybdenum compounds, due to a lack of data on exposure-response
      relationships for short-term and long-term non-lethal effects, or confounding,
      such as a limited number of animals in study.
          Alternatively, the Committee has considered whether it would be possible to
      recommend an HBR-OEL for soluble and insoluble molybdenum compounds, as
      two separate groups, based on the recommendations made for molybdenum
      trioxide and sodium molybdate. In the literature, it was namely suggested that
      soluble molybdenum compounds would be more toxic than insoluble
      compounds. However, data are not only limited in reporting, but also vary
      considerable regarding study design (e.g., exposure duration, duration of study,
      route of exposure, number of exposure groups, animal species, effect end points).
      This makes comparison between soluble and insoluble compounds very difficult.
      Also part of the data concern mortality, which suggests that relative high
      exposure levels have been used. In conclusion, based on the data presented in
      this report, the Committee is of the opinion that there is insufficient reliable
      information available to propose HBR-OELs for soluble and/or insoluble
      molybdenum compounds as two separate groups.
          In addition, the Committee noted that molybdenum trioxide when absorbed
      by the body, is present in the circulation as molybdate. This might suggest that
      molybdenum trioxide is expected to have the same systemic effects as sodium
      molybdate, and that the health-based recommended occupational exposure limits
      are interchangeable. The Committee, however, is of the opinion that the limits
      cannot be interchanged, because the solubility in water of both compounds differ
      more than a factor of 100 (see Table 2).
9.3   Groups at extra risk
      Since no relevant occupational exposure data are available, no specific groups at
      risk can be identified.
 4    Molybdenum and molybdenum compounds
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<pre>9.4 Health-based recommended occupational exposure limits and
    classifications
    Health-based recommended occupational exposure limits
    The Committee recommends a health-based occupational exposure limit for:
    • Molybdenum trioxide, namely of 0.1 mg molybdenum trioxide/m3
        (= 0.07 mg molybdenum/m3)
    • Sodium molybdate, namely of 9,9 mg sodium molybdate/m3
        (= 4,6 mg molybdenum/m3).
    Based on personal inhalable dust or aerosol exposure, measured as an
    eight-hour time weighted average concentration. The available data are
    insufficient to recommend an HBR-OEL for metallic molybdenum and
    any other molybdenum compounds.
    Classifications
    Regarding carcinogenicity, the Committee recommends classifying molybdenum
    trioxide, in category 2 (‘suspected carcinogen to man’)*. The available data are
    insufficient to evaluate the carcinogenic properties of metallic molybdenum and
    other molybdenum compounds.
    Regarding reproduction toxicity, the Committee recommends classifying sodium
    molybdate and other molybdates in fertility category 2 (‘suspected human
    reproductive toxicant’). The available data on metallic molybdenum or any other
    molybdenum compounds are insufficient to evaluate fertility effects. For the
    same reason, data on molybdenum or any molybdenum compounds are
    insufficient to evaluate developmental toxicity and effects on lactation.
    See Annex F for the classification system.
    Hazard assessment                                                                85
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<pre>6 Molybdenum and molybdenum compounds</pre>

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<pre>hapter 10
       Recommendations for research
       Clear dose-response relationships concerning exposure of workers to
       molybdenum and molybdenum compounds should be examined. Unexposed
       control groups should always be included in the study design. Measurements of
       occupational exposure to molybdenum in air are needed in order to identify
       workers that are at risk and operations that lead to high exposure. Reproduction
       toxic properties of other molybdenum compounds should be further studied.
       Recommendations for research                                                     87
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<pre>8 Molybdenum and molybdenum compounds</pre>

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7 Bedwal RS, Bahuguna A. Zinc, copper and selenium in reproduction. Experientia 1994; 50(7): 626-
  640.
4 Molybdenum and molybdenum compounds
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<pre>8 Fayed AH. Serum and testicular trace element concentration in rabbits at different ages. Biol Trace
  Elem Res 2010; 134(1): 64-67.
9 Wong WY, Flik G, Groenen PM, Swinkels DW, Thomas CM, Copius-Peereboom JH e.a. The impact
  of calcium, magnesium, zinc, and copper in blood and seminal plasma on semen parameters in men.
  Reprod Toxicol 2001; 15(2): 131-136.
0 Al-Saleh E, Nandakumaran M, Al-Shammari M, Al-Harouny A. Maternal-fetal status of copper, iron,
  molybdenum, selenium and zinc in patients with gestational diabetes. J Matern Fetal Neonatal Med
  2004; 16(1): 15-21.
  References                                                                                          95
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<pre>A Request for advice
B The Committee
C The submission letter
D Comments on the public review draft
E Evaluation by the Subcommittee on the classification of carcinogenic
  substances
F Classification of substances with respect to carcinogenicity
G Evaluation by the Subcommittee on the classification of reproductive toxic
  substances
H BMD analysis: inhalation study on pathological respiratory tract effects by
  molybdenum trioxide
  BMD analysis: diet study on body weight effects by sodium molybdate
  Annexes
                                                                              97
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<pre>nnex A
     Request for advice
     In a letter dated October 11, 1993, ref DGA/G/TOS/93/07732A, to, the State
     Secretary of Welfare, Health and Cultural Affairs, the Minister of Social Affairs
     and Employment wrote:
     Some time ago a policy proposal has been formulated, as part of the simplification of the
     governmental advisory structure, to improve the integration of the development of recommendations
     for health based occupation standards and the development of comparable standards for the general
     population. A consequence of this policy proposal is the initiative to transfer the activities of the
     Dutch Expert Committee on Occupational Standards (DECOS) to the Health Council. DECOS has
     been established by ministerial decree of 2 June 1976. Its primary task is to recommend health based
     occupational exposure limits as the first step in the process of establishing Maximal Accepted
     Concentrations (MAC-values) for substances at the work place.
     In an addendum, the Minister detailed his request to the Health Council as
     follows:
     The Health Council should advice the Minister of Social Affairs and Employment on the hygienic
     aspects of his policy to protect workers against exposure to chemicals. Primarily, the Council should
     report on health based recommended exposure limits as a basis for (regulatory) exposure limits for air
     quality at the work place. This implies:
     •    A scientific evaluation of all relevant data on the health effects of exposure to substances using a
          criteria-document that will be made available to the Health Council as part of a specific request
     Request for advice                                                                                        99
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<pre>       for advice. If possible this evaluation should lead to a health based recommended exposure limit,
       or, in the case of genotoxic carcinogens, a ‘exposure versus tumour incidence range’ and a
       calculated concentration in air corresponding with reference tumour incidences of 10-4 and 10-6
       per year.
   •   The evaluation of documents review the basis of occupational exposure limits that have been
       recently established in other countries.
   •   Recommending classifications for substances as part of the occupational hygiene policy of the
       government. In any case this regards the list of carcinogenic substances, for which the
       classification criteria of the Directive of the European Communities of 27 June 1967 (67/548/
       EEG) are used.
   •   Reporting on other subjects that will be specified at a later date.
   In his letter of 14 December 1993, ref U 6102/WP/MK/459, to the Minister of
   Social Affairs and Employment the President of the Health Council agreed to
   establish DECOS as a Committee of the Health Council. The membership of the
   Committee is given in Annex B.
00 Molybdenum and molybdenum compounds
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<pre>nnex B
     The Committee
     •  R.A. Woutersen, chairman
        Professor of Translational Toxicology, Wageningen University, Wageningen,
        and TNO Quality of Life, Zeist
     •  P.J. Boogaard,
        Toxicologist, Shell International BV, The Hague
     •  D.J.J. Heederik
        Professor of Risk assessment in Occupational Epidemiology, Institute for
        Risk Assessment Sciences, Utrecht University
     •  R. Houba
        Occupational Hygienist, The Netherlands Expertise Centre for Occupational
        Respiratory Disorders, Utrecht
     •  H. van Loveren
        Professor of Immunotoxicology, Maastricht University, and National
        Institute for Public Health and the Environment, Bilthoven
     •  G.J. Mulder
        Emeritus Professor of Toxicology, Leiden University, Leiden
     •  T.M. Pal
        Occupational Physician, Netherlands Center for Occupational Diseases,
        Amsterdam
     •  A.H. Piersma
        Professor of Reproductive Toxicology, Utrecht University, and National
        Institute for Public Health and the Environment, Bilthoven
     The Committee                                                                101
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<pre>   •   H.P.J. te Riele
       Professor of Molecular Biology, VU University Amsterdam, and the
       Netherlands Cancer Institute, Amsterdam
   •   I.M.C.M. Rietjens
       Professor of Toxicology, Wageningen University and Research Centre
   •   G.M.H. Swaen
       Epidemiologist, Exponent, the USA
   •   R.C.H. Vermeulen
       Epidemiologist/Environmental Hygienist, Institute for Risk Assessment
       Sciences, Utrecht University
   •   P.B. Wulp
       Occupational Physician, Labour Inspectorate, Groningen
   •   B.P.F.D. Hendrikx, advisor
       Social and Economic Council, The Hague
   •   J.M. Rijnkels, scientific secretary
       The health Council, The Hague
   The Health Council and interests
   Members of Health Council Committees are appointed in a personal capacity
   because of their special expertise in the matters to be addressed. Nonetheless, it
   is precisely because of this expertise that they may also have interests. This in
   itself does not necessarily present an obstacle for membership of a Health
   Council Committee. Transparency regarding possible conflicts of interest is
   nonetheless important, both for the chairperson and members of a Committee
   and for the President of the Health Council. On being invited to join a
   Committee, members are asked to submit a form detailing the functions they
   hold and any other material and immaterial interests which could be relevant for
   the Committee’s work. It is the responsibility of the President of the Health
   Council to assess whether the interests indicated constitute grounds for non-
   appointment. An advisorship will then sometimes make it possible to exploit the
   expertise of the specialist involved. During the inaugural meeting the
   declarations issued are discussed, so that all members of the Committee are
   aware of each other’s possible interests.
02 Molybdenum and molybdenum compounds
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<pre>nnex C
     The submission letter (in English)
     Subject           : Submission of the advisory report molybdenum and
                         molybdenum compounds
     Your Reference    : DGV/MBO/U-932342
     Our reference     : U-7988/JR/fs/459-B69
     Enclosed          :1
     Date              : December 11, 2013
     Dear Minister,
     I hereby submit the advisory report on the effects of occupational exposure to
     molybdenum and molybdenum compounds.
     This advisory report is part of an extensive series in which health-based
     recommended exposure limits are derived for the concentrations of various
     substances in the workplace. The advisory report in question was prepared by the
     Health Council’s Dutch Expert Committee on Occupational Safety (DECOS)
     and assessed by the Standing Committee on Health and the Environment.
     The submission letter (in English)                                               103
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<pre>   I have today sent copies of this advisory report to the State Secretary of
   Infrastructure and the Environment and to the Minister of Health, Welfare and
   Sport, for their consideration.
   Yours sincerely,
   (signed)
   Professor W.A. van Gool,
   President
04 Molybdenum and molybdenum compounds
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<pre>nnex D
     Comments on the public review draft
     A draft of this advisory report was released in 2010 for public review. The
     following organisations and persons have commented on the draft:
     • Mr. J. Lentz, National Institute for Occupational Safety and Health, USA
     • Ms. S. Carey, International Molybdenum Association, UK.
     Based on new data, in 2013 an adjusted draft was released for public review. The
     following organisations and persons have commented on this draft:
     • Ms. S. Carey, International Molybdenum Association, UK.
     The comments and the replies by the Committee can be inspected at the website
     of the Health Council: www.healthcouncil.nl.
     Comments on the public review draft                                              105
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<pre>nnex E
     Evaluation by the Subcommittee on
     the classification of carcinogenic
     substances
     Evaluation of data on carcinogenicity and genotoxicity
     There are no human data on the possible carcinogenic activity of molybdenum
     and molybdenum compounds.
         The US National Toxicology program performed an extensive inhalation
     study in rats and mice concerning the carcinogenic effects of molybdenum
     trioxide.43,56 In male mice, the number of animals with lung tumours was
     statistically significantly increased at the lowest exposure concentration of
     10 mg/m3 compared to controls. This increase, however, was not dose-
     dependent. The incidence of lung tumours (adenomas) in female mice was
     statistically significantly increased as well after exposure to 30 and 100 mg/m3.
     In exposed male and female rats, no statistically significantly increased incidence
     in tumours was observed. Furthermore, the subcommittee noted that rats exposed
     to 30 mg/m3 showed inflammatory changes in the lungs, comparable with the
     effects observed for particles. On the other hand, these inflammatory effects were
     not observed in mice. Overall, the subcommittee concludes that there is limited
     evidence of carcinogenicity of molybdenum trioxide in animals.
         No mutagenic activity was observed for molybdenum trioxide, ammonium
     molybdate and sodium molybdate using in vitro assays. Molybdenum trioxide
     did not show clastogenic effects. In contrast to molybdenum trioxide, ammonium
     molybdate and sodium molybdate showed clastogenic effects, but these were
     minimal, and in one study negative (sodium molybdate). Overall, there is
     Evaluation by the Subcommittee on the classification of carcinogenic substances     107
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<pre>   insufficient evidence that the three molybdenum compounds have genotoxic
   potential. Therefore, the subcommittee is of the opinion that molybdenum
   trioxide, ammonium molybdate and sodium molybdate are probably not
   genotoxic.
   Recommendation for classification
   Based on the available information, the subcommittee is of the opinion that
   molybdenum trioxide is a suspected carcinogen to man, and recommends
   classifying the compound in category 2*.
       The available data on other molybdenum compounds, including metallic
   molybdenum, are insufficient to evaluate the carcinogenic properties of these
   compounds.
   The subcommittee
   •   R.A Woutersen, chairman
       Toxicologic Pathologist, TNO Quality of Life, Zeist; Professor of
       Translational Toxicology, Wageningen University and Research Centre
   •   J. Van Benthem
       Genetic Toxicologist, National Health Institute for Public Health and the
       Environment, Bilthoven
   •   P.J. Boogaard
       Toxicologist, SHELL International BV, The Hague
   •   G.J. Mulder
       Emeritus Professor of Toxicology, Leiden University
   •   Ms M.J.M. Nivard
       Molecular Biologist and Genetic Toxicologist, Leiden University Medical
       Center
   •   G.M.H. Swaen
       Epidemiologist, Dow Benelux NV, Terneuzen
   •   E.J.J. van Zoelen
       Professor of Cell Biology, Radboud University Nijmegen
   •   J.M. Rijnkels, scientific secretary
       Health Council, The Hague
   Date last meeting: June 2011.
   See Annex F for classification system.
08 Molybdenum and molybdenum compounds
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<pre> nnex        F
             Classification of substances with
             respect to carcinogenicity
             The Committee expresses its conclusions in the form of standard phrases:
 ategory      Judgement of the committee (GRGHS)                                    Comparable with EU Category
                                                                                    67/548/EEC         EC No 1272/2008
                                                                                    (before            (as from
                                                                                    12/16/2008         12/16/2008
A             The compound is known to be carcinogenic to humans.                   1                  1A
               • It acts by a stochastic genotoxic mechanism.
               • It acts by a non-stochastic genotoxic mechanism.
               • It acts by a non-genotoxic mechanism.
               • Its potential genotoxicity has been insufficiently investigated.
                 Therefore, it is unclear whether the compound is genotoxic.
B             The compound is presumed to be as carcinogenic to humans.             2                  1B
               • It acts by a stochastic genotoxic mechanism.
               • It acts by a non-stochastic genotoxic mechanism.
               • It acts by a non-genotoxic mechanism.
               • Its potential genotoxicity has been insufficiently investigated.
                 Therefore, it is unclear whether the compound is genotoxic.
              The compound is suspected to be carcinogenic to man.                  3                  2
3)            The available data are insufficient to evaluate the carcinogenic      Not applicable     Not applicable
              properties of the compound.
4)            The compound is probably not carcinogenic to man.                     Not applicable     Not applicable
ource: Health Council of the Netherlands. Guideline to the classification of carcinogenic compounds. The Hague: Health
 ouncil of the Netherlands, 2010; publication no. A10/07E.86
             Classification of substances with respect to carcinogenicity                                              109
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<pre>nnex G
     Evaluation by the Subcommittee on
     the Classification of reproductive
     toxic substances
     Effects on fertility
     In a cross-sectional study, Meeker et al. (2008, 2010) reported reduced sperm
     concentrations, sperm morphology, and serum testosterone levels in men
     exposed to molybdenum. According to the committee, more human studies are
     needed to reach a final conclusion on whether molybdenum is able to affect
     fertility in men. No other human studies are available concerning the effects of
     molybdenum and its compounds on fertility.
         Molybdenum trioxide. In a study by the US National Toxicology Program, in
     rats and mice no statistically significant effects were observed on male fertility
     (sperm counts, concentration of epididymal spermatozoa, decreased epidydimus
     weight) after inhalation of molybdenum trioxide.
         Molybdates. A number of studies were available concerning the effects
     on fertility after oral exposure to molybdates. In a poorly reported study,
     Pandey et al. (2002) demonstrated that oral exposure to sodium molybdate
     decreased the sperm motility and total sperm count in the absence of general
     toxicity (doses applied up to 50 mg/kg bw).73 In addition, untreated pregnant rats
     showed increased implantation loss after mating with treated male rats. In
     another poorly reported study, Jeter et al. (1954) showed that the fertility of male
     rats (decreased number of litters) was decreased after exposure to disodium
     molybdate dihydrate in diets.74 Furthermore, histopathologic examinations
     revealed degeneration of the seminiferous tubules. However, the body weight
     Evaluation by the Subcommittee on the Classification of reproductive toxic substances 111
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<pre>   gain of both male and female rats was statistically significantly decreased over
   the first eleven weeks. IMOA commissioned two animal experiments, in which
   rats were given sodium molybdate dihydrate at doses of up to 20 mg/kg/bw/day
   (28 days) or 60 mg/kg bw/day (90 days). No exposure-related fertility effects
   were observed.52,53
       When female weanlings exposed to sodium molybdate dehydrate were mated
   with untreated male rats, Fungwe et al. (1990) found no effect on pregnancy rate,
   but the oestrus cycle length was statistically significantly prolonged.75 On the
   other hand, no effect on oestrus cycle length of guinea pigs was observed by
   Howell et al. (1993) after oral molybdate treatment.76 Also no changes in the
   oestrus cycles were observed in a study, in which female rats received sodium
   molybdate dihydrate in their diet for 90 days.53
       A possible explanation for the observed adverse effects on sperm quality and
   male fertility could be the lower availability of copper. Molybdenum is known to
   be a copper chelator, which may lead to copper deficiency, as is described in
   cattle (see Chapter 6). Trace elements, such as copper (and zinc) play an essential
   role in spermatogenesis and male fertility.87-89 Lower levels of copper may affect
   spermatogenesis, and thus sperm quality and male fertility, such as is observed in
   some animal studies.
       In conclusion, effects on male fertility were observed in two poorly reported
   studies (Pandey and Singh, 2002; Jeter et al. (1954).84,85 In addition, there are
   indications that exposure to molybdates might affect female fertility (prolonged
   oestrus cycle) in the study of Fungwe et al. (1990). However, these effects were
   not confirmed by Howell et al. (1993) and IMOA (2011). Summarizing, there are
   deficiencies in reporting of the studies but the effects cannot be ignored. Overall,
   there is evidence of fertility effects of molybdates in animals. In addition, a
   human study (Meeker et al., 2008, 2010) gave inconclusive indications for a
   possible effect of molybdate on male fertility. The subcommittee, therefore,
   recommends classifying molybdate compounds in category 2 (‘suspected human
   reproductive toxicant’) for effects on fertility.
       About the effects of exposure to molybdenum trioxide, the subcommittee is
   of the opinion that a lack of appropriate data precludes the assessment of the
   compound for effects on fertility.
   Effects on development
   No human studies concerning the effects of molybdenum compounds on
   development are available.
12 Molybdenum and molybdenum compounds
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<pre>     Six studies in laboratory animals were available concerning the effects on
development after oral exposure to molybdate compounds. Increased number of
resorptions, and decreased foetal weight and foetal length were found in female
Sprague Dawley rats (Fungwe et al. 1990).75 Although these effects were
observed in the presence of maternal toxicity (decreased weight gain of the
dams), the committee agrees with the authors that the decreased maternal weight
is probably due to weight loss of the progeny. In a poorly reported three-
generation-study with only one exposure group, CD-mice showed an increase in
early deaths among the progeny of the F1-generation and F3-generation
(Schroeder 1971).78 In the F3-generation, increased number of pairs without
offspring, reduced number of litter, increased number of litters with only
stillbirths and underdeveloped pups were observed in the presence of increased
mortalities of the dams. Jeter et al. (1954) found a decreased weight gain of the
pups during lactation in Long Evans rats.74 However, it was not clear whether
these effects were a result of decreased milk production or due to direct exposure
via the drinking water. Finally, in a poorly reported study, Howell et al. (1993)
found developmental effects (aborted and resorbing fetuses) in the presence of
severe maternal toxicity (death).76 In two animal studies, sodium molybdate
dihydrate did not cause maternal toxicity, nor fertility effects and malformations
in the progeny. The compound was given via the diet at doses up to 40 mg
molybdenum/kg bw/day during gestation days 6 and 20.72,77
     In conclusion, the subcommittee is of the opinion that the study of
Fungwe et al. (1990) gives some indications for effects on the development of
the progeny. However, this study is not sufficient for a classification. The
remaining studies do not support the findings of Fungwe et al. (1990) as the
observed effects were found in the presence of maternal toxicity. No final
conclusion can be made from the two studies in which no maternal and
developmental effects were observed, since, for classification and labelling, this
indicates that the chosen exposure levels were too low to induce adverse health
effects. Therefore the subcommittee recommends not classifying molybdate
compounds for effects on development due to a lack of appropriate data.
     With respect to the effects of exposure to molybdenum trioxide, the
subcommittee is of the opinion that a lack of appropriate data precludes the
assessment of molybdenum trioxide for effects on development.
Effects on lactation
Aquilio et al. (1996) detected in human breast milk molybdenum levels of
6.8 µg/L.29 Another study by Al-Saleh et al. (2004), levels of 13±1 µg/L in
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<pre>   maternal venous blood at delivery are reported (N=17).90 This molybdenum
   concentration was below the calculated safe level of 25 µg per litre breast milk.
   Therefore, the subcommittee concludes that the available data do not indicate
   that a label for the effects on lactation is warranted and recommends no labelling.
   Proposed classification for effects on fertility
   For molybdate compounds: the subcommittee recommends classifying
   molybdate compounds in category 2 (suspected human reproductive toxicant),
   and labelling with H361f (suspected of damaging fertility).
   For molybdenum trioxide: lack of appropriate data precludes the assessment of
   molybdenum trioxide for effects on fertility
   Proposed classification for developmental toxicity
   Lack of appropriate data precludes the assessment of molybdenum compounds
   (molybdate compounds and molybdenum trioxide) for effects on development
   Proposed labelling for effects during lactation
   Lack of appropriate data precludes the assessment of molybdenum compounds
   (molybdate compounds and molybdenum trioxide) for effects during lactation
   The Subcommittee
   •   A.H. Piersma, chairman
       Professor of Reproductive and Developmental Toxicology, National Institute
       for Public Health and the Environment, Bilthoven
   •   D. Lindhout
       Professor of Medical Genetics, Paediatrician (not practising), Clinical
       Geneticist, University Medical Centre, Utrecht
   •   N. Roeleveld
       Reproductive Eepidemiologist, Radboud University Nijmegen Medical
       Centre, Nijmegen
   •   J.G. Theuns-van Vliet
       reproductive toxicologist, TNO Triskelion BV, Zeist
   •   D.H. Waalkens-Berendsen
       Reproductive Toxicologist, Zeist
14 Molybdenum and molybdenum compounds
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<pre>•   P.J.J.M. Weterings
    Toxicologist, Weterings Consultancy BV, Rosmalen
•   J.T.J. Stouten, scientific secretary
    Health Council of the Netherlands, The Hague
•   J.M. Rijnkels, scientific secretary
    Health Council of the Netherlands, Den Haag
Date last meeting: September 2013.
Notice on classification
The classification is based on the evaluation of published human and animal
studies concerning adverse effects with respect to fertility and development as
well as lactation of the above mentioned compound.
Classification for reproduction (fertility (F) and development (D)):
Category 1                         Known or presumed human reproductive toxicant (H360(F/D))
   Category 1A                     Known human reproductive toxicant
   Category 1B                     Presumed human reproductive toxicant
Category 2                         Suspected human reproductive toxicant (H361(f/d))
No classification for effects on fertility or development
Classification for lactation:
                                   Effects on or via lactation (H362)
                                   No labelling for lactation
The classification and labelling of substances is performed according to the
guidelines of the European Union (Regulation (EC) 1272/2008). 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 subcommittee 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.
• Adverse effects in a reproductive study, occurring without reporting the
    parental or maternal toxicity, may lead to a classification other than category
Evaluation by the Subcommittee on the Classification of reproductive toxic substances 115
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<pre>       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.
   •   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.
16 Molybdenum and molybdenum compounds
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<pre>nnex H
     BMD-analysis: inhalation study on
     pathological respiratory tract effects
     by molybdenum trioxide
     Software        : US EPA BMDS version 2.1.1.
     Model type      : Dichotomous, restricted models.
     BMR, risk type  : 10%, extra risk (default value for dichotomous
                       (quantal) animal data).
     BMDL            : Lowest 95% confidence interval of the BMD.
     Model fitting   : Based on visual inspection of graphs, judgment on
                       BMD-BMDL deviation (model accepted at a deviation
                       of < factor 10), and calculated differences in log-likelihoods
     Data source     : NTP (1997) and Chan et al. (1998).43,56
                       Data only analysed using statistical difference (p<0.05)
                       between exposed and control group.
     Exposure        : 6 hours/day, 5 days/week for 105 weeks;
                       inhalation of molybdenum trioxide.
     Effects         : Pathological lesions in respiratory tract of rats and mice of
                       both sexes.
     BMD-analysis: inhalation study on pathological respiratory tract effects by molybdenum
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<pre>                                                      0           10          30             100    BMDLa
                                                      mg/m3       mg/m3       mg/m3          mg/m3  mg/m3
Male F344/N rats (cases/group size)
 Lung: alveolus chronic inflammation                    2/50       3/50       25/50*         47/50*  9.67
 Larynx: epiglottis, squamous metaplasia                0/49      11/48*      16/49*         39/49*  3.33
 emale F344/N rats (cases/group size)
 Lung: alveolus chronic inflammation                  14/50       13/50       43/50*         49/50*  6.58
 Nose: respiratory epithel. hyaline degeneration        1/48      13/49*      50/50*         50/50*  7.20
 Larynx: epiglottis, squamous metaplasia                0/49      18/49*      29/49*         49/50*  1.87
Male B6C3F1 mice (cases/group size)
 Lung: alveolar/bronchiolar epithelium metaplasia       0/50      32/50*      36/49*         49/50*  0.52
 Larynx: epiglottis, squamous metaplasia                0/50      26/49*      37/48*         49/50*  0.70
 emale B6C3F1 mice (cases/group size)
 Lung: alveolar/bronchiolar epithelium metaplasia       2/50      26/50*      39/49*         46/49*  0.71
 Lung: adenoma/carcinoma                                3/50       6/50        8/49          15/49* 18.00
 Larynx: epiglottis, squamous metaplasia                1/49      36/50*      43/49*         49/50*  0.29
  p<0.01.
    Model of choice: Loglogistic.
             Graph BMD-analysis: larynx female B6C3F11 mice, squamous metaplasia epiglottis.
 18          Molybdenum and molybdenum compounds
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<pre>nnex I
     BMD-analysis: diet study on body
     weight effects by sodium molybdate
     Software        : US EPA BMDS version 2.1.1.
     Model type      : Continuous, restricted constant variance models, lognormal
                       distribution.
     BMR, risk type  : 10% response, relative deviation (default for changes in body
                       weight).
     BMDL            : Lowest 95% confidence interval of the BMD.
     Model fitting   : Based on visual inspection of graphs, judgment on model
                       deviation (BMD-values of the models Exponential5 and Hill
                       must be close), and judgment on BMD-BMDL deviation
                       (model accepted at a deviation of < factor 10).
     Data source     : IMOA (2011).53 Data only analysed using statistical
                       difference (p<0.05) between exposed and control groups.
     Exposure        : Daily for 90 days; oral administration in the diet of sodium
                       molybdate dihydrate.
     Effects         : Effects on body weight and body weight gain in male rats.
                       Data given below concern weights and weight gains at the
                       end of the exposure period.
     BMD-analysis: diet study on body weight effects by sodium molybdate             119
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<pre>                      0                  5                 17              60               Lowest         Model of
                      mg /kg bw          mg/kg bw          mg/kg bw        mg/kg bw         BMDL           choicea
                                                                                            mg/kg bw
Mean body weight (grams ± SD)
                      587.1 ± 50.3       583.9 ± 41.4      576.3 ± 47.9    498.5 ± 32.9*    26.0           Exp4
Mean body weight changes from baseline (grams ± SD)
                      246.3 ± 38.9       242.6 ± 37.6      240.1 ±33.9     164.4 ± 30.1*    10.9           Exp4
 p<0.05.
    Exp4 corresponds to Exponential Model 4. Model of choice based on lowest BMDL-value. Group size: 0, 5, 17, and
    60 mg/kg bw, n = 20, 10, 10 and 19, respectively; concentration concerns mg molybdenum/kg bw.
 20        Molybdenum and molybdenum 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 reports 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 and              realise significant                 which carry certain
opportunities?                        health benefits?                    health risks?
Environmental health                  Healthy working                     Innovation and
Which environmental                   conditions                          the knowledge
influences could have                 How can employees                   infrastructure
a positive or negative                be protected against                Before we can harvest
effect on health?                     working conditions                  knowledge in the
                                      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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