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

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<pre>Aan de Staatssecretaris van Sociale Zaken en Werkgelegenheid
Onderwerp       :  aanbieding advies
Uw kenmerk      :  DGV/BMO-U-932542
Ons kenmerk     :  U 949/AB/jt/543-Z2
Bijlagen        :  1
Datum           :  3 mei 2000
Mijnheer de Staatssecretaris,
Bij brief van 3 december 1993, nr. DGV/BMO-U-932542, verzocht de Staatssecretaris
van Welzijn, Volksgezondheid en Cultuur namens de Minister van Sociale Zaken en
Werkgelegenheid om naast het afleiden van gezondheidskundige advieswaarden ook te
adviseren over andere onderwerpen ten behoeve van de bescherming van beroepsmatig
aan stoffen blootgestelde personen. In 1995 heeft de Staatssecretaris van Sociale Zaken
en Werkgelegenheid besloten tot het opstellen van een zogenaamde niet-limitatieve repro-
tox-lijst. Op deze lijst komen stoffen die volgens de richtlijnen van de Europese Unie in-
gedeeld moeten worden in categorie 1 of 2 wat betreft effecten op de voortplanting. De
Gezondheidsraad is verzocht om voor stoffen een classificatie volgens de EU-criteria
voor te stellen.
In 1996 heb ik hiervoor de Commissie Reproductietoxische stoffen ingesteld.
Hierbij bied ik u - gehoord de Beraadsgroep Gezondheid en Omgeving - de publikatie
van de commissie aan over kwik en kwikverbindingen. Deze publikatie heb ik heden ter
kennisname aan de Minister van Volksgezondheid Welzijn en Sport en aan de Minister
van Volkshuisvesting, Ruimtelijke Ordening en Milieubeheer gestuurd.
Hoogachtend,
w.g.
prof. dr JJ Sixma
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<pre>Mercury and its compounds
Evaluation of the effects on reproduction, recommendation for classification
Committee for Compounds toxic to reproduction,
a committee of the Health Council of the Netherlands
to
the Minister and State Secretary of Social Affairs and Employment
No. 2000/05OSH, The Hague, 3 May 2000
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<pre>Preferred citation:
Health Council of the Netherlands: Committee for Compounds toxic to reproduction.
Mercury and its compounds; Evaluation of the effects on reproduction, recommendation
for classification. The Hague: Health Council of the Netherlands, 2000; publication no.
2000/05OSH.
all rights reserved
ISBN: 90-5549-314-7
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<pre>    Contents
    Samenvatting 7
    Executive summary 9
1   Scope 11
1.1 Background 11
1.2 Committee and procedure 11
1.3 Additional considerations 12
1.4 Labelling for lactation 13
1.5 Data 14
1.6 Presentation of conclusions 14
1.7 Final remark 14
2   Mercury (metallic) 15
2.1 Introduction 15
2.2 Human studies 15
2.3 Animal studies 17
2.4 Overall conclusions 19
3   Methylmercury 21
3.1 Introduction 21
3.2 Human studies 21
    Contents                       5
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<pre>3.3 Animal studies 23
3.4 Overall conclusion 24
4   Phenylmercury acetate 26
4.1 Introduction 26
4.2 Human studies 26
4.3 Animal studies 27
4.4 Overall conclusion 28
5   Mercuric chloride and Mercuric nitrate 29
5.1 Introduction 29
5.2 Human studies 30
5.3 Animal studies 30
5.4 Overall conclusion 32
6   Lactation (organic and inorganic mercury) 33
6.1 Human studies 33
6.2 Animal studies 34
6.3 Overall conclusion 36
    References 38
    Annexes 43
A   The committee 44
B   Comments on the public draft 46
C   Directive (93/21/EEC) of the European Community 47
D   Calculation safe levels of mercury in (human) breast milk 53
E   Abbreviations 55
    Contents                                                     6
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<pre>Samenvatting
Op verzoek van de Minister van Sociale Zaken en Werkgelegenheid beoordeelt de Ge-
zondheidsraad de effecten op de reproductie van stoffen waaraan mensen tijdens de be-
roepsuitoefening kunnen worden blootgesteld. De Commissie Reproductietoxische
stoffen, een commissie van de Raad, adviseert een classificatie van reproductietoxische
stoffen volgens Richtlijn 93/21/EEC van de Europese Unie. In het voorliggende rapport
heeft de commissie kwik en kwikverbindingen onder de loep genomen.
De aanbevelingen van de commissie zijn:
    Metallisch kwik
      voor effecten op de fertiliteit adviseert de commissie om metallisch kwik niet te
      classificeren wegens onvoldoende gegevens
      voor effecten op de ontwikkeling adviseert de commissie metallisch kwik in catego-
      rie 2 te classificeren (stoffen die dienen te worden beschouwd alsof zij bij de mens
      ontwikkelingsstoornissen veroorzaken) en met R61 (kan het ongeboren kind scha-
      den) te kenmerken
      voor effecten tijdens de lactatie is de commissie van mening dat er onvoldoende ge-
      gevens zijn om metallisch kwik te kenmerken.
    Methylkwik
      voor effecten op de fertiliteit adviseert de commissie om methylkwik niet te classifi-
      ceren wegens onvoldoende gegevens
Samenvatting                                                                                 7
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<pre>    voor effecten op de ontwikkeling adviseert de commissie methylkwik in categorie 1
    te classificeren (stoffen waarvan bekend is dat zij bij de mens ontwikkelingsstoor-
    nissen veroorzaken) en met R61 (kan het ongeboren kind schaden) te kenmerken
    voor effecten tijdens de lactatie adviseert de commissie om methylkwik met R64
    (kan schadelijk zijn via de borstvoeding) te kenmerken.
   Fenylkwikacetaat
    voor effecten op de fertiliteit adviseert de commissie om fenylkwikacetaat niet te
    classificeren wegens onvoldoende gegevens
    voor effecten op de ontwikkeling adviseert de commissie om fenylkwikacetaat niet
    te classificeren wegens onvoldoende gegevens
    voor effecten tijdens de lactatie is de commissie van mening dat er onvoldoende ge-
    gevens zijn om fenylkwikacetaat te kenmerken.
   Kwikchloride/kwiknitraat
    voor effecten op de fertiliteit adviseert de commissie om kwikchloride/ kwiknitraat
    niet te classificeren wegens onvoldoende gegevens
    voor effecten op de ontwikkeling adviseert de commissie om kwikchloride/kwikni-
    traat niet te classificeren wegens onvoldoende gegevens
    voor effecten tijdens de lactatie is de commissie van mening dat er onvoldoende ge-
    gevens zijn om kwikchloride/kwiknitraat te kenmerken.
Samenvatting                                                                            8
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<pre>Executive summary
On request of the Minister of Social Affairs and Employment, the Health Council of the
Netherlands evaluates the effects on the reproduction of substances at the workplace.
The Health Council’s Committee for Compounds Toxic to Reproduction recommends to
classify compounds toxic to reproduction according to the Directive 93/21/EEC of the
European Union. In the present report the committee has reviewed mercury and its com-
pounds.
The committee’s recommendations are:
    Mercury (metallic)
      for effects on fertility, the committee recommends no classification of metallic mer-
      cury, due to lack of data
      for developmental toxicity, the committee recommends to classify metallic mercury
      in category 2 (substances which should be regarded as if they impair fertility in
      humans) and to label metallic mercury with R61
      the committee is of the opinion that a lack of appropriate data precludes the label-
      ling of metallic mercury for effects during lactation.
    methylmercury
      for effects on fertility, the committee recommends no classification of methylmer-
      cury, due to lack of data
      for developmental toxicity, the committee recommends to classify methylmercury
      in category 1 (substances known to cause developmental toxicity in humans) and
      labelled with R61
Executive summary                                                                           9
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<pre>    for effects during lactation, the committee recommends that methylmercury should
    be labelled with R64 (may cause harm to breastfed babies).
   phenylmercury acetate
    for effects on fertility, the committee recommends no classification of phenylmer-
    cury acetate, due to lack of data
    for developmental toxicity, the committee recommends no classification of phenyl-
    mercury acetat, due to lack of data
    the committee is of the opinion that a lack of appropriate data precludes the label-
    ling of phenylmercury acetate for effects during lactation.
   mercuric chloride/mercuric nitrate
    for effects on fertility, the committee recommends no classification of mercuric
    chloride/mercuric nitrate, due to lack of data
    for developmental toxicity, the committee recommends no classification of mercu-
    ric chloride/mercuric nitrate, due to lack of data
    the committee is of the opinion that a lack of appropriate data precludes the label-
    ling of mercuric chloride and nitrate for effects during lactation.
Executive summary                                                                        10
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<pre>Chapter 1
        Scope
1.1     Background
        As a result of the Dutch regulation on registration of compounds toxic to reproduction
        that came into force on 1 April 1995, the Minister of Social Affairs and Employment re-
        quested the Health Council of the Netherlands to classify compounds toxic to reproduc-
        tion. The classification is performed according to the guidelines of the European Union
        (Directive 93/21/EEC) by the Health Council’s Committee for Compounds Toxic to Re-
        production. The committee’s advice on the classification will be applied by the Ministry
        of Social Affairs and Employment to extend the existing list of compounds classified as
        toxic to reproduction (class 1 and 2) of the European Union.
1.2     Committee and procedure
        The present document contains the classification of mercury and its compounds by the
        Health Council’s Committee for Compounds Toxic to Reproduction. The committee dis-
        tinguishes four different groups of mercury compounds in this report: (I) Metallic mer-
        cury (chapter 2); (II) Methyl mercury (chapter 3); (III) phenylmercury acetate (chapter
        4); (IV) Mercury chloride and mercury nitrate (chapter 5). In chapter 6, the effects of the
        different mercury compounds during lactation are described.
             The members of the committee are listed in Annex A. The first draft of this report
        was prepared by Mrs ir IDH Waalkens-Berendsen at the Department of Neurotoxico-
        logy and Reproduction Toxicology of the TNO Nutrition and Food Research Institute,
        Scope                                                                                       11
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<pre>    Zeist, The Netherlands, by contract with the Ministry of Social Affairs and Employment.
    The classification is based on the evaluation of published human and animal studies con-
    cerning adverse effects with respect to fertility and development and lactation of the
    above mentioned compound.
    Classification and labelling was performed according to the guidelines of the European
    Union listed in Annex C.
     Classification for fertility and development:
     Category 1      Substances known to impair fertility in humans (R60)
                     Substances known to cause developmental toxicity in humans (R61)
     Category 2      Substances which should be regarded as if they impair fertility in humans (R60)
                     Substances which should be regarded as if they cause developmental toxicity in humans
                     (R61)
     Category 3      Substances which cause concern for human fertility (R62)
                     Substances which cause concern for humans owing to possible developmental toxic ef-
                     fects (R63)
     No classification for effects on fertility or development
     Labelling for lactation:
                     May cause harm to breastfed babies (R64)
                     No labelling for lactation
    In December 1999, the President of the Health Council released a draft of the report for
    public review. The individuals and organisations that commented on the draft report are
    listed in Annex B. The committee has taken these comments into account in deciding on
    the final version of the report.
1.3 Additional considerations
    The classification of compounds toxic to reproduction on the basis of the Directive
    93/21/EEC is ultimately dependent on an integrated assessment of the nature of all pa-
    rental and developmental effects observed, their specificity and adversity, and the dosa-
    ges at which the various effects occur. The directive necessarily leaves room for
    interpretation, dependent on the specific data set under consideration. In the process of
    using the directive, the committee has agreed upon a number of additional considera-
    tions.
         If there is sufficient evidence to establish a causal relationship between human expo-
         sure to the substance and impaired fertility or subsequent developmental toxic ef-
    Scope                                                                                                  12
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<pre>         fects in the progeny, the compound will be classified in category 1, irrespective the
         general toxic effects (see Annex C, 4.2.3.1 category 1).
         Adverse effects in a reproductive or developmental study, in the absence of data on
         parental toxicity, occurring at dose levels which cause severe toxicity in other stu-
         dies, need not necessarily lead to a category 2 classification.
         If, after prenatal exposure, small reversible changes in foetal growth and in skeletal
         development (e.g. wavy ribs, short rib XIII, incomplete ossification) in offspring oc-
         cur in a higher incidence than in the control group in the absence of maternal effects,
         the substance will be classified in category 3 for developmental toxicity. If these ef-
         fects occur in the presence of maternal toxicity, they will be considered as a conse-
         quence of this and therefore the substance will not be classified for developmental
         toxicity (see Annex C, 4.2.3.3 developmental toxicity final paragraph).
         Clear adverse reproductive effects will not be disregarded on the basis of reversibili-
         ty per se.
         Effects on sex organs in a general toxicity study (e.g. in a subchronic or chronic
         toxicity study) may warrant classification for fertility.
         The committee not only uses guideline studies (studies performed according to
         OECD standard protocols*) for the classification of compounds, but non-guideline
         studies are taken into consideration as well.
1.4 Labelling for lactation
    The recommendation for labelling substances for effects during lactation is also based on
    Directive 93/21/EEC. The Directive defines that substances which are absorbed by wo-
    men and may interfere with lactation or which may be present (including metabolites) in
    breast milk in amounts sufficient to cause concern for the health of a breastfed child,
    should be labelled with R64. Unlike the classification of substances for fertility and de-
    velopmental effects, which is based on a hazard identification only (largely independent
    of dosage), the labelling for effects during lactation is based on a risk characterisation
    and therefore also includes consideration of the level of exposure of the breastfed child.
         Consequently, a substance should be labelled for effects during lactation when it is
    likely that the substance would be present in breast milk in potentially toxic levels. The
    committee considers a compound as potentially toxic to the breastfed child when exposu-
    re to this compound via the milk results in an intake exceeding an exposure limit for the
    general population, e.g. the acceptable daily intake (ADI).
*   Organisation for Economic Cooperation and Development
    Scope                                                                                        13
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<pre>1.5 Data
    Literature searches were conducted in the on-line databases Toxline and Medline, star-
    ting from 1966 up 1995. Literature was selected primarily on the basis of the text of the
    abstracts. Publications cited in the selected articles, but not selected during the primary
    search, were reviewed if considered appropriate. In addition, handbooks and a collection
    of most recent reviews were consulted. References are divided in literature cited and lite-
    rature consulted but not cited. Before finalising the public draft the committee performed
    an additional literature search in Medline and Toxline for the period 1995 to 1999. The
    results of this search were no reason for the committee to adjust the recommendations.
         The committee chose to describe human and animal studies in the text, starting with
    review articles. Of each study the quality of the study design (performed according to in-
    ternationally acknowledged guidelines) and the quality of documentation are considered.
1.6 Presentation of conclusions
    The classification is given with key effects, species and references specified. In case a
    substance is not classified as toxic to reproduction, one of two reasons is given:
         Lack of appropriate data preclude assessment of the compound for reproductive
         toxicity.
         Sufficient data show that no classification for toxic to reproduction is indicated.
1.7 Final remark
    The classification of compounds is based on hazard evaluation* only, which is one of a
    series of elements guiding the risk evaluation process. The committee emphasises that
    for derivation of health based occupational exposure limits these classifications should
    be placed in a wider context. For a comprehensive risk evaluation, hazard evaluation
    should be combined with dose-response assessment, human risk characterisation, human
    exposure assessment and recommendations of other organisations.
*   for definitions see Tox95
    Scope                                                                                       14
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<pre>Chapter 2
        Mercury (metallic)
2.1     Introduction
         Name               :   mercury
         CAS-no             :   7439-97-6
         Use                :   as dental amalgam, in common consumer products such as light bulbs, baro-
                                meters, thermometers and other medical equipment
         Atom weight        :   200.59
         Chem formula       :   Hg
2.2     Human studies
2.2.1   Fertility
        Lauwerys et al. (1985) examined the fertility of Belgian male workers employed in a
        zinc-mercury factory, in a chloralkali plant or in plants manufacturing electrical equip-
        ment (103 workers in total, versus 101 controls) (Lau85). No adverse effects were detec-
        ted on male fertility, expressed as the difference between expected and observed number
        of children.
             Rowland et al. (1994) examined the reproductive effects in 296 female dental assis-
        tants (versus 111 controls) in California USA. after exposure to metallic mercury va-
        pour (Row94). Preparation of a high number of amalgams per week and/or poor
        Mercury (metallic)                                                                                15
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<pre>      hygienic working conditions were associated with effects on fertility. However, in case
      of a low number of amalgams and/or good hygienic circumstances, fertility was even
      better than in the controls, which was considered an unaccountable difference.
          Alcer et al. (1989) examined the effects of long-term exposure to elemental mercury
      at an Energy plant in Michigan USA. in 241 male workers (versus 254 controls)
      (Alc89). No effects were detected on the total number of pregnancies, number of live
      born children, congenital abnormalities and illnesses; a difference was found in the num-
      ber of miscarriages, which was already elevated in the “exposed” group, before actual
      exposure started.
          The rate of spontaneous abortions among wives of 152 workers in a chloralkali
      plant occupationally exposed to mercury vapour was compared with the rate among the
      wives of 374 controls in the same plant (Cor91). As an increased number of abortions
      was observed in the exposed group in the presence of confounding factors such as smo-
      king and alcohol consumption, the committee concluded that this study did not provide
      information on causality.
2.2.2 Developmental studies
      In a preliminary study, Sikorski et al. (1987) examined the reproductive effects of expo-
      sure to metallic mercury in Polish female dentists and dental assistants (81 females, ver-
      sus 34 controls) (Sik87). An increase in spontaneous abortions, stillbirths and congenital
      malformations (a.o. 5 babies with spina bifida) was observed as well as an increase in
      menstrual disorders, which significantly correlated with the number of years active in the
      dental profession. Larsson (1995) discussed the validity of the original publication of
      Sikorski and commented or cited the following comments made by others: “The base po-
      pulation from which the 81 study subjects, or 34 controls, were selected, was not defi-
      ned. Exposed and control subjects were not matched according to age and medical
      history” (Lar95). Exposure to mercury was measured in scalp or pubic hair; this deter-
      mination was performed at examination in 1985 and 1986 and not at the time of preg-
      nancy (children with spina bifida were born in 1968, 1972, 1977, 1980 and 1982). In the
      opinion of Larsson (Lar95), the study of Sikorski contained an erroneous interpretation
      of results and distortion of conclusions. The committee supports these conclusions of
      Larsson.
          Alcer et al. (1989) examined the effects of long-term exposure to elemental mercury
      at an Energy plant in Michigan USA., in 241 male workers (versus 254 controls)
      (Alc89). No effects were detected on the total number of pregnancies, number of live
      born children and congenital abnormalities.
          Ericson and Källén (1989) examined the reproductive effects of exposure to metallic
      mercury in Swedish female dentists, dental assistants and dental technicians (Eri89). No
      Mercury (metallic)                                                                         16
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<pre>      adverse effects were found as to spontaneous abortions, birth weight, congenital malfor-
      mations or infant survival. No information was presented about the actual exposure le-
      vel.
2.2.3 Lactation
      See chapter 6.
2.3   Animal studies
2.3.1 Fertility
      Baranski and Szymczyk (1973 cited in: Barlow and Sullivan 1982) exposed groups of
      24 female rats to mercury vapour (0 and 2.5 mg/m3 for 6h/day for 21 days) (Bar 73). A
      significant increase in the length of the oestrous cycle in mercury-exposed rats, from a
      mean of 4.3 days before exposure to a mean of 6.7 days at the end of exposure was
      found. Oestrous cycle duration in control animals increased from 4.5 to 5.1 days during
      the same period. The authors also exposed female rats to 0 or 2.5 mg/m3 metallic mercu-
      ry vapour, 6h/day for 6-8 weeks before mating. All 18 treated and 23 control females
      that did mate became pregnant. The total numbers of treated and untreated females was
      not reported. The occurrence of slight general toxicity was presented as a non significant
      reduction in mean body weight.
2.3.2 Developmental toxicity
      Baranski and Szymczyk (1973 cited in: Barlow and Sullivan 1982) exposed female rats
      to 0 or 2.5 mg/m3 metallic mercury vapour for 6h/day for 6-8 weeks before mating, but
      not during pregnancy (Bar73). A non significant reduction in mean maternal body
      weight was recorded. There were no effects on the mean number of pups/litter or on the
      number of live pups/litter at birth. However, postnatal mortality was significantly incre-
      ased, particularly during the first 4 days of life when 26% of the pups from the mercury-
      exposed group died compared with 1% in the control group. At 2 months of age, off-
      spring body and organ weights were determined: male offspring weights were unaffec-
      ted, but female offspring from the mercury-exposed group had significantly lower kidney
      and liver weights and significantly higher ovary weights than controls.
           They also exposed groups of 12 female rats to 0 or 2.5 mg/m3 metallic mercury va-
      pour by inhalation for 6h/day for 3 weeks before pregnancy and again on days 7-20 of
      pregnancy, and allowed them to litter. Maternal weight gain was reduced, but not signifi-
      cantly, in the mercury-exposed group. There were no significant effects on pregnancy ra-
      Mercury (metallic)                                                                         17
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<pre>      te, number of litters born, or on total litter size (i.e. live and dead pups) at birth.
      However, mean live litter size at birth was reduced significantly to 7.6 pups in the mer-
      cury-exposed group compared with 9.6 pups in controls. In the first 4 days of life 96%
      of pups from the exposed group died; none survived to weaning (Bar73).
           In a further experiment, groups of 8 female rats were similarly exposed, and killed
      on gestation day 20. A significant reduction in live litter size was confirmed, and found
      to be due to a decrease in the number of implantations, reflecting a decrease in ovulation
      and/or increase in pre-implantation losses.
           Berlin et al. (1992) exposed 10 pregnant squirrel monkeys to mercury vapour at a
      concentration of 1 mg/m3, beginning at week 3 to week 7 of gestation and continuing to
      the termination of pregnancy (approximately week 22) (Ber92). One monkey was ex-
      posed to 24 h/day, 5 days/week, 4 monkeys were exposed for 7h/day, 5 days/week and 5
      monkeys were exposed for 4 h/day, 5 days/week. Ten unexposed monkeys were assigned
      as controls in addition to historical controls. There was a 60% incidence of abnormal
      pregnancies in the exposed monkeys compared to 5% in the breeding colony. The inci-
      dence of abortion and neonatal mortality showed a dose-related increase. A decrease in
      birth weight was also observed. Histopathological examination of the brain of the off-
      spring showed a number of changes. Maternal toxicity was not reported.
           The effect of neonatal exposure of rats to mercury vapour at a concentration 0.05
      mg/m3, 1 h or 4 h from postnatal days 11-17, on the behaviour in adulthood were studied
      by Fredriksson et al. (1992) (Fre92). Tests for spontaneous motor activity were perfor-
      med at the ages of 2 and 4 months. Rats exposed for 4 h/day showed a marked increase
      in locomotion and total activity but a decrease for rearing when tested at 2 months of
      age. At 4 months of age these rats showed marked hypoactivity with respect to all three
      variables. Rats exposed for 1h/day showed no significant differences at 2 months com-
      pared to controls. However, at the age of 4 months the same pattern (increase in varia-
      bles locomotion and total activity but a decrease for rearing) already noticed in the
      4h/day group at 2 months was observed in this group. In the spatial learning tasks ap-
      plied, neonatally exposed pups showed a retarded acquisition to the radial maze, while
      there was no difference compared to controls in the circular swim maze.
           The behaviour of offspring of squirrel monkeys exposed to 0.5 or 1 mg/m3 of mercu-
      ry vapour during the last 2/3 part or more of gestation were studied by Newland et al
      1996 (New96). Persistent behavioural effects of prenatal mercury vapour exposure in-
      cluded instability in lever-press durations and steady-state performance under concurrent
      schedules of reinforcement as well as aberrant transitions.
2.3.3 Lactation
      See chapter 6.
      Mercury (metallic)                                                                         18
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<pre>2.4 Overall conclusions
    Male fertility man was not affected in any of the human studies (Lau85, Alc89). The ef-
    fects described by Cordier et al. 1991 on spontaneous abortion after paternal exposure
    did not provide evidence of a causal relationship. The data on human female fertility and
    reproduction were ambiguous: Sikorski et al. 1987 and Rowland et al. 1994 reported ef-
    fects on fertility (disturbance of the menstrual cycle) and reproduction (spontaneous
    abortion, perinatal death), whereas Ericson and Kallèn 1989 did not observe effects in
    their Swedish epidemiological study among dental workers. The committee is of the
    opinion that the differences between these studies might be caused by a lack of control
    for age, social status, diet, smoking, selection bias and quality of the working conditions
    which influence the actual exposure to metallic mercury vapour.
        The effects found on fertility in rats (Baranski and Szymczyk 1973) were found at
    high concentrations at which general toxicity may be assumed.
        In conclusion, the committee recommends not to classify metallic mercury with res-
    pect to effects on fertility because of a lack of appropriate data.
    Data from human studies for developmental effects provided no basis for classification
    of metallic mercury.
        Exposure of rats to metallic vapour before mating and during gestation resulted in
    an increased pre-implantation loss, reduced number of live pups at birth and in postnatal
    mortality in the absence of clear maternal toxicity (Bar73). In squirrel monkeys (Ber92)
    abnormal pregnancies, increased number of abortions, and neonatal mortality were
    found after exposure to high concentrations of mercury vapour at which general toxicity
    may be assumed. Neonatal exposure of rats (Fre92) and prenatal exposure in squirrel
    monkeys (New96) resulted in persistent behavioural changes.
        In conclusion, with respect to effects on development the committee recommends to
    classify metallic mercury in category 2 (substances that should be regarded as if they
    cause developmental toxicity in humans) and to label the compound with R61 (may
    cause harm to the unborn child).
    Proposed classification for fertility
    Lack of appropriate data precludes assessment of the metallic mercury for fertility.
    Proposed classification for developmental toxicity
    Category 2, R 61.
    Mercury (metallic)                                                                          19
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<pre>Proposed labelling for effects during lactation
See chapter 6.
Mercury (metallic)                              20
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<pre>Chapter 3
        Methylmercury
3.1     Introduction
         Name            :    methylmercury
         CAS-no          :    22967-92-6
         Use             :    fungicide
         Mol weight      :    215.59
         Chem formula    :    CH3Hg+
3.2     Human studies
3.2.1   Fertility
        No publications were found concerning effects of methylmercury on human fertility.
3.2.2   Developmental studies
        Methylmercury has caused major epidemics of poisoning in the general population. The
        two epidemics of methylmercury poisoning in Japan, in Minamata Bay and in Niigata,
        were caused by accumulation of industrially released mercury in edible fish. In Iraq,
        poisoning was caused by ingestion of bread contaminated with methylmercury fungicides
        (WHO76).
        Methylmercury                                                                         21
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<pre>           The reports on the Minamata outbreak described only slight symptoms in the mo-
      thers whose children, which had been exposed in utero, had cerebral palsy and/or micro-
      cephaly. In this study, it was concluded that the foetus is more sensitive to the effects of
      methylmercury than adults (WHO76).
           Surveys conducted on a selected Iraqi population to determine the extent of exposure
      to methylmercury revealed cerebral palsy and psychomotor retardation in children which
      had been exposed in utero (Ami74, Ami79). The number of births registered in 1973, the
      year following the methylmercury poisoning epidemic, was decreased by 2000, whereas
      increases in number of births of 10000 and 8000 had occurred in the 2 years prior to the
      epidemic (registered births in Iraq: 1970, 48055; 1971, 58837; 1972, 66549; 1973
      64582). However, no data were reported for the years after 1973 (Gre85).
           Further analysis of the Japanese and Iraqi data revealed additional information rela-
      ting to the effects of prenatal methylmercury exposure: methylmercury inhibits the
      growth of the foetal brain and the migration of neurones from the embryological genera-
      tion layer to the final destination in the cortex. This inhibition in foetal brain develop-
      ment results in the behavioural changes and reduced cognitive and motor ability found in
      clinical cases. Cytological studies demonstrated that methylmercury interferes with mi-
      crotubule formation, cell division, and neuronal protein synthesis (WHO 1990).
           Grandjean et al. (1997) studied the neurodevelopmental effects in children (age 7 ye-
      ars) in the Faroe islands (Gra97). The median hair concentration was 4.5 ppm (mg/kg
      hair) and in 13% of the children more than 10 ppm (mg/kg hair). In the cohort with ma-
      ternal hair mercury concentrations from 3-10 ppm neuropsychological changes were ob-
      served.
           Davidson et al. (1998) studied the neurodevelopmental consequences of exposure to
      methylmercury from fish eating in Seychelles children at the age of 66 months (Dav98).
      Mean maternal hair mercury concentration were 6.8 ppm (range 3-26.7 ppm). In this
      study no adverse effects of prenatal or postnatal methylmercury exposure were found.
           Mahaffey (1998) suggested that the discrepancy in outcome between the studies of
      Grandjean et al. 1997 and Davidson et al. 1998 might be explained by the use of tests
      with a lower detection limit for subtle cognitive and neuromotor disturbances in the latter
      study (Mah98). The committee supports the suggestion of Mahaffey.
3.2.3 Lactation
      See chapter 6.
      Methylmercury                                                                                22
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<pre>3.3   Animal studies
3.3.1 Fertility
      Lee and Dixon (1975) reported effects on spermatogenesis, testis histology and fertility
      in CDF1 mice after intraperitoneal exposure to a dose of methylmercury equivalent to 1
      mg mercury/kg; no data on general toxicity were presented in this study (Lee75). Fertili-
      ty as studied from serial matings up to 70 days after exposure indicated a significant de-
      crease in fertility, compared with controls. The dose levels used in this study were close
      to doses at which general toxicity was observed in other studies.
           Mohamed et al. (1987) studied the effects of oral treatment with methylmercury of
      adult male monkeys (Macaca fascicularis) on sperm production, motility and morpho-
      logy and serum testosterone levels (Moh87). Sperm parameters were affected; these ef-
      fects were not accompanied by histological abnormalities at the end of the treatment
      period.
           Burbacher et al. (1984) did not observe an effect on menstrual cycle or menses
      length after oral treatment of 0, 50 or 90 µg/kg bw/day methyl mercury hydroxide to
      monkeys (macaca fascicularis) (Bur84). Pregnancy and abortion rates were not statisti-
      cally significantly changed. The offspring of the methyl mercury-treated females tended
      to be smaller (birth weight and crown-rump length). Treatment with 90 µg/kg bw per
      day produced signs of toxicity in all 4 female monkeys.
           Mitsumori et al. (1990) reported tubular atrophy of the testes in B6C3F1 mice after
      2-year feeding of 0.4, 2 and 10 ppm (mg/kg feed) methylmercury at the highest dose-le-
      vel (Mit90). At 2 ppm (mg/kg feed) effects on the kidneys and at 10 ppm on the perip-
      heral nervous system, cerebrum and cerebellum, kidneys and stomach were observed.
           Vachhrajani et al. (1992) studied the cellular distribution pattern of methylmercury
      at different stages of the seminiferous epithelium in the testis of rats intraperitoneally in-
      jected with 5 or 10 µg/kg body weight per day during 15, 30, 60 or 90 days. As pro-
      found cell death occurred between zygotene to pachytene stages and dividing
      spermatocytes to step 1 spermatids, the number of spermatids was conspicuously decre-
      ased at later times. General toxicity was not described in this study. The committee con-
      siders the exposure route and duration of exposure not relevant for classification for
      fertility.
3.3.2 Developmental toxicity
      In 1990 the WHO concluded that the nervous system is a target of methylmercury, and
      that foetuses appear to be more sensitive than adults. Methylmercury is foetotoxic in
      Methylmercury                                                                                  23
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<pre>      mice (Verschaeve and Leonard 1984 in: WHO 1990), teratogenic in rats (e.g. Kutscher
      et al. 1985 in: WHO 1990), and adversely affects the behaviour of rat (Elsner et al.
      1988) and monkey offspring (e.g. Gunderson et al. 1986 in: WHO 1990).
3.3.3 Lactation
      See chapter 6.
3.4   Overall conclusion
      No reports were found concerning effects of methylmercury on human fertility. The ef-
      fects of methylmercury found in animal studies in which fertility was studied were insuk-
      ficient to classify methylmercury for effects on fertility.
           In conclusion, the committee recommends not to classify methyl mercury with res-
      pect to effects on fertility because of a lack of appropriate data.
      Methylmercury affects the development of the central nervous system both in humans
      and animals: it seriously affects the development of the brain, resulting in behavioural
      disorders (Ami74, Ami79; WHO90).
           In view of human and animal data with respect to developmental toxicity, the com-
      mittee recommends to classify methylmercury in category 1 (substances known to cause
      developmental toxicity in humans) and to label the compound with R 61 (may cause
      harm to the unborn child).
      Proposed classification for fertility
      Lack of appropriate data precludes assessment of the methylmercury for fertility.
      Proposed classification for developmental toxicity
      Cat 1, R 61.
      Proposed labelling for effects during lactation
      See chapter 6.
      Methylmercury                                                                             24
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<pre>Chapter 4
        Phenylmercury acetate
4.1     Introduction
         Name              :   phenylmercury acetate
         CAS-no            :   62-38-4
         Use               :   fungicide
         Mol weight        :   336.75
         Chem formula      :   C6H-Hg-OOCCH3
4.2     Human studies
4.2.1   Fertility
        No publications were found concerning effects of phenylmercury on human fertility.
4.2.2   Developmental toxicity
        With respect to human data, Schardein (1993) reported that exposure to phenylmercury
        acetate was found to have no relation with congenital malformations among 889 preg-
        nancies (Sch93). No details were reported.
        Phenylmercury acetate
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<pre>4.2.3 Lactation
      See chapter 6.
4.3   Animal studies
4.3.1 Fertility
      Five groups of rats, 24 animals per group, received Fungitox OR, which contains
      phenylmercury acetate, in their food over a 6-months period. The fungicide was given in
      doses of 0, 1, 2, 4 and 8 ppm mercury equivalents (mg/kg feed). Gain in body weight
      was not affected by the fungicide. The mercury compound accumulated in all the organs
      studied but particularly in the kidneys. After 6 months, 6 males and 6 females were ma-
      ted within the groups. Rats receiving 8 ppm mercury equivalents (mg/kg feed) had a
      44% drop in progeny compared to the controls (Pie68). The study was poorly reported
      and exposure to other compounds in Fungitox OR was not described.
4.3.2 Developmental toxicity
      Dzierzawski (1979) reported that phenylmercury acetate caused defects of the central
      nervous system in mice and hamsters, and multiple defects in rabbits (cited in Schardein
      1993) (Dzi79). Teratogenic effects of the compound have not been demonstrated in the
      rat.
           Murakami et al. (1956) studied the effects of phenylmercury acetate after vaginal
      application and subcutaneous injection in albino mice and observed an increased number
      of resorptions and fetuses with abnormalities (Mur56). In maternal animals exposure to
      phenyl mercury acetate resulted in effects on parenchymal cells of liver and kidney.
           Gale and Ferm (1971) administered phenylmercury acetate intravenously to preg-
      nant golden hamsters and induced resorptions and fetuses with abnormalities (Gal71).
      General toxicity is not described.
4.3.3 Lactation
      See chapter 6.
      Phenylmercury acetate                                                                    26
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<pre>4.4 Overall conclusion
    No data were found with respect to effects on human fertility. The committee concluded
    that the animal data presented by Piechocka (1968) were insufficient for classification
    for fertility as well, because the study was poorly reported and the exposure to other
    compounds was clear.
         In conclusion, the committee recommends not to classify phenylmercury acetate with
    respect to effects on fertility because of a lack of appropriate data.
    No data were found with respect to effects on development in man.
         Congenital malformations, predominantly of the central nervous system, were repor-
    ted in animals (Mur56, Gal71, Dzi79). However, general toxicity was either not descri-
    bed in the publications, or the effects were observed at levels causing general toxicity.
         In conclusion, the committee recommends not to classify phenylmercury acetate with
    respect to developmental effects because of a lack of appropriate data.
    Proposed classification for fertility
    Lack of appropriate data precludes assessment of phenylmercury acetate for fertility.
    Proposed classification for developmental toxicity
    Lack of appropriate data precludes assessment of phenylmercury acetate for develop-
    mental effects.
    Proposed labelling for effects during lactation
    See chapter 6.
    Phenylmercury acetate                                                                     27
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<pre>Chapter 5
        Mercuric chloride and Mercuric nitrate
5.1     Introduction
         Name                :  mercuric chloride
         CAS-no              :  7487-94-7
         Use                 :  preservation wood; disinfectant; etching steel and iron; tanning leather;
                                electroplating aluminium; treatment seed potatoes
         Mol weight          :  271.52
         Chem formula        :   HgCl2
         Name                :  mercuric nitrate
         CAS no: 10045-94-0  :  10045-94-0
         Use                 :  manufacture of felt; mercury fulminate; fungicide (destroying phylloxera)
         Mol weight          :  324.66
         Chem formula        :  Hg(NO3)2
        Mercuric chloride and mercuric nitrate are both inorganic mercury salts which were as-
        sumed to show the same kinetics in the human body; both will form a Hg+ ion.
        Mercuric chloride and Mercuric nitrate
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<pre>5.2   Human studies
5.2.1 Fertility
      Schardein (1993) reported that mercuric chloride has been related to spontaneous abor-
      tion in two studies (1950 and 1960). No details were reported.
5.2.2 Developmental toxicity
      No publications were found concerning effects of mercuric chloride and mercuric nitrate
      on developmental toxicity.
5.2.3 Lactation
      See chapter 6.
5.3   Animal studies
5.3.1 Fertility
      Lach and Srebro (1972) exposed groups of 10 female mice with normal cycles to mercu-
      ric nitrate by subcutaneous injection, at doses of 0.1 mg/day for 8 days, or 0.2 mg/day
      for 12 days ( ≈ 4 or 8 mg/kg bw/day, respectively). In the 0.1 mg/day group 3/10 sho-
      wed no oestrous period at all and none had more than one oestrous period, during the 8
      days of exposure (Lac72). Cycles returned to normal in the 12 days after the end of ex-
      posure. In de 0.2 mg/day group, 4/10 showed no oestrous period and 3/10 only one oe-
      strous period during the 12 days of treatment. Duration of di-oestrous was significantly
      increased from 30% of the cycle length before treatment to 70% during treatment. In the
      15 days after the end of exposure, 4/10 failed to show any oestrous period, only one of
      these 4 having an anoestrous during exposure. Total days in di-oestrus in the 15-day
      post-exposure were 45%. No data on general toxicity were presented in this study. Ho-
      wever, the dose levels used in this study were close to doses at which general toxicity
      was observed in other studies.
           Lee and Dixon (1975) reported effects on spermatogenesis, testis histology and ferti-
      lity of methyl mercury in mice after intraperitoneal (i.p.) exposure to a dose of mercuric
      chloride equivalent to 1 mg mercury/kg bw (Lee75). Effects on fertility were studied
      from serial matings up to 70 days after exposure. A significant decrease was indicated in
      fertility, compared with controls. No data on general toxicity were presented in this stu-
      Mercuric chloride and Mercuric nitrate                                                     29
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<pre>      dy. However, the dose levels used in this study were close to doses at which general toxi-
      city was observed in other studies.
           Histochemical investigations of 3 beta-hydroxy-delta 5-steroid dehydrogenase (delta
      5-3 beta OHD) activity in the testicular tissue of rats administered mercuric chloride i.p.
      at dosages of 0.05 mg/kg bw and 0.1 mg/kg bw daily for 90 days revealed a graded inhi-
      bition of delta 5-3 beta OHD (last step of the testosterone synthesis) activity which was
      positively related to dosage and to the duration of treatment with this compound
      (Cho85).
           Testicular changes following i.p. administration of mercuric chloride (1, 2 and 5
      mg/kg bw per day) over one month were studied in rats, mice, guinea pigs and hamsters
      (Cho82). Mercuric chloride (5 mg/kg bw) caused testicular degeneration and cellular de-
      formation, observed in both the seminiferous tubules and the Leydig cells in all species:
      a significant decrease of testicular weight was also observed. There was no cellular de-
      formation at the dose of 2 mg/kg bw: only spermatogenic inhibition and Leydig cell
      atrophy were observed in the animals. At the dose of 1 mg/kg, testicular degeneration
      was observed only in the hamster, only partial degeneration was recorded in the rat and
      the mouse and no change was noted in the guinea pig. Effects of general toxicity were
      not described in this study. For the different mammalian species the LD50 ranged from
      14-25 mg/kg bw.
5.3.2 Developmental toxicity
      Holt and Webb (1986) exposed pregnant Wistar rats intravenously to mercuric chloride
      during different periods of gestation (Hol86). During the mid-gestation the minimum ef-
      fective teratogenic dose of mercury (0.79 mg/kg bw) was high in relation to the maternal
      LD50 (c. 1 mg/kg bw) and the incidence of foetal malformations, mainly brain defects,
      was 23% in all live foetuses. In rats of different gestational ages, foetal Hg2+ decreased
      sharply between day 12 and day 13. The teratogenic effects on the foetus and damage to
      the maternal kidneys, however, were essentially the same in animals dosed with Hg2+ ei-
      ther immediately before or immediately after these gestational ages.
5.3.3 Lactation
      See chapter 6.
      Mercuric chloride and Mercuric nitrate                                                      30
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<pre>5.4 Overall conclusion
    With respect to human data, there are indications that mercuric chloride may cause
    spontaneous abortion. However, no information on this study were reported (Schardein
    1993).
        In animals, the effects on male fertility (Lee75, Cho82) were found at dosages at
    which toxicity may be expected. However, general toxicity is not described in these stu-
    dies.
        In conclusion, the committee recommends not to classify both mercury salts with
    respect to effects on fertility because of a lack of appropriate data.
    No publications were found concerning effects of mercuric chloride and mercuric nitrate
    on developmental toxicity in man.
        Mercuric chloride induces developmental effects in rats at a dose level which also
    may cause maternal toxicity (Holt and Webb 1986).
        In conclusion, the committee recommends not to classify both mercury salts with
    respect to developmental effects because of a lack of appropriate data.
    Proposed classification for fertility
    Lack of appropriate data precludes assessment of the mercury salts for fertility.
    Proposed classification for developmental toxicity
    Lack of appropriate data precludes assessment of the mercury salts for developmental
    effects.
    Proposed labelling for effects during lactation
    See chapter 6.
    Mercuric chloride and Mercuric nitrate                                                   31
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<pre>Chapter 6
        Lactation (organic and inorganic
        mercury)
6.1     Human studies
        In 1968, a total mercury concentration of 63 µg/l (mean) and 50 µg/l (mean) was detec-
        ted in breast milk of healthy women from the polluted Minamata district and from an
        agricultural area in Japan, respectively (Fuj77).
             Pitkin et al. (1976) found detectable mercury levels in 14 of 32 samples of non-ex-
        posed women with an established lactation of 56 or more days (Pit76). The total mercu-
        ry concentration was 0.9 µg/l.
             Fujita and Takabatake (1977) detected total mercury levels of 3.6 + 2.2 µg/l in bre-
        ast milk of mothers of the Tokyo Metropolitan area (Fuj77). No correlation between
        mercury levels in blood and breast milk was detected.
             Wilson et al. (1980) estimated that the concentration of methylmercury in human
        breast milk was around 29 µg/l in Iraqi women after the poisoning with methylmercury
        (Wil80).
             Skerfving (1988) studied the total mercury content and the methylmercury content in
        breast milk (Ske88). The total mercury concentration in milk averaged 3.1 (range
        0.2-6.3) µg/l in 15 mothers and the mean methylmercury concentration in milk was 0.6
        (range 0.2-1.2) µg/l in 9 mothers.
             Klemann et al. (1990) studied the relationship between dental amalgam fillings and
        mercury content in human breast milk and amniotic fluid (Kle90). The concentration of
        total mercury in the breast milk of 86 women, at five to ten days after delivery, was 1.9
        + 1.6 µg/l. No significant correlation to maternal amalgam surface area was found.
        Lactation (organic and inorganic mercury)
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<pre>         Oskarson et al. (1996) collected breast milk, blood and hair samples 6 weeks after
    delivery from 30 women who lived in the north of Sweden (Osk96). Total mercury con-
    centration in breast milk was 0.6 + 0.4 µg/kg. The level of mercury in milk reflected the
    plasma level. Methyl mercury is bound predominantly to erythrocytes, whereas inorganic
    mercury is distributed almost equally between erythrocytes and plasma; the latter distri-
    bution would favour the lactational transfer of inorganic mercury from blood. In addi-
    tion, an efficient transfer of inorganic mercury from plasma into milk has been shown in
    animals (Sun91). Approximately half of the total mercury content in milk was in the
    form of inorganic mercury. Total and inorganic mercury in milk were correlated with the
    number of amalgam fillings. There was no significant correlation between milk levels of
    mercury in any chemical form and the estimated methylmercury intake (Osk96).
         Vimy et al. (1997) detected that women with amalgam fillings had significantly hig-
    her mercury levels in breast milk (0.236 + 0.034 µg/l) than women without amalgam fil-
    lings (0.146 +0.025 µg/l) (Vim97).
         Drexler and Schaller (1998) studied the mercury concentration in breast milk resul-
    ting from amalgam fillings and dietary habits and found that the concentration of mercu-
    ry in the breast milk collected immediately after delivery showed a significant
    association with the number of amalgam fillings as well as with the frequency of meals
    (Dre98). After 2 months of lactation, the concentrations of total mercury in breast milk
    were lower (mean <0.25 µg/l; range <0.25-11.7 µg/l) compared with the first sample
    (mean 0.90 µg/l, range <0.25-20.3 µg/l) and were positively associated with fish con-
    sumption and not longer with the number of amalgam fillings. The discrepancy between
    the studies of Kle90 and Fuj77, as regards the correlation between the number of amal-
    gam fillings and mercury content of breast milk is probably related to the time of sam-
    pling (shortly after birth in Dre98). The authors concluded that mercury concentrations
    in breast milk were mainly the result of dietary habits. The influence of amalgam fil-
    lings, at least at the beginning of breast feeding, on the mercury concentration in breast
    milk appeared relatively small.
    No publications were found concerning the excretion of phenylmercury acetate and mer-
    cury salts in human breast milk
6.2 Animal studies
    Vimy et al. (1990) studied in 5 ewes whether mercury from amalgam fillings enters into
    breast milk in detectable amounts (Vim90). On day 112 of gestation, 12 occlusal amal-
    gam fillings with radioactive mercury (203Hg) were inserted. Radioactive mercury was
    detected in the milk. 2 Days after birth levels of 60 µg Hg/l were detected.
    Lactation (organic and inorganic mercury)                                                  33
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<pre>     Yoshida et al. (1992) exposed guinea pigs to mercury vapour for 120 minutes within
12 hours after parturition at mean concentration of 6-10 mg/m3 (Yos92). Mercury con-
centrations in milk were slightly lower than in plasma mercury concentrations of the ma-
ternal guinea pigs on PN (postnatal) days 3, 5 and 10. However, the decrease in mercury
concentration in breast milk with time was slower than that in maternal plasma. The
mercury concentrations detected in milk amounted to 9-14 µg/l.
     A single oral doses of methyl 203Hg ( 0.5, 3.3, 7.7 or 9.4 mg mercury/kg body
weight) were given to rats on day 9 of lactation and the transfer of mercury in milk was
investigated (Sun91). A linear, dose-dependent transfer of mercury from plasma to milk
was found. After 24 hour the concentrations in milk were 6, 52, 210 or 240 µg/l; after
72 hours 6, 64, 160 or 170 µg/l. Transfer of mercury into milk is dependent on the expo-
sure situation and preferentially inorganic mercury is transported into milk.
     Nordenhäll et al. (1994) studied the effects of lactational exposure to 203Hg -labelled
methylmercury 1 day after parturition (Nor94). Milk was collected twice during the first
week. The fraction of inorganic mercury in milk and kidneys of the pups was determined
following separation of inorganic mercury and methylmercury by ion exchange chroma-
tography. The concentration of 203Hg in milk on the 1st day after methylmercury admini-
stration was 0.12 nmol/g (26 µg/l). 203Hg was mainly excreted as methylmercury during
the first 6 days of lactation. The excretion of methylmercury in milk corresponded to at
least 5% of the dose administered to the dam.
     Yoshida et al. (1994) injected maternal guinea pigs intraperitoneally with methyl-
mercury and mercuric chloride (1mg/kg body weight) 12 hours after parturition (Yos94).
In the offspring, the highest total methylmercury concentrations were found in the kid-
ney, followed by the liver and the brain. Brain mercury concentrations were significantly
higher in the offspring of methylmercury-treated dams than in those treated with mercu-
ric chloride. Methylmercury levels in milk decreased on PN day 10 to 3 µg/l and were
relatively constant on PN day 3 and 5 (13 and 11 µg/l, respectively).
     After exposure to mercuric chloride, total mercury levels in milk were highest on PN
day 3, (76 µg/l) and declined to 19 µg/l on PN day 10.
From the proposed ADI of 0.08 µg/kg body weight/day (RIVM: Jan94), a acceptable le-
vel of about 0.4 µg/l breast milk can be calculated for methyl mercury (see Annex E).
     From the proposed ADI of 4 µg/kg body weight/day (RIVM: Jan94), a acceptable
level of about 20 µg/l breast milk can be calculated for inorganic mercury (see Annex
E).
Lactation (organic and inorganic mercury)                                                    34
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<pre>6.3 Overall conclusion
    From the above mentioned human and animal studies, it can be concluded that the con-
    centrations of mercury due to the consumption of food contaminated with methylmercury
    (Fuj77, Wil80, Ske88) caused methylmercury concentrations in human breast milk
    which exceeded the calculated acceptable levels of 0.4 µg/l breast milk. Therefore, the
    committee recommends to label methylmercury with R64 (May cause harm to breastfed
    babies).
        No appropriate data were available concerning the excretion of metallic mercury,
    phenyl mercury acetate and mercury salts in human or animal milk. Therefore, a lack of
    appropriate data precludes assessment of metallic mercury, phenyl mercury acetate and
    mercury salts for labelling for effects during lactation.
    Proposed labelling for effects during lactation for metallic mercury
    Lack of appropriate data precludes assessment of metallic mercury for labelling for ef-
    fects during lactation.
    Proposed labelling for effects during lactation for methyl mercury
    R64.
    Proposed labelling for effects during lactation for phenyl mercury acetate
    Lack of appropriate data precludes assessment of phenyl mercury acetate for labelling
    for effects during lactation.
    Proposed labelling for effects during lactation for mercury salts
    Lack of appropriate data precludes assessment of mercury salts for labelling for effects
    during lactation.
    Lactation (organic and inorganic mercury)                                                35
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<pre>For the committee,
The Hague, 3 May 2000
dr ASAM van der Burght,                dr BJ Blaauboer,
scientific secretary                   chairman
Lactation (organic and inorganic mercury)               36
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<pre>      References
Alc89 Alcer KH, Brix KA, Fine LJ, Kallenbach LR, Wolfe RA. Occupational mercury exposure and male repro-
      ductive health. Amer J Ind Med 1989; 15: 517-529.
Ami74 Amin-Zaki L, Elhassani SB, Majeed MA, Clarkson TW, Doherty RA, Greenwood MR. Intra-uterine me-
      thylmercury poisoning in Iraq. Pediatr 1974; 54: 587-595.
Ami79 Amin-Zaki L, Majeed MA, Elhassani SB, Clarkson TW, Greenwood MR, Doherty RA. Prenatal mercury
      poisoning, clinical observations over five years. AMA Dis Child 1979; 133: 172-177.
Bar73 Baranski B, Szymczyk I. Effects of mercury vapours upon reproductive function on white female rats.
      Medycyna Pracy 1973; 24 (3): 249-261 (see Barlow and Sullivan 1982).
Bar82 Barlow SM, Sullivan FM(editors). Reproductive Hazards of Industrial Chemicals. An evaluation of ani-
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Ern91 Ernst E, Lauritsen G. Effects of organic and inorganic mercury on human sperm motility. Pharmacol
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      (Dutch translation and see Shepard 1989).
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Mah98 Mahaffey KR. Methylmercury exposure and neurotoxicity. JAMA 1998; 280: 737-738.
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      References                                                                                               40
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<pre>Wei84 Weigert P, Müller J, Klein H, Zufelde KP, Hillebrand J. Arsen, Blei, Cadmium un Quecksilber in und
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      References                                                                                         41
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<pre>A The committee
B Comments on the public draft
C Directive (93/21/EEG) of the European Community
D Calculation safe levels of inorganic mercury in (human) breast milk
E Abbreviations
  Annexes
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<pre>Annex A
      The committee
         BJ Blaauboer, chairman
         Toxicologist; Research Institute of Toxicology, Utrecht
         JN van den Anker
         Professor of pediatrics and Neonatology; Erasmus University, Rotterdam
         AM Bongers, advisor
         Ministry of Social Affairs and Employment, The Hague
         HFP Joosten
         Toxicologist; NV Organon, Department of Toxicology and Drug Disposition, Oss
         D Lindhout
         Professor of Clinical Genetics/Teratology; Erasmus University, Rotterdam
         JHJ Copius Peereboom-Stegeman
         Toxicologist; Catholic University Nijmegen, Nijmegen
         AH Piersma
         Reproductive toxicologist; National Institute of Public Health and the Environment,
         Bilthoven
         A Stijkel
         Toxicologist; Environmental Awareness Foundation, ‘s-Graveland
         PJJM Weterings
         Toxicologist; Weterings Consultancy BV, Rosmalen
         ASAM van der Burght, scientific secretary
         Health Council of the Netherlands, The Hague
      The committee
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<pre>The first draft of the present document was prepared by IDH Waalkens-Berendsen, from
the TNO Nutrition and Food Research Institute in Zeist, by contract with the Ministry of
Social Affairs and Employment.
Secretarial assistance: E Vandenbussche-Parméus.
Lay-out: J van Kan.
The committee                                                                            44
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<pre>Annex B
      Comments on the public draft
      A draft of this report was released in 1999 for public review. No persons or organisa-
      tions have commented on the draft document.
      Comments on the public draft
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<pre>Annex C
      Directive (93/21/EEC) of the European
      Community
      4.2.3         Substances toxic to reproduction
      4.2.3.1       For the purposes of classification and labelling and having regard to the present
                    state of knowledge, such substances are divided into 3 categories:
      Category 1:
      Substances known to impair fertility in humans
      There is sufficient evidence to establish a causal relationship between human exposure to the substance
      and impaired fertility.
      Substances known to cause developmental toxicity in humans
      There is sufficient evidence to establish a causal relationship between human exposure to the substance
      and subsequent developmental toxic effects in the progeny.
      Category 2:
      Substances which should be regarded as if they impair fertility in humans:
      Directive (93/21/EEC) of the European Community
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<pre>There is sufficient evidence to provide a strong presumption that human exposure to the substance may
result in impaired fertility on the basis of:
     Clear evidence in animal studies of impaired fertility in the absence of toxic effects, or, evidence of
     impaired fertility occurring at around the same dose levels as other toxic effects but which is not a
     secondary non-specific consequence of the other toxic effects.
     Other relevant information.
Substances which should be regarded if they cause developmental toxicity to humans:
There is sufficient evidence to provide a strong presumption that human exposure to the substance may
result in developmental toxicity, generally on the basis of:
     Clear resuts in appropriate animal studies where effects have been observed in the absence of signs
     of marked maternal toxicity, or at around the same dose levels as other toxic effects but which are
     not a secondary non-specific consequence of the other toxic effects.
     Other relevant information.
Category 3:
Substances which cause concern for human fertility:
Generally on the basis of:
     Results in appropriate animal studies which provide sufficient evidence to cause a strong suspicion
     of impaired fertility in the absence of toxic effects, or evidence of impaired fertility occurring at
     around the same dose levels as other toxic effects, but which is not a secondary non-specific conse-
     quence of the other toxic effects, but where the evidence is insufficient to place the substance in Ca-
     tegory 2.
     Other relevant information.
Substances which cause concern for humans owing to possible developmental toxic effects:
Generally on the basis of:
     Results in appropriate animal studies which provide sufficient evidence to cause a strong suspicion
     of developmental toxicity in the absence of signs of marked maternal toxicity, or at around the same
     dose levels as other toxic effects but which are not a secondary non-specific consequence of the
     other toxic effects, but where the evidence is insufficient to place the substance in Category 2.
     Other relevant information.
Directive (93/21/EEC) of the European Community                                                              47
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<pre>4.2.3.2       The following symbols and specific risk phrases apply:
Category 1:
For substances that impair fertility in humans:
T; R60: May impair fertility
For substances that cause developmental toxicity:
T; R61: May cause harm to the unborn child
Category 2:
For substances that should be regarded as if they impair fertility in humans:
T; R60: May impair fertility
For substances that should be regarded as if they cause developmental toxicity in humans:
T; R61: May cause harm to the unborn child.
Category 3:
For substances which cause concern for human fertility:
Xn; R62: Possible risk of impaired fertility
For substances which cause concern for humans owing to possible developmental toxic effects:
Xn; R63: Possible risk of harm to the unborn child.
4.2.3.3       Comments regarding the categorisation of substances toxic to reproduction
Reproductive toxicity includes impairment of male and female reproductive functions or capacity and the
induction of non-inheritable harmful effects on the progeny. This may be classified under two main head-
ings of 1) Effects on male or female fertility, 2) Developmental toxicity.
1    Effects on male or female fertility, includes adverse effects on libido, sexual behaviour, any aspect
     of spermatogenesis or oogenesis, or on hormonal activity or physiological response which would in-
Directive (93/21/EEC) of the European Community                                                            48
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<pre>      terfere with the capacity to fertilise, fertilisation itself or the development of the fertilised ovum up
      to and including implantation.
2     Developmental toxicity, is taken in its widest sense to include any effect interfering with normal de-
      velopment, both before and after birth. It includes effects induced or manifested prenatally as well
      as those manifested postnatally. This includes embrytoxic/fetotoxic effects such as reduced body
      weight, growth and developmental retardation, organ toxicity, death, abortion, structural defects (te-
      ratogenic effects), functional defects, peri-postnatal defects, and impaired postnatal mental or physi-
      cal development up to and including normal pubertal development.
Classification of chemicals as toxic to reproduction is intended to be used for chemicals which have an
intrinsic or specific property to produce such toxic effects. Chemicals should not be classified as toxic to
reproduction where such effects are solely produced as a non-specific secondary consequence of other
toxic effects. Chemicals of most concern are those which are toxic to reproduction at exposure levels
which do not produce other signs of toxicity.
The placing of a compound in Category 1 for effects on Fertility and/or Developmental Toxicity is done
on the basis of epidemiological data. Placing into Categories 2 or 3 is done primarily on the basis of ani-
mal data. Data from in vitro studies, or studies on avian eggs, are regarded as ‘supportive evidence’ and
would only exceptionally lead to classification in the absence of in vivo data.
In common with most other types of toxic effect, substances demonstrating reproductive toxicity will be
expected to have a threshold below which adverse effects would not be demonstrated. Even when clear
effects have been demonstrated in animal studies the relevance for humans may be doubtful because of
the doses administrated, for example, where effects have been demonstrated only at high doses, or where
marked toxicokinetic differences exist, or the route of administration is inappropriate. For these or simi-
lar reasons it may be that classification in Category 3, or even no classification, will be warranted.
Annex V of the Directive specifies a limit test in the case of substances of low toxicity. If a dose level of
at least 1000 mg/kg orally produces no evidence of effects toxic to reproduction, studies at other dose le-
vels may not be considered necessary. If data are available from studies carried out with doses higher
than the above limit dose, this data must be evaluated together with other relevant data. Under normal
circumstances it is considered that effects seen only at doses in excess of the limit dose would not neces-
sarily lead to classification as Toxic to Reproduction.
Effects on fertility
For the classification of a substance into Category 2 for impaired fertility, there should normally be clear
evidence in one animal species, with supporting evidence on mechanism of action or site of action, or
chemical relationship to other known antifertility agents or other information from humans which would
Directive (93/21/EEC) of the European Community                                                                 49
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<pre>lead to the conclusion that effects would be likely to be seen in humans. Where there are studies in only
one species without other relevant supporting evidence then classification in Category 3 may be appropri-
ate.
Since impaired fertility may occur as a non-specific accompaniment to severe generalised toxicity or
where there is severe inanition, classification into Category 2 should only be made where there is eviden-
ce that there is some degree of specificity of toxicity for the reproductive system. If it was demonstrated
that impaired fertility in animal studies was due to failure to mate, then for classification into Category 2,
it would normally be necessary to have evidence on the mechanism of action in order to interpret whether
any adverse effect such as alteration in pattern of hormonal release would be likely to occur in humans.
Developmental toxicity
For classification into Category 2 there should be clear evidence of adverse effects in well conducted stu-
dies in one or more species. Since adverse effects in pregnancy or postnatally may result as a secondary
consequence of maternal toxicity, reduced food or water intake, maternal stress, lack of maternal care,
specific dietary deficiencies, poor animal husbandry, intercurrent infections, and so on, it is important
that the effects observed should occur in well conducted studies and at dose levels which are not associa-
ted with marked maternal toxicity. The route of exposure is also important. In particular, the injection of
irritant material intraperitoneally may result in local damage to the uterus and its contents, and the re-
sults of such studies must be interpreted with caution and on their own would not normally lead to classi-
fication.
Classification into Category 3 is based on similar criteria as for Category 2 but may be used where the
experimental design has deficiencies which make the conclusions less convincing, or where the possibili-
ty that the effects may have been due to non-specific influences such as generalised toxicity cannot be ex-
cluded.
In general, classification in category 3 or no category would be assigned on an ad hoc basis where the
only effects recorded are small changes in the incidences of spontaneous defects, small changes in the
proportions of common variants such as are observed in skeletal examinations, or small differences in
postnatal developmental assessments.
Effects during Lactation
Substances which are classified as toxic to reproduction and which also cause concern due to their effects
on lactation should in addition be labelled with R64 (see criteria in section 3.2.8).
Directive (93/21/EEC) of the European Community                                                                50
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<pre>For the purpose of classification, toxic effects on offspring resulting only from exposure via the breast
milk, or toxic effects resulting from direct exposure of children will not be regarded as ‘Toxic to Repro-
duction’, unless such effects result in impaired development of the offspring.
Substances which are not classified as toxic to reproduction but which cause concern due to toxicity
when transferred to the baby during the period of lactation should be labelled with R64 (see criteria in
section 3.2.8). This R-phrase may also be appropriate for substances which affect the quantity or quality
of the milk.
R64 would normally be assigned on the basis of:
a    toxicokinetic studies that would indicate the likelihood that the substance would be present in po-
     tentially toxic levels in breast milk, and/or
b    on the basis of results of one or two generation studies in animals which indicate the presence of ad-
     verse effects on the offspring due to transfer in the milk, and/or
c    on the basis of evidence in humans indicating a risk to babies during the lactational period.
     Substances which are known to accumulate in the body and which subsequently may be released in-
     to milk during lactation may be labelled with R33 and R64.
Directive (93/21/EEC) of the European Community                                                             51
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<pre>Annex D
      Calculation safe levels of mercury in
      (human) breast milk
      Assumptions:
          Body weight woman: 60 kg
          Body weight infant: 4.5 kg (4-5 kg)
          Intake breast milk: 900 ml (800-1000 ml)
          An infant is as sensitive for the effects of mercury as an adult.
      Calculation safe levels of inorganic mercury in (human) breast milk
      The RIVM (Jan94) proposed an ADI for inorganic mercury of 4 µg/kg body weight/day.
          Safe intake level per infant is 18 µg/infant/day.
          Safe level of mercury in breast milk is 20 µg/l.
      In conclusion, the committee considers 20 µg inorganic mercury/l breast milk as a safe
      level.
      Calculation safe levels of methylmercury in (human) breast milk
      The RIVM (Jan94) proposed an ADI for methylmercury of 0.08 µg/kg body weight/day.
          Safe intake level per infant is 0.36 µg/infant/day.
          Safe level of methyl mercury in breast milk is 0.4 µg/l.
      Calculation safe levels of mercury in (human) breast milk
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<pre>In conclusion, the committee considers 0.4 µg methylmercury/l breast milk as a safe le-
vel.
Calculation safe levels of mercury in (human) breast milk                               53
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<pre>Annex E
      Abbreviations
      Abbreviations used:
      ADI         Acceptable daily intake
      bw          body weight
      d           day
      F           female(s)
      GD          Gestation day
      i.p.        intraperitoneal
      i.v.        intravenous
      M           male(s)
      n           number of animals
      no          number
      ns          not significant
      NOAEL no adverse effect level
      OECD        Organisation for Economic Cooperation and Development
      PN          postnatal
      w           week
      Abbreviations
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<br><br>