<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>Cadmium and its compounds
Evaluation of the effects on reproduction, recommendation for classification
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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 cadmium en cadmiumverbindingen. Deze publicatie 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>Cadmium 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. 2000/04OSH, The Hague, 3 May 2000
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<pre>Preferred citation:
Health Council of the Netherlands: Committee for Compounds toxic to reproduction.
Cadmium and its compounds; Evaluation of the effects on reproduction, recommenda-
tion for classification. The Hague: Health Council of the Netherlands, 2000; publication
no. 2000/04OSH.
all rights reserved
ISBN: 90-5549-315-5
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<pre>    Contents
    Samenvatting 7
    Executive summary 8
1   Scope 9
1.1 Background 9
1.2 Committee and procedure 9
1.3 Additional considerations 10
1.4 Labelling for lactation 11
1.5 Data 12
1.6 Presentation of conclusions 12
1.7 Final remark 12
2   Scope 13
2.1 Introduction 13
2.2 Human studies 13
2.3 Animal studies 16
2.4 Overall conclusion 23
    References 26
    Contents                       5
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<pre>  Annexes 32
A The committee 33
B Comments on the public draft 35
C Directive (93/21/EEC) of the European Community 36
D Fertility and developmental toxicity studies 42
E Calculation safe levels of Cd in (human) breast milk 51
F Abbreviations 52
  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 cadmium en cadmiumverbindingen onder de loep genomen.
De aanbevelingen van de commissie zijn:
    Voor effecten op de fertiliteit adviseert de commissie cadmium en cadmiumverbin-
    dingen in categorie 3 (stoffen die in verband met hun mogelijke voor de vruchtbaar-
    heid van de mens schadelijke effecten reden geven tot bezorgdheid) te classificeren
    en met R62 (mogelijk gevaar voor verminderde vruchtbaarheid) te kenmerken.
    Voor effecten op de ontwikkeling adviseert de commissie cadmium en cadmiumver-
    bindingen in categorie 3 (stoffen die in verband met hun mogelijke voor de ontwik-
    keling schadelijke effecten reden geven tot bezorgdheid voor de mens) te
    classificeren en met R63 (mogelijk gevaar voor beschadiging van het ongeboren
    kind) te kenmerken.
    Voor effecten tijdens lactatie adviseert de commissie om cadmium en cadmiumver-
    bindingen met R64 (kan schadelijk zijn via de borstvoeding) te kenmerken.
Samenvatting                                                                            7
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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 cadmium and its com-
pounds.
The committee’s recommendations are:
    For effects on fertility, the committee recommends to classify cadmium and its com-
    pounds in category 3 (substances which cause concern for human fertility) and to
    label cadmium and its compounds with R62 (possible risk for impaired fertility).
    For developmental toxicity, the committee recommends to classify cadmium and its
    compounds in category 3 (substances which cause concern for humans owing to
    possible developmental toxic effects) and to label cadmium and its compounds with
    R63 (possible risk of harm to the unborn child).
    For effects during lactation, the committee recommends that cadmium and its com-
    pounds should be labelled with R64 (may cause harm to breastfed babies)
Executive summary                                                                       8
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<pre>Annex 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 cadmium and its compounds by the
      Health Council’s Committee for Compounds Toxic to Reproduction. 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 Neurotoxicology and Reproduction
      Toxicology of the TNO Nutrition and Food Research Institute, 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 concerning adverse ef-
      fects with respect to fertility and development and lactation of the above mentioned com-
      pound.
      Scope                                                                                     9
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<pre>    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-
         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.
    Scope                                                                                                  10
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<pre>         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, eg the acceptable daily intake (ADI).
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
*   Organisation for Economic Cooperation and Development
    Scope                                                                                        11
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<pre>    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 studies in the text, starting with review arti-
    cles. Of each study the quality of the study design (performed according to international-
    ly acknowledged guidelines) and the quality of documentation are considered.
         Animal data are described in the text and summarised in Annex D.
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                                                                                       12
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<pre>Chapter 2
        Cadmium and its compounds
2.1     Introduction
         Name              :    cadmium
         Use               :    protective plating on steel, electrode material in batteries, pigment, plastic
                                stabilizer, by-product of zinc production
         Atom weight       :    112.40
         Chem formula      :    Cd / Cd2+
         CAS number        :    7440-43-9
        Cadmiumchloride, cadmiumoxide and cadmiumsulphate are considered to be (non-geno-
        toxic) carcinogens.
2.2     Human studies
        Man may be exposed to cadmium (Cd) either occupationally, via smoking of tobacco or
        via the diet and drinking water. Exposure via food is the main route for the non-smoking
        population.
        Fertility
        Mason (1990) studied the effects of occupational exposure to cadmium (concentration
        unknown) on the pituitary-testicular endocrine axis of workers (n=77), as measured by
        Cadmium and its compounds                                                                              13
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<pre>serum testosterone (T), luteinizing hormone (LH) and follicular-stimulating hormone
(FSH) (Mas90). Cd exposure estimates were constructed for each subject from atmosp-
heric measurements; these exposure estimates were validated by in vivo neutron activa-
tion analyses of liver Cd burdens. The lack of testicular endocrine effects was in contrast
to significant dose-related changes in renal glomerular and tubular function demonstra-
ted in the same population.
     Gennart et al. (1992) studied the male reproductive function in Belgian melters
(n=83) who were exposed to Cd (Gen92). The mean urinary Cd level was 6.9 µg per
gram creatinine. Fertility in these workers was not affected when compared to an unex-
posed population.
     Xu et al. (1993) determined the concentrations of Cd and other trace elements (Pb,
Se and Zn) in blood and seminal plasma of men (n=221) undergoing initial screening for
infertility (Xu93). The authors detected a relation between increased Cd concentrations
in blood and decreased sperm density in oligozoospermic men but not in normospermic
men. High Cd concentration in seminal plasma was associated with low semen volume.
     Keck et al. (1995) did not find a correlation between Cd levels in seminal plasma
and semen parameters (semen volume, count, motility and morphology) and fertility in
12 men with proven fertility and 44 normozoospermic patients as well as 118 unselected
patients of an infertility clinic in Germany (Kec95).
Development
Huel et al. (1984) investigated the effects of maternal occupational Cd exposure on child
development (Hue84). Despite statistically significant evidence of increased exposure to
Cd, no adverse health effects were documented in the exposed new-borns included in this
study. Six years later, each of these 26 children was given a psychometric test. Statisti-
cal analysis showed a significant inverse relationship between the degree of in utero ex-
posure to Cd and Pb and the child’s motor and perceptual abilities (Bon86).
     Kuhnert et al. (1987) studied the effects of smoking during pregnancy on decreased
infant weight (Kuh87). In smokers (n=77) maternal whole blood Cd, placental Cd and
placental Zn levels were inversely related to birth weight.
     Loiacono et al. (1992) studied the effects of Cd on birth weight of children of mo-
thers who lived in the vicinity of a Pb smelter in Titova Mitrovica, Yugoslavia (Loi92).
Control subjects were studied in Pristina, a non-exposed town located 25 miles to the
south. Birth weights of children of a group of non-smoking women from Titova Mitrovi-
ca were compared to those of non-smoking women from Pristina. No association bet-
ween placental Cd concentrations and birth weight was observed.
     Marlowe et al. (1983) suggested a relation between pre- and postnatal Cd and Pb
exposure and mental retardation in children (Mar83).
Cadmium and its compounds                                                                   14
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<pre>Lactation
Casey (1977) studied the levels of some trace elements in human breast milk in New Ze-
aland and detected concentrations lower than 1 µg Cd/l (Cas77).
     Larsson et al. (1981) reported levels of 0.1 µg Cd/l (median) in breast milk of
Swedish women (Lar81). They did not find significant differences in Cd levels between
3- and 6-month samples. The authors calculated a median weekly intake of Cd by
3-months old infants of 0.1 µg/kg body weight.
     Sharda et al. (1983) found no significant changes in Cd levels from colostrum (20
µg Cd/l) to mature milk (17 µg Cd/l) in Indian women (Sha83).
     Vuori et al. (1983) studied Cd concentrations in human breast milk of Finnish wo-
men in the first, third and sixth months and detected levels of 2.0, 1.5 and 1.6 µg Cd/l
(median) (Vuo83).
     Kovar et al. (1984) collected 5 days postpartum breast milk from 28 British mothers
from an urban population and detected mean concentrations Cd of 0.4 µg/l (Kov84).
     Sternowsky and Wessolowski (1985) found Cd concentrations in colostrum and ma-
ture milk of non-smoking women living in an urban area in Germany of 23.2 and 15.1
µg Cd/l, respectively and in milk of women living in a rural area in Germany of 26.6 and
13.5 µg Cd/l, respectively (Ste85).
     Radish et al. (1987) studied the concentrations of Cd in human breast milk in smo-
kers and non-smokers in various districts of West-Berlin (Germany) and detected median
levels of 0.16 and 0.07 µg Cd/l (Rad87).
     Schramel et al. (1988) detected levels of 0.88 µg Cd/l in human breast milk in Ger-
many (Sch88).
     Zahradnicek et al. (1989) found levels of 0.31 µg Cd/l in Czechoslovakia in
1985-1986.
     Ende and Hille (1992) reported Cd levels of lower than 0.4 (in 1987), 2 (in 1988), 2
(in 1989) and 0.4 µg Cd/l (in 1990) in human breast milk in Germany (End92).
     Plöckinger et al. (1993) reported Cd levels in human milk below the detection limit
in Austrian women (Plö93).
     Hallén et al. (1995) determined Cd levels in breast milk obtained 6 weeks after deli-
very from women living in the vicinity of a copper and lead metal smelter and in a con-
trol area (Hal95). Milk Cd levels in women in the control area, 0.07 µg Cd/l, were
somewhat higher than in women from the smelter area, 0.05 µg Cd/l.
From the ADI for Cd of 400-500 µg/person/day an acceptable level of about 5 µg/l bre-
ast milk can be calculated (see Annex E).
Cadmium and its compounds                                                                  15
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<pre>2.3 Animal studies
    Tables 1 and 2 (annex D) summarise fertility and developmental studies with cadmium
    in experimental animals.
    Fertility studies, oral exposure
    In a multigeneration reproduction study with Charles River CD mice, Cd was offered
    continuously in the drinking water at a level of 10 mg/l. In this study the following ef-
    fects were observed: arterial hypertension, a high incidence of preweaning mortality,
    small litters, a low mating index and an extended precoital time (Sch71). The strain
    could not be bred beyond the F2b-generation.
         Chronic exposure of groups of random bred white male rats to 0.00005, 0.0005 or
    0.005 mg/kg body weight in the drinking water (dose levels corresponding to 0.001, 0.01
    and 0.1 mg Cd2+/l) resulted in the high dose group in several alterations, among them
    loss of body weight and a reduced spermatogenesis, and an increase of number of tubu-
    les with cast-off epithelium and with 12th stage meiosis (Kra76).
         Dixon et al. (1976) studied the effects of (I) a single oral dose of 0, 6.25, 12.5 and
    25 mg Cd/kg body weight or (II) of drinking water containing 0.001, 0.01 and 0.1 mg
    Cd/l for 90 days in rats (Dix76). After acute dosing serial matings were performed for
    70 days and testes were examined microscopically on day 1 and 7 and for 6 succeeding
    7-day intervals. No effect on fertility was observed after acute (I) or chronic (II) oral Cd
    administration .
         Kotsonis and Klaassen (1978) studied the toxicity of Cd in male Sprague Dawley
    rats after oral administration of CdCl2 in the drinking water (0, 10, 30 or 100 mg/l) for
    24 weeks (Kot78). Fertility was tested after 3, 6, 12 and 24 weeks and appeared not af-
    fected. At necropsy after 24 weeks no effect on testis weight and histopathology was ob-
    served. At 30 and 100 mg/l, effects on the kidney were detected.
         Groups of 9-10 male and female Sprague-Dawley rats were, starting from concep-
    tion, chronically exposed to 0, 0.1, 1.0 or 5.0 mg/l CdCl2 in the drinking water. They
    were sacrificed either on postnatal day (PN) 50 or around PN 130. Sacrifice on PN 50
    revealed a decreased liver weight in the 5.0 mg/l group, and no effect on sperm count.
    Adult sacrifice showed a decreased liver weight in the 1.0 and 5.0 mg/l groups, and a de-
    creased serum progesterone level and litter size, and an increased preimplantation loss in
    the 5.0 mg/l group (Las80).
         Groups of 14 male or female Sprague-Dawley rats were administered 0, 0.1, 1.0 or
    10 mg/kg body weight/day Cd (as CdCl2) by gavage for 6 weeks prior to and during a 3
    weeks mating period (with untreated females) (Sut80a and b). Body weights of males
    Cadmium and its compounds                                                                    16
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<pre>treated with 1.0 and 10 mg/kg body weight/day were depressed. No effects were found
on copulation ability, pregnancy or litter size. The treated males were also mated with
the treated females whose body weight was only depressed in the 10 mg group. Adverse
effects were observed in the 10 mg group on numbers of copulations, pregnancies, im-
plantation sites and on foetal body weight and length. The females of the mid and high
dose groups showed mild to overt signs of toxicity as concluded from body and organ
weights.
     Groups of male Sprague-Dawley rats were exposed to 0, 17.2, 34.4 or 68.8 mg/l Cd
in the drinking water for 70 days (Zen82). Following mating with untreated females, no
differences were observed in mating success, number of pregnancies, litter size and pup
body weight. Histological examination of the testis revealed no differences with the con-
trols.
     Bomhard et al. (1987) studied the chronic effects of single and multiple oral and
subcutaneous Cd administrations on the testis of Wistar rats (Bom87). Animals having
received orally (gavage) 1 x 100 or 1 x 200 mg/kg body weight or subcutaneously 1 x 2
or 1 x 2.5 mg/kg body weight showed severe lesions of the whole testicular parenchyma
with massive calcification of the necrotic tubules and pronounced fibrosis of the intersti-
tium. All animals receiving 2.5 mg/kg body weight subcutaneously had a Leydig cell tu-
mour in at least one testis. Rats treated with 2.5 mg/kg body weight did not differ in
appearance, general behaviour or food and water consumption of the control animals;
some transient inflammatory reactions were observed at the injection site.
     Andersen et al. (1988) studied the effects of a single oral dose of CdCl2 (0, 270, 530
and 790 µmol g/kg body weight 0, 30, 60 and 90 mg/kg) on mortality and tissue damage
in CBA/Bom male mice (And88). In the 30 mg/kg bw group effects were observed on li-
ver, stomach and duodenum. Effects on the testis were firstly observed in the 60 mg/kg
group.
     Male and female Sprague Dawley derived rats received CdCl2 by gavage at doses of
25, 51, 107 and 225 mg/kg body weight/day for 1 or 10 consecutive days or in drinking
water solutions at concentrations of 13-323 mg CdCl2/l for 10 consecutive days (Bor89).
After a single dose of CdCl2, an apparent treatment-related but not statistically signifi-
cant decrease in body weight was observed in the males. Furthermore, absolute and rela-
tive spleen weights were significantly lower and lung weights were significantly higher.
No effects were observed in the females after a single dose. Dose-dependent mortality
was observed in the 10 day gavage study. Body weight gain was reduced in a dose-de-
pendent manner in both males and females. Absolute and/or relative brain, liver, spleen,
lung, thymus, kidney and testis weights of treated males were reduced in a dose depen-
dent manner. In females, absolute and/or relative liver, spleen, thymus and kidney
weights were reduced in a dose dependent manner. Focal necrotic changes were observed
in renal tubular epithelium and tubular degeneration was reported in males and females.
Cadmium and its compounds                                                                   17
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<pre>Testicular and hepatic changes were observed in males. In the drinking water study
dose-dependent changes in body weight gain and absolute and/or organ weights were ob-
served. However, the testis weights of the Cd dosed males were comparable to those in
the controls.
     Male Wistar rats, age 5 weeks, were given 0 or 10 mg Cd/l in drinking water for 52
weeks. Animals were sacrificed at the end of week 28, 40 and 56 and examined for his-
topathological examination of testis, kidney and liver (Say91). All Cd-treated male rats
showed pathological testicular alterations, and liver and kidney damage after chronic ex-
posure. Cd levels were found to be highest in the kidney. At the end of the 52-week peri-
od, reproductive capacity of the Cd-treated rats was investigated by mating the treated
males with 2 untreated females. All control males and only 60% of the Cd-treated males
were fertile.
Fertility studies, subcutaneous exposure
A single subcutaneous injection of CdCl2 (10 mg/kg body weight) induced profound cel-
lular and vascular changes in the ovaries of prepuberal rats (Kar59). At 96 hours after
treatment some recovery of the ovary changes was observed; by 168 hours the process
of recovery was complete.
     A single subcutaneous injection of CdCl2 in adult rats (40 µmol Cd/kg body weight,
~ 4.5 mg/kg bw) resulted in decreased weights of testis, seminal vesicles and prostate
and severe histopathological changes of reproductive organs (Par60).
     Male CBA-mice were exposed to Cd by subcutaneous injection of 2.2 µmol
CdCl2/kg body weight (~ 0.2 mg/kg bw) for 5 days/week for 6 months (Nor75). A decre-
ase in normal (testosterone-dependent) proteinuria was shown and morphological exami-
nation of the seminal vesicles revealed a smaller weight and size as well as histological
indications of lower secretory activity of the epithelium compared to controls.
     Lohiya et al. (1976) injected male adult Langurs subcutaneously with a single dose
of 0, 4 or 12 mg CdCl2/kg body weight (Loh76). Animals dosed with 4 mg/kg were sa-
crificed after 30 days and animals dosed with 12 mg/kg were sacrificed after 60 days.
No effects of CdCl2 treatment on body weights were observed. Testes of the 12 mg/kg
group were small and oedematous; the weight of the reproductive organs was reduced. In
the 4 mg/kg group, no macroscopical effects on organ weights were observed. Histologi-
cal examinations of the testis and epididymis of CdCl 2 treated animals showed severe le-
sions in the testis and epididymis which were more severe in the high dose group.
     Groups of sexually immature and mature female Syrian hamsters (Cr:RGH), mice
(BALB/cAnNCr, DBA/2NCr, C57BL/6NCr, NFS/NCr) and rats (F344/NCr, WF/NCr)
received a single subcutaneous injection with 20 to 47.5 µmol CdCl 2/kg body weight
(2.2 to 5.3 mg/kg body weight) in the dorsal thoracic midline (Reh88). They were killed
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<pre>1 to 56 days after administration. Upon sacrifice ovarian necrosis was observed. The lo-
west adverse effect levels depended on species (hamster was the most susceptible), strain
(BALB mice were most, DBA mice were least susceptible; no difference between the rat
strains), and age (immature animals were more susceptible).
     Wlodarczyk et al. (1995) studied the effect of Cd on the male reproductive system
of Golden hamsters (Wlo95). Hamsters were subcutaneously injected with a single dose
of 0 or 0.5 mg Cd/kg body weight. Five males of each dose group were sacrificed 1, 4
and 10 weeks after treatment. The testis, epididymis and accessory sex glands were
weighed and histologically examined. Epididymal sperm was enumerated and sperm
morphology was evaluated. In the Cd-treated animals decrease in organ weight and pa-
thological changes of the reproductive organs were detected at all time intervals but in-
tensified to the end of the experiment (10 weeks). Furthermore, sperm number in the
epididymis was decreased.
Developmental toxicity, oral exposure
A multigeneration reproduction study with CD mice in which Cd was offered conti-
nuously in the drinking water at a level of 10 mg/l, resulted in maternal arterial
hypertension and a high incidence of runts and bent tails (Sch71).
     Groups of 14 female and male Sprague-Dawley rats were administered 0, 0.1, 1.0 or
10 mg Cd/kg food/day for 6 weeks by gavage, after which they were mated; exposure
continued during mating and gestation up to GD 20, when the females were sacrificed
(Sut80a and b). Adverse effects were observed in the 10 mg/kg group on foetal body
weight and length; the foetuses were anaemic and malnutritioned, but the placenta
weight was increased. Numbers of implantation sites and live foetuses decreased, and
number of resorptions increased significantly in the 10 mg group, and slightly in the 1.0
mg group. No malformations were observed. The females of the mid and high dose
groups showed mild to overt signs of toxicity. The treated males also mated with untrea-
ted females which showed no effects upon sacrifice.
     Untreated female Sprague-Dawley rats were mated to males, previously exposed to
0, 17.2, 34.4 or 68.8 mg Cd/l in drinking water (Zen82). Part of the females was sacrifi-
ced on GD 20. No adverse effects were observed. The other females were allowed to lit-
ter; the resulting offspring was followed for general and behaviourial changes, which
were not detected.
     Female CF1 mice were bred for 6 consecutive generations (Whe88). Levels of 0.25,
5.0 and 50 mg/kg food Cd (CdCl2) were added to the diet. The highest dose had no effect
on fertility or pup survival during lactation, but caused a 15% decrease in litter size at
birth and a 25% decrease in pup growth.
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<pre>     Andersson et al. (1997) gave Cd in the drinking water (5 mg/l) to female Sprague
Dawley rats during the lactation period, from parturition to postnatal day 17, and/or to
the offspring until postnatal day 42 (And97). Mean body weights of the dams and off-
spring, food and water intake were comparable to controls. Relative weights of liver,
kidney and brain were comparable as well. Plasma urea nitrogen levels in rats exposed
to Cd postweaning were significantly higher than in the control group, whereas exposure
during lactation and postweaning did not induce differences. No obvious neuropathology
was observed after Cd exposure. Exposure to Cd during lactation as low as 5 mg/l in
drinking water lead to neurochemical disturbances of the serotonergic system in off-
spring.
     Three consecutive generations of Wistar rats were orally (gavage) treated with 0,
3.5, 7.0 and 14.0 mg Cd/kg body weight as CdCl2 over the period of gestation, lactation
and 8 weeks after weaning (Nag97). Behavioural tests were performed in male rats from
each generation at the age of 12 weeks. Main results of the behavioural tests were chan-
ged in vertical exploration activity (rearing) and increased exploration of an open field
centre. The spontaneous and evoked electrophysiological variables showed dose-and ge-
neration dependent changes. In most tests the 3.5 mg/kg group was not affected. Treat-
ment with the mid- and high- dose resulted in significantly lower body weights. Pup body
weights were comparable to those in the control groups and there were no visible malfor-
mations. In the F3-generation reduced relative kidney and spleen weights were observed
in the high-dose group.
     Antonio et al. (1998) reported altered neurotransmitter levels in brains of new-born
Wistar rats after exposure to cadmiumacetate (10 mg/l) via the drinking water from the
start of pregnancy to parturition or until postnatal day 5 (Ant98).
     Corpas and Antonio (1998) exposed Wistar rats to Cd (10 mg/l) via drinking water
during gestation or during early lactation (from delivery until PN 5) (Cor98). Pups ex-
posed in utero were sacrificed on PN 0. Pups exposed during early lactation were sacri-
ficed on postnatal day 5. Pup weight, testicular and ovary weight were recorded at
necropsy. Furthermore, seminiferous tubule diameter and number of prospermatogonia
in the testis of the pups were measured. On postnatal day 5 ovary and testis weights we-
re reduced in the Cd-treated pups; in addition seminiferous tubule diameter and number
of prospermatogonia were reduced in Cd-treated pups on PN 0 and 5. On PN 0 and 5 a
reduced DNA/RNA ratio was observed in ovary and testis of the Cd-treated pups.
     Female Wistar rats were given orally (gavage) 0, 3.5, 7.0 or 14 mg Cd/kg body
weight as CdCl2 in 3 different treatment regimens: (I) GD 5-15, (II) GD 5-15 and 4
weeks postnatally or (III) GD 5-15, 4 weeks postnatally followed by the same treatment
of male rats of the F1-generation for 8 weeks (Dés98). Behavioural tests were performed
in F1-males at the age of 12 weeks. The number of pups/litter was slightly lower and the
pup weights were slightly (not significantly) decreased in the high dose group. Body
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<pre>weight gain of the male offspring was comparable to the control group. At necropsy kid-
ney weights of all treatment regimes of the high dose group were decreased. Behavioural
changes were observed in the 7 and 14 mg/kg group in the groups exposed during gesta-
tion and lactation. Some changes in the behavioural tests were only seen when F1-pups
were also treated with Cd during the postweaning period.
Developmental toxicity, other exposure routes
Parízek studied the effects in rats of Cd on the placenta after injection of 0.02 mmol Cd
salt/kg body weight (~ 2.2 mg/kg) between gestation day (GD) 17 and 21 (Par64). Sub-
cutaneous injection of Cd was followed in all cases by rapidly progressive placental
changes, chiefly in the pars foetalis, which was completely transformed within 24 hours
into an extensive blood clot with little remaining necrotic tissue. In most cases the pla-
cental changes were accompanied by haemorrhages into the uterine cavity and were
found within 6 hour after Cd injection. Complete destruction of the pars foetalis resulted
in interruption of pregnancy, with either delivery of the dead conceptus or resorption.
     Groups of 4 to 8 mated female Wistar rats [Crl:(WI)BR] received a subcutaneous
injection with 0, 40 or 50 µmol CdCl 2/kg (~ 4.5 or 5.6 mg/kg) on GD 12 or 18 (Sal89).
They were sacrificed on GD 19 or 20. A reduced blood flow in the chorionallantoic pla-
centa was measured after 12 days of exposure, both in the 40 and in the 50 µmol groups.
No foetal changes were inflicted in the 40 µmol Cd/kg group on GD12. On GD 18, 40
µmol/kg resulted in resorptions; the 50 µmol/kg group showed on GD 12 foetal lethality,
and on GD 18 both foetal lethality and a decreased foetal body weight. Malformations
were not observed, apart from 1 case of cleft palate in the 50 µmol/kg on GD 12 group.
     Pelletier and Satinder (1991) studied the effects of daily subcutaneous injection of
0.075 or 0.225 mg CdCl2/kg body weight during gestation in 3 genetic lines of rats: Ro-
man HighAvoidance (RHA), Roman Low Avoidance (RLA) and Satinder’s Heterogene-
ous stock (SHS) (Pel91). Cd-exposed progeny from the RHA line weighed significantly
less than control RHA progeny (PN 41-44); however, SHS progeny of the low-dose
group weighed significantly more than progeny from any other group (PN 14-44). Un-
conditioned response level (UER) was determined on PN 39 and acquisition of conditio-
ned avoidance responses was tested from PN 41-44. Significant effects on behaviour
were observed in the high dose group. Maternal body weights, food consumption, length
of gestation, litter size at birth and weaning, foetal mortality and physical development
were not affected by Cd treatment.
     Soukupova and Dostal (1991a) administered a single dose, subcutaneously, of 0, 2,
4 or 6 mg CdCl2/kg body weight on GD 8, 9, 10, 11, 12, 13 or 14 to random bred ICR
mice (Sou91a). The embryolethal effect was highest after treatment with 6.0 mg/kg on
GD 12 and 13 (50.0 and 61.3%). Among survivors foetuses with haemorrhagic bullae,
Cadmium and its compounds                                                                  21
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<pre>limb malformations, exencephaly, cleft palate, open eyelids and tail deformities occur-
red. Mainly right-sided limbs were malformed. Administration of 2 and 4 mg/kg body
weight induced fore limb polydactylies, whereas with 6 mg also oligodactylies were in-
duced. Foetal weight was only reduced in the 6 mg group dosed on GD 12. Reduction of
the foetal thymus weight was observed in the 6 mg groups dosed from GD 9-14.
     Soukupova et al. (1991b) exposed mated random bred ICR mice, subcutaneously, to
2.5 and 5 mg CdCl2/kg body weight on GD 16 and detected that the immune response of
their offspring was altered (Sou91b).
     Ferm et al. (1968) studied the effects of intravenous injection of 2 or 4 mg
3CdSO4.8H2O/kg body weight to pregnant golden hamsters on GD 7 (Fer68). Animals
were killed on GD 11 or 14. The number of embryonic resorptions and malformed foetu-
ses was increased in the Cd-treated groups. Maternal animals injected with 10 mg
3CdSO4.8H2O/kg body weight or more, all died shortly after injection. Cd levels from 5
- 10 mg induced foetal resorption rates of almost 100% without noticeable effect on the
mothers.
     Groups of 15 pregnant Wistar-Porton rats received a single intravenous injection of
1.1 or 1.25 mg Cd/kg body weight between GD 9 and 15 (Sam79). They were sacrificed
on GD 20. No effects were observed after administration of the low dose; the effects of
the high dose depended on, amongst others, the moment of injection: the later exposed,
the stronger the increase of resorptions and the larger the decrease in number of abnor-
mal foetuses. The observed malformations included hydrocephalus, an- and microphthal-
mia, gastroschisis and umbilical hernia. A reduction in maternal blood flow was
observed.
     Hartsfield et al. (1992) injected Syrian golden hamsters intravenously with 0, 2 and
3 mg CdCl2 on GD 7; females were sacrificed on GD 14 and foetuses were weighed and
examined for viability and external malformations (Har92). Resorptions were noted.
Maternal body weight of the Cd treated groups was reduced. The number of non-viable
foetuses and foetuses with malformations were increased in the 2 and 3 mg Cd group
and foetal weight and length were decreased in these groups.
     De et al. (1993) studied the effects of Cd exposure during the preimplantation period
of pregnancy on the subsequent development and implantation of mouse embryos. Injec-
tion with 38 µmol Cd/kg body weight (~4.3 mg) on GD 1 had little effect on the initia-
tion and maintenance of pregnancy when examined on GD 7 (De93). At examination of
a similar treated group on GD 4, sites were absent in 62 % of the females. Thus, Cd tre-
atment on GD 1 delayed temporarily, but did not prevent implantation and was not em-
bryolethal. The same dose administered on GD 3 caused pregnancy failure in all mice
examined on GD 7; no implantation sites were detected on GD 4.
Cadmium and its compounds                                                                  22
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<pre>    Lactation
    Lucis and Shaikh (1972) injected 109Cd subcutaneously to rats during pregnancy or du-
    ring the lactation period (Luc72). In both cases 109Cd was present in a low concentra-
    tions in the milk recovered from the stomach of the pups.
         Houpert et al. (1997) studied the amount of Cd eliminated through milk in ewes
    (Hou97). After Cd was orally or intravenously administered, the levels in milk increased
    rapidly and could be detected 6 hours after administration. Levels reached a maximum
    value on the 2nd or 3rd day after administration. These values then decreased, first
    quickly and later slowly.
2.4 Overall conclusion
    Only a few publications concerning the effects of cadmium and its compounds on human
    fertility were found. Mason (Mas90), Gennart et al. (Gen92) and Keck et al. (Kec95)
    did not report an effect on fertility related to Cd exposure. Xu et al. (Xu93) detected a
    relation between increased Cd concentrations in blood and decreased sperm density in
    oligozoospermic men but not in normospermic men. Furthermore, in the publication of
    Mason (Mas90) it was reported that renal effects were found in the absence of testicular
    endocrine effects.
         In animal studies, effects of Cd treatment on male and female reproductive organs
    were observed after oral or subcutaneous administration (gavage, drinking water or diet)
    in rats, mice, hamsters and monkeys (Kar59, Par60, Sch71, Nor75, Kra76, Loh76,
    Las80, Sut80a, 80b, Bom87, And88, Reh88, Bor89, Say91, Wlo95). Laskey et al.
    (Las80), Sutou et al. (Sut80a, 80b), Andersen (And88), Borzelleca et al. (Bor89) and
    Saygi et al. (Say91) detected effects on the reproductive organs or fertility at dose levels
    which caused general toxicity (effects on kidney, liver or body weight). In other studies
    general toxicity was not always described but may be present in view of the levels used
    (Kar59, Par60, Sch71, Nor75, Kar76, Loh76, Bom87, Reh88, Wlo95). Dixon et al.
    (Dix76), Kotsonis et al. (Kot78) and Zenick et al. (Zen82) did not find any effects on
    fertility.
         In conclusion, the committee recommends to classify cadmium and its compounds
    for fertility in category 3 (substances which cause concern for human fertility) and to la-
    bel the compounds with R 62 (possible risk of impaired fertility).
    In human studies involving Cd, effects were observed on birth weight (Kuh87, Loi92),
    motor and perceptual abilities (Bon86) and mental retardation of offspring (Mar83). Ho-
    wever, it is not clear from these studies whether the effects described were due to expo-
    sure to Cd or to other substances (i.e Pb exposure).
    Cadmium and its compounds                                                                    23
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<pre>     In animal studies, effects of Cd on development (resorptions, foetal death, malfor-
mations, foetal/pup weight, behavioural performance, neurochemical disturbances of the
serotonergic system and altered immune response) were observed after subcutaneous or
oral administration (gavage, drinking water or diet) in rats, mice, hamsters (Par64,
Fer68, Sch71, Sam79, Sut80a and b, Whe88, Sal89, Pel91, Sou91a and b, Har92,
De93, And97, Nag97, Ant98, Dés98). Furthermore, in utero Cd exposure affected the
development of the reproductive organs in the offspring (Cor98). In the animal studies
maternal toxicity was often not described in detail; however, general toxicity may be as-
sumed due to the levels used.
     In conclusion, based on the effects found in animal studies, which predominantly oc-
curred at levels of maternal toxicity, the committee recommends to classify cadmium and
its compounds in category 3 (substances which cause concern for humans owing to pos-
sible developmental toxic effects) and label to compounds with R 63 (possible risk of
harm to the unborn child).
In most publications cited (Cas77, Lar81, Vuo83, Kov84, Rad87, Sch88, Zah89 End92
Plö93, Hal95), Cd levels in human breast milk were below the calculated safe level of
about 5 µg/l. However, in 2 publications from India and Germany Cd levels were detec-
ted in human breast milk in concentrations of about 20 µg/l (Sha83, Ste85).
     Cd was detected in milk of animals (Luc72, Hou97).
     In conclusion, the committee recommends to label Cd with R64 (May cause harm
for breastfed babies).
Proposed classification for fertility
Category 3, R 62.
Proposed classification for developmental toxicity
Category 3, R 63.
Proposed labelling for effects during lactation for Cd
R64.
Cadmium and its compounds                                                                 24
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<pre>For the committee,
The Hague, 3 May 2000
dr ASAM van der Burght,   dr BJ Blaauboer,
scientific secretary      chairman
Cadmium and its compounds                  25
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<pre>Sou91b Soukupova D, Dostal M., Piza J. Developmental toxicity of cadmium in mice. II. Immunotoxic effects.
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Bar82  Barlow SM, Sullivan FM. Cadmium and its compounds In: Reproductive hazards of industrial chemicals.
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Bha82  Bhattacharyya MH, Whelton BD, Peterson D. Gastrointestinal absorption of cadmium in mice during ge-
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       References                                                                                                  29
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<pre>Bru95 Brus R, Kostrzewa RM, Felinska W, et al. Ethanol inhibits cadmium accumulation in brains of offspring
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Byc94 Byckowski J Z, Gearhart JM, Fisher JW. “Occupational” exposure of infants to toxic chemicals via bre-
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Eis94 Eisenmann CJ, Miller RK. The placental transfer and toxicity of selenite relative to cadmium in the hu-
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Gup96 Gupta A, Shukla GS. Ontogenic profile of brain lipids following perinatal exposure to Cadmium. J Appl
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Kab98 Kabzinski AKM. Application of covalent affinity chromatography with thiol-disulphide interchange for
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<pre>Par57 Parizek J. The destructive effect of cadmium ion on testicular tissue and its prevention by Zinc. J Endo-
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Pia94 Piazek M, Laskey JW. Acute cadmium exposure and ovarian steroidogenesis in cycling and pregnant
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Pie78 Pietrzak-Flis Z. Rehnberg GL, Favor MJ, et al. Chronic ingestion of cadmium and/or tritium in rats. En-
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Whe93 Whelton BD. Cadmium-109 metabolism in mice. IV. Diet versus maternal stores as source of cadmium
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      References                                                                                                 31
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<pre>A The committee
B Comments on the public draft
C Directive (93/21/EEG) of the European Community
D Fertility and developmental toxicity studies
E Calculation safe levels of Cd in (human) breast milk
F Abbreviations
  Annexes
                                                       32
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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                                                                          33
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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                                                                            34
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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 organi-
         sations have commented on the draft document.
      Comments on the public draft                                                            35
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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                                                         36
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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                                                              37
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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                                                            38
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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                                                                 39
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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                                                                40
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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                                                             41
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<pre>Annex D
      Fertility and developmental toxicity
      studies
      Fertility and developmental toxicity studies 42
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<pre>Table 1.1 Fertility studies in animals with Cd.
authors       species         route       experimental period         dose         findings                            remarks
Kar et al.    Colony bred     s.c. injec- administration: a single    0 or 10 mg   Cellular and vascular changes in
(1959)        albino rat      tion        dose                        CdCl2/       the ovary; partly recovered after
              (n=?)                       sacrifice:                  kg bw        96 h, completely recovered after
                                          0,6,24,48,96,168,360 h                   168 h
                                          after injection
Parízek       Rat (n=?)       s.c. injec- administration: a single    0 or 40 µmol Decreased weights of testis, se-    Experimental
(1960)                        tion        dose                        CdCl2/kg bw  minal vesicles and prostate.        procedures
                                          sacrifice: up to 4 months   (4.5 mg/kg   Severe histopathological changes    poorly descri-
                                          after injection             bw)          of reproductive organs              bed.
Schroeder     Charles Ri-     drinking    multigeneration study       0 or 10 mg   arterial hypertension, low mating
and Mitche- ver DC            water       administration: conti-      Cd/l         index, small litters, high pup
ner (1971)    mouse (ma-                  nuously                                  mortality, strain could not be
              les & fema-                                                          bred beyond F2b-generation
              les) (:n=5)
Nordberg      Male CBA-       s.c. injec- administration: 5 d/w for 0 or 2.2 µmol  Decreased proteinuria and a de-
(1975)        mice            tion        6 m.                        CdCl2/kg bw  creased weight and size of the se-
              (n=8)                                                   (0.2 mg/kg   minal vesicles. Indications of a
                                                                      bw)          lower secretory capacity of semi-
                                                                                   nal vesicles.
Dixon et al.  Sprague-        gavage      1) acute, serial breeding   1) 0, 6.25,  1) no effects on male fertility we-
(1976)        Dawley rats     (1) or      2) subchronic               12.5 or 25   re observed
              (n=10)          drinking    administration: 1) single   mg CdCl2     2) no effects on body weight and
                              water (2)   dose to males 2) 30, 60,    2) 0, 0.001, weights of testis, prostate and se-
                                          90d.                        0.01 or 0.1  minal vesicles. No effects on cli-
                                          sacrifice: 1) up to 6 w af- mg CdCl2/l   nical parameters and serum
                                          ter injection 2) 30, 60, 90              hormone levels. No effect on tes-
                                          d                                        tis histopathology.
Krasovskii et random bred drinking        administration: conti-      0, 0.00005,  0.005 mg: decreased body
al. (1976)    white rat       water       nuously                     0.0005 or    weight, reduced spermatogenesis
              (males)                                                 0.005 mg
              (n=?)                                                   Cd/kg bw
bw = body weight; w=week; d = day; s.c. = subcutaneous; PN = postnatal
             Fertility and developmental toxicity studies                                                                         43
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<pre>Table 1.2 Fertility studies in animals with Cd.
authors    species        route       experimental       dose             findings                                   remarks
                                      period
Lohiya et Langurs         s.c. injec- administration:    1) 0 or 4 mg     2) testis small and oedematous; weight
al. (1976) (male adult) tion          single dose        CdCl2/ kg bw     reproductive organs reduced. 1) + 2)
           (n=3)                      sacrifice: 1) 30   2) 0 or 12 mg    dose depended histological lesions in
                                      d after injection; CdCl2/ kg bw     testis and epididymis.
                                      2) 60 d after in-
                                      jection
Kotsonis   Sprague-       drinking    administration: 0, 10, 30 or 100    At 30 and 100 mg/l tubular necrosis in
and        Dawley rats water          continuously for mg/l CdCl2         kidney.
Klaassen   (males)                    24 w                                No effect on fertility; no effects on his-
(1978)     (n=6)                      sacrifice:                          topathology and weight of testis
                                      3,6,12,24 w
Laskey et Sprague-        drinking    administration: 0, 0.1, 1.0 or 5.0  1.0 mg: PN 130 depressed liver weight
al. (1980) Dawley rat     water       continuously       mg CdCl2/l       5.0 mg: PN 50+130 depressed liver
           (males &                   sacrifice: PN 50,                   weight; preimplantation loss, reduced
           females)                   130                                 litter size
           (n=9-10)
Sutou et Sprague-         gavage      administration: 0, 0,1, 1.0 or 10   untreated females: -                       NB treated males
al.        Dawley rat                 6 w prior to ma- mg CdCl2 /kg       treated females, mid & high dose: re-      were mated with
(1980a,b) (males &                    ting, mating, ge- bw                duced body and organ weight, high do-      treated and
           females)                   station                             se: reduced copulation, no. of implants,   untreated females
           (n=13-14)                                                      no. live foetuses, foetal body weight,
                                                                          length
Zenick et Sprague-        drinking    administration:    0, 17.2, 34.4 or no effect on reproductive system
al. (1982) Dawley rat     water       70 d               68.8 mg Cd/l     no effect on reproductive parameters
           (males)                                       (0, 1 2 and 4
           (n=5)                                         mg/kg bw)
bw = body weight; w=week; d = day; s.c. = subcutaneous; PN = postnatal
            Fertility and developmental toxicity studies                                                                            44
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<pre>Table 1.3 Fertility studies in animals with Cd.
authors       species           route             experimental period dose            findings                         remarks
Bomhard       Wistar rats ma- 1) gavage           1) single dose       1) 0 or 50 mg  1) effects comparable with
et al. (1987) le                                                       CdCl2/ kg bw   controls
              n=30/ Cd group 2) s.c. injection 2) single dose          2) 0 or 2.5 mg 2) transient inflammatory re-
              n=10/control                                             CdCl2/ kg bw   action at injection site, severe
              group                                                                   lesions testes and malignant
                                                                                      Leydig cell tumours in all
                                                                                      animals
                                3) gavage         3) 10 weekly doses   3) 0 or 5 mg   3) effects comparable with
                                                                       CdCl2/kg bw    control
                                4) s.c. injection 4) 10 weekly doses 4) 0 or 0.25 mg  4) effects comparable with
                                                  Studies 1-4: necrop- CdCl2 /kg bw   controls
                                                  sy after 12, 18 and
                                                  30 months
              Supplementary                       Supplementary stu- Supplementary
              studies 5 and 6                     dies:                studies:
              25 males/group 5) gavage            5) single dose       5) 0 or 200 mg 5) most animals (28 of 35)
                                                                       CdCl2 /kg bw   died within 3 days after admi-
                                                                                      nistration; other animals se-
                                                                                      vere lesions testis
                                6) s.c.           6) single dose       6) 0 or 2 mg   6) transient inflammatory re-
                                injection                              CdCl2 /kg bw   action at injection site and
                                                                                      transient decrease body
                                                                                      weight; severe lesions testis
              study 7           7) gavage         7) single dose       7) 0 or 100 mg 7) most animals died (24 of
              35 males/group                      Studies 5-7: necrop- CdCl2 /kg bw   25); 1 animal severe lesions
                                                  sy after 6 months                   testis
bw = body weight, s.c. = subcutaneous
             Fertility and developmental toxicity studies                                                                   45
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<pre>Table 1.4 Fertility studies in animals with Cd.
authors      species             route          experimental pe- dose                     findings                               remarks
                                                riod
Andersen     CBA/Bom male        oral           administration:     0, 270, 530, 790      Histological effects on liver,
et al.       mice (n=7-15)       (stomach       single dose         µmol/kg bw            stomach and duodenum were firstly
(1988)                           tube)          sacrifice: 10 d af- (0,30,60,90           observed in the 30 mg/kg group
                                                ter dosing          mg/kg bw)             Histological effects on testis were
                                                                                          firstly observed in the 60 mg/kg
                                                                                          group
Rehm and hamster (1              s.c. injec-    administration: a   0 or 20-47.5          40 µmol/kg group: species, age and
Waalkes strain) (n=6-48) tion                   single dose at      µmol/kg bw            strain dependent severe toxicity to
(1988)       mouse (3 strains)                  21-24 d, or 8 w     (2.2 -5.3 mg/         lethality due to liver necrosis
             (n=5-12)                           old sacrifice:      kg bw)                all hamsters, most groups mice and
             rat (2 strains)                    1,2,3,4,7,14,28,5                         high dose groups rats: haemorrhagic
             (n=4-35)                           6 d after admini-                         necrosis of the ovaries
             (females)                          stration
Borzella et Sprague-Dawley 1) gavage            administration:     1) 0, 25, 51, 107 or  1d gavage: not statistically signifi-
al.          rats (male and fe- or              1) 1 or 10 conse-   225 mg CdCl2/ kg      cant effects on body weights, statis-
(1989)       male)               2) drinking    cutive days, 2)     bw, 2) 0 or 13-323    tically significant effects on spleen
             (n=10)              water          10 d                mg CdCl2/l            and lung weights of males
                                                necropsy: 24 h                            10 d gavage: dose-dependent effects
                                                after last dosing                         on mortality, body weights, organ
                                                                                          weights (inclusive testis) of male
                                                                                          and females. Histopathological
                                                                                          changes in kidney, testis and liver
                                                                                          Drinking water: dose-dependent ef-
                                                                                          fects on body weights and organ
                                                                                          weights (not testis)
bw = body weight; d = day; s.c. = subcutaneous; w = week
Table 1.5 Fertility studies in animals with Cd.
authors        apecies          route        experimental period       dose          findings                                   remarks
Saygi et al.   Wistar rats      drinking     administration: conti- 0 or 10 mg       Histopathological effects on testis, liver
(1991)         (control n=8;    water        nuously for 52 w to       CdCl2/l       and kidney.
               experimental                  males only                              Reduced fertility after 52 weeks Cd ex-
               group n=20)                   necropsy: 28, 40, 56 w                  posure (100% control v.s. 60% Cd-trea-
                                                                                     ted males)
Wlodarczyk Golden ham-          s.c injec- administration: single 0 or 0.5 mg        Decreased weights and histopathological
et al. 1995 sters (males)       tion         dose                      CdCl2/kg      changes of testis, epididymis and acces-
               (n=15)                        necropsy: 1,4,10 w af- bw               sory sex organs.
                                             ter treatment                           Decreased number of sperm cells in epi-
                                                                                     didymis after 4 weeks of treatment.
bw = body weight; s.c. = subcutaneous; w = week
              Fertility and developmental toxicity studies                                                                            46
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<pre>Table 2.1 Developmental toxicity studies in animals with Cd.
authors            species     route      experimental pe- dose          findings                           remarks
                                          riod
Pa ízek (1964)     Wistar rat  s.c. in-   Administration:   0 or 0.02    rapid progressive placental chan-
                   (control    jection    single dose bet-  mmol         ges mainly of pars foetalis resul-
                   n=12; Cd               ween GD 17-21     CdCl2/kg bw  ting in a extensive blood clot
                   group n=70)                              ( 2.2 mg/kg) within 24 h and interruption of
                                                                         pregnancy.
Ferm et al.        Golden      i.v. in-   Administration: 0, 2 or 4 mg   Increased number of embryonic Maternal animals
(1968)             hamsters    jection    single dose of on 3CdSO4.8H2   resorptions and malformed foetu- receiving more
                   (n=14-20)              GD 7.             O/ kg bw     ses.                               than 10 mg/kg all
                                          Sacrifice: GD 11                                                  died. Cd levels of
                                          or 14                                                             5-10 mg/kg indu-
                                                                                                            ced 100% fetal re-
                                                                                                            sorptions without
                                                                                                            effects on mo-
                                                                                                            thers.
Schroeder & Mit- Charles Ri- drinking multigeneration       0 or 10 mg   maternal arterial hypertension,
chener (1971)      ver CD      water      study             CdCl2/l      runts, bent tails
                   mouse (n=5)            administration:
                                          continuously
Samarawickrama Wistar-         i.v. in-   administration: 0, 1.1 or 1.25 1.1 mg: no effects
and Webb (1979) Porton rat     jection    1x, on GD         mg Cd/kg bw  1.25 mg: reduced maternal blood
                   (n=15)                 10,11,12,13,14                 flow, time of administration-de-
                                          or 15                          pendent decrease litter size, in-
                                          sacrifice: GD 20               crease resorptions, incidence of
                                                                         hydrocephalus, an-&microphthal-
                                                                         mia, gastroschisis, umbilical her-
                                                                         nia
Sutou et al.       Sprague-    gavage     administration: 6 0, 0.1, 1.0, 1-10 mg: reduced maternal body
(1980a,b)          Dawley rat             w prior to ma-    10 mg CdCl2  and organ weight
                   (n=13-14)              ting, mating, ge- /kg bw       10 mg: increased placenta
                                          station                        weight, no. resorptions; reduced
                                          sacrifice: GD 20               foetal bw & length, no. implanta-
                                                                         tion sites, live foetuses
             Fertility and developmental toxicity studies                                                                    47
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<pre>Table 2.2 Developmental toxicity studies in animals with Cd.
authors       species       route     experimental    dose           findings                                      remarks
                                      period
Zenick et al. Sprague-      drinking administration   0, 17.2, 34.4, GD 20 sacrifice: no foetal effects, postnatal NB: the fema-
(1982)        Dawley rat    water     males: 70 d     68.8 mg Cd/l behavioural assessment: no effects              les were not
              (n=5 males              sacrifice fema- (0, 1, 2 and 4                                               exposed
              and 15 fema-            les: GD 20 or   mg/kg bw)
              les)                    females were
                                      allowed to lit-
                                      ter
Whelton       CF1 mice      diet      administration: 0, 0.25, 5 or 50 mg: no effect on fertility and survival,
et al. (1988) (n=60-77)               continuously    50             decreased litter size (15%) and decreased
                                      for 6 genera- mg CdCl2/kg pup growth (25%)
                                      tions
Saltzman      Wistar rat    s.c. in-  administration: 0, 40 or 50    reduced maternal blood flow from uterus to
et al. (1989) (n=4-8)       jection   GD 12 or 18     µmol           chorioallantoic placenta causing time- and
                                      sacrifice:      CdCl2/kg       dose-dependent foetolethality
                                      GD 20 or 19     ( 4.5 or 5.6
                                                      mg/kg)
Pelletier     3 genetic     s.c. in-  administration: 0, 0.075 or    Different effects of Cd on progeny weights.
and Satinder lines of rats  jection   daily during    0.225 mg       Significant effects on behaviour high-dose
(1991)        (n=9)                   gestation       CdCl2/kg bw group
                                                                     No effects on physical development, body
                                                                     weight, food consume, length of gestation,
                                                                     litter size, foetal mortality
Suokupova ICR mice          s.c. in-  administration: 0, 2 or 6 mg   Embryolethlity statistically sifnificantly
et al. 1991a (n=?)          jection   single dose on CdCl2 kg/bw     correlated to day of treatment (highest on
                                      GD 8, 9, 10,                   GD12 and 13.6 mg/kg).
                                      11, 12, 13, 14                 Haemorrhagic bullae, (right-sided) limb
                                      sacrifice:                     malformations, exencephaly, cleft palate,
                                      GD18                           open eyelids and tail deformities were obe-
                                                                     served.
                                                                     Reduced foetal thymus weight GD9-14 in
                                                                     higher dose groups
             Fertility and developmental toxicity studies                                                                       48
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<pre>Table 2.3 Developmental toxicity studies in animals with Cd.
authors    species         route       experimental    dose               findings                                       remarks
                                       period
Suokupova ICR mice         s.c. injec- administration: 0, 2.5 or 5.0 mg   Deviations in several immune functions of off-
et al.     (n=4)           tion        single dose on CdCl2 kg/bw         spring
1991b                                  GD 16
Hartsfield Syrian gol- i.v. injec- administration: 0, 2 or 3 mg           Reduction maternal body weight increased
et al.     den hamsters tion           single dose on CdCl2 /kg bw        number of non-viable foetuses and foetuses
(1992)     (n=10)                      GD 7                               with malformations; fetal weight and length
                                       sacrifice: GD                      were decreased
                                       14
De et al.  CD-1 mice       s.c. injec- administration: 0, 25 or 38 µmol   Cd on GD 1: Cd delayed implantation, not em-
(1993)     (n=3-15)        tion        single injec-   CdCl2 /kg bw (2.9  bryolethal at GD 7
                                       tion on GD 1 or 4.3 mg/kg bw)      Cd on GD 3: no implantation sited at GD 4,
                                       or 3                               pregnancy failures at GD 7
                                       sacrifice: GD 4
                                       or 7
Andersson Sprague-         drinking    administration: 0 or 5 mg CdCl2 /l No effects on body weights, food and water in-
et al.     Dawley rats     water       dams from                          take of dams and offspring. No effect on
(1997)     (n=4)                       parturition to                     weights of liver, kidney and brain of pups.
                                       PN 17.                             Increased levels of plasma nitrogen only in
                                       Offspring: PN                      pups exposed postweaning.
                                       day 17-42                          No obvious neuropathological effects.
                                       Sacrifice: 1 w                     Cortical serotonin levels were reduced in pups
                                       after treatment                    of all Cd groups
w = body weight; s.c. = subcutaneous; i.v. = intravenous; GD = gestation day
            Fertility and developmental toxicity studies                                                                      49
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<pre>Table 2.4 Developmental toxicity studies in animals with Cd.
authors     species      route    experimental period         dose           findings                                    remarks
Nagy-       Wistar rats gavage    administration: 5 d/w du- 0, 3.5, 7.0 or   7 and 14 mg/kg reduced BW of parents
majtényi et (n=5-10)              ring pregnancy, lactation 14.0 mg          7 and 14 mg/kg affected most behavioural
al. (1997)                        and 8 weeks after wea-      CdCl2/kg bw    and electrophysiological parameters of ma-
                                  ning for 3 generations (fe-                le rats investigated at the age of 12 weeks
                                  males 7 d/w from start                     No effects on pup body weights, no visible
                                  mating until weaning)                      malformations and no clinical signs
                                                                             In F3-gen. kidney and spleen weights were
                                                                             reduced in highest dose group
Antonio et Wistar rat    drinking administration: from ini-   0 or 10 mg     Altered neurotransmitter levels in several
al. (1998) (n=4)         water    tiation of pregnancy to     Cd-acetate /l regions of the brain
                                  parturition or to PN 5
Corpas et   Wistar rat   drinking administration:             0 or 10 mg     On PN 0 and 5 diameter of seminiferous
al. (1998)  (n=4)        water    1) during gestation         Cd-acetate /l tubule, number of prospermatogo nia and
                                  2) during gestation and                    DNA, RNA and protein content of testis
                                  up to PN 5                                 and ovary were reduced.
                                  sacrifice of pups:                         On PN 5 weight of testis and ovary were
                                  1) PN 0; 2) PN 5                           reduced.
Dési et al. Wistar rat   gavage   administration:             0, 3.5, 7.0 or Pups, litter, pup weight and kidney weight
(1998)      (n=?)                 1) GD 5-15,                 14.0 mg        were decreased in high dose group.
                                  2) GD 5-15 + 4 w post-      CdCl2 /kg bw Behavioural and electrophysiological tests
                                  natal                                      of F1 males of 12 w old were influenced
                                  3) GD 5-15 + 4 w post-                     by Cd
                                  natal + F1-males 8 w
w = body weight; d = day; w = week; GD = gestation day; PN = postnatal
             Fertility and developmental toxicity studies                                                                     50
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<pre>Annex E
      Calculation safe levels of Cd in (human)
      breast milk
      Assumptions:
          Body weight woman: 60 kg
          Body weight infant: 4.5 kg (4-5 kg)
          Intake breast milk: 900 ml (800-1000ml)
          An infant is as sensitive for the effects of Cd as an adult.
      The Dutch Health Council (1988) proposed a safe intake level of 400-500 µg/per-
      son/week.
          This results in a calculated intake of 57-71 µg/person/day and 0.95-1.18 µg/kg body
      weight/day. Safe intake level per infant is 4.28-5.31 µg/infant/day. Safe level of Cd in
      breast milk is 4.76-5.9 µg/l.
          In conclusion, the committee considers 5 µg Cd/l breast milk as a safe level.
      Calculation safe levels of Cd in (human) breast milk                                     51
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<pre>Annex F
      Abbreviations
      Abbreviations used:
      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                                                    52
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