<b>Bijsluiter</b>. De hyperlink naar het originele document werkt niet meer. Daarom laat Woogle de tekst zien die in dat document stond. Deze tekst kan vreemde foutieve woorden of zinnen bevatten en de opmaak kan verdwenen of veranderd zijn. Dit komt door het zwartlakken van vertrouwelijke informatie of doordat de tekst niet digitaal beschikbaar was en dus ingescand en vervolgens via OCR weer ingelezen is. Voor het originele document, neem contact op met de Woo-contactpersoon van het bestuursorgaan.<br><br>====================================================================== Pagina 1 ======================================================================

<pre>             Health Council of the Netherlands
          Tellurium
             Evaluation of the effects on reproduction,
             recommendation for classification
2014/07
</pre>

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<pre>Tellurium
     Evaluation of the effects on reproduction,
     recommendation for classification
</pre>

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<pre></pre>

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<pre>Aan de minister van Sociale Zaken en Werkgelegenheid
Onderwerp             : Aanbieding advies Tellurium
Uw kenmerk            : DGV/MBO/U-932542
Ons kenmerk           : U-8075/HS/cn/543-H14
Bijlagen              :1
Datum                 : 3 april 2014
Geachte minister,
Graag bied ik u hierbij het advies aan over de effecten van tellurium op de vruchtbaarheid
en het nageslacht; het betreft ook effecten op de lactatie en via de moedermelk op
de zuigeling.
      Dit advies maakt deel uit van een uitgebreide reeks waarin voor de voortplanting
giftige stoffen worden geclassificeerd volgens richtlijnen van de Europese Unie. Het gaat
om stoffen waaraan mensen tijdens de beroepsuitoefening kunnen worden blootgesteld.
Dit advies is opgesteld door een vaste commissie van de Gezondheidsraad,
de Subcommissie Classificatie reproductietoxische stoffen. Het is vervolgens getoetst
door de Beraadsgroep Gezondheid en omgeving van de Gezondheidsraad.
Ik heb dit advies vandaag ter kennisname toegezonden aan de staatssecretaris van
Infrastructuur en Milieu en aan de minister van Volksgezondheid, Welzijn en Sport.
Met vriendelijke groet,
prof. dr. W.A. van Gool,
voorzitter
Bezoekadres                                                        Postadres
Rijnstraat 50                                                      Postbus 16052
2515 XP Den Haag                                                   2500 BB Den Haag
E - m a il : s .s t o u t e n @ g r. n l                           w w w. g r. n l
Te l e f o o n ( 0 7 0 ) 3 4 0 7 0 0 4
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<pre></pre>

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<pre>Tellurium
Evaluation of the effects on reproduction,
recommendation for classification
Subcommittee on the Classification of Reproduction Toxic Substances,
a Committee of the Health Council of the Netherlands
to:
the Minister of Social Affairs and Employment
No. 2014/07, The Hague, April 3, 2014
</pre>

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<pre>The Health Council of the Netherlands, established in 1902, is an independent
scientific advisory body. Its remit is “to advise the government and Parliament on
the current level of knowledge with respect to public health issues and health
(services) research...” (Section 22, Health Act).
     The Health Council receives most requests for advice from the Ministers of
Health, Welfare & Sport, Infrastructure & the Environment, Social Affairs &
Employment, Economic Affairs, and Education, Culture & Science. The Council
can publish advisory reports on its own initiative. It usually does this in order to
ask attention for developments or trends that are thought to be relevant to
government policy.
     Most Health Council reports are prepared by multidisciplinary committees of
Dutch or, sometimes, foreign experts, appointed in a personal capacity. The
reports are available to the public.
                 The Health Council of the Netherlands is a member of the European
                 Science Advisory Network for Health (EuSANH), a network of science
                 advisory bodies in Europe.
This report can be downloaded from www.healthcouncil.nl.
Preferred citation
Health Council of the Netherlands. Tellurium - Evaluation of the effects on
reproduction, recommendation for classification. The Hague: Health Council of
the Netherlands, 2014; publication no. 2014/07.
all rights reserved
ISBN: 978-90-5549-996-0
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<pre>   Contents
   Samenvatting 9
   Executive summary 11
   Scope 13
.1 Background 13
.2 Committee and procedure 13
.3 Labelling for lactation 14
.4 Data 15
.5 Presentation of conclusions 15
.6 Final remark 16
   Tellurium 17
.1 Introduction 17
.2 Human studies 18
.3 Animal studies 19
.4 Conclusions 24
   References 27
   Contents                       7
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<pre>  Annexes 29
A The Committee 31
B The submission letter (in English) 33
C Comments on the public draft 35
D Regulation (EC) 1272/2008 of the European Community 37
E Additional considerations to Regulation (EC) 1272/2008 49
F Developmental toxicity studies 51
  Tellurium
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<pre>Samenvatting
In het voorliggende advies heeft de Gezondheidsraad tellurium onder de loep
genomen. Tellurium wordt gebruikt als additief in koper, ijzer en staal, in
gevulcaniseerd rubber, als pigment in glas en keramiek, en in sommige andere
applicaties. Dit advies past in een reeks adviezen waarin de Gezondheidsraad op
verzoek van de minister van Sociale Zaken en Werkgelegenheid de effecten van
stoffen op de voortplanting beoordeelt. Het gaat vooral om stoffen waaraan
mensen tijdens de beroepsuitoefening kunnen worden blootgesteld. De
Subcommissie Classificatie reproductietoxische stoffen van de Commissie
Gezondheid en beroepsmatige blootstelling aan stoffen van de raad, hierna
aangeduid als de commissie, kijkt zowel naar effecten op de vruchtbaarheid van
mannen en vrouwen als naar effecten op de ontwikkeling van het nageslacht.
Daarnaast worden effecten op de lactatie en via de moedermelk op de zuigeling
beoordeeld.
Op basis van Verordening (EG) 1272/2008 van de Europese Unie doet de
commissie een voorstel voor classificatie. Voor tellurium komt de commissie tot
de volgende aanbevelingen:
• voor effecten op de fertiliteit adviseert de commissie om tellurium niet te
    classificeren wegens onvoldoende geschikte gegevens
• voor effecten op de ontwikkeling adviseert de commissie tellurium te
    classificeren in categorie 1B (stoffen waarvan verondersteld wordt dat zij
Samenvatting                                                                    9
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<pre>      toxisch zijn voor de menselijke voortplanting) en te kenmerken met H360D
      (kan het ongeboren kind schaden)
  •   voor effecten tijdens of via lactatie adviseert de commissie om tellurium niet
      te kenmerken wegens onvoldoende geschikte gegevens.
0 Tellurium
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<pre>Executive summary
In the present report, the Health Council of the Netherlands reviewed tellurium.
Tellurium is used as an additive to copper, iron and steel, in vulcanized rubber, as
a colouring agent in glass and ceramics, and in some other applications. This
report is part of a series, in which the Health Council evaluates the effects of
substances on reproduction, at request of the Minister of Social Affairs and
Employment. It mainly concerns substances to which man can be occupationally
exposed. The Subcommittee on the Classification of Reproduction Toxic
Substances of the Dutch Expert Committee on Occupational Safety of the Health
Council, hereafter called the Committee, evaluates the effects on male and
female fertility and on the development of the progeny. Furthermore, the
Committee considers the effects of a substance on lactation and on the progeny
via lactation.
The Committee recommends classification according to Regulation (EC) 1272/
2008 of the European Union. For tellurium, these recommendations are:
• for effects on fertility, the Committee recommends not classifying tellurium
    due to a lack of appropriate data
• for effects on development, the Committee recommends classifying tellurium
    in category 1B (presumed human reproductive toxicant) and labelling with
    H360D (may damage the unborn child)
• for effects on or via lactation, the Committee recommends not labelling
    tellurium due to a lack of appropriate data.
Executive summary                                                                    11
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<pre>2 Tellurium</pre>

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<pre> hapter 1
        Scope
1.1     Background
        As a result of the Dutch regulation on registration of compounds toxic to
        reproduction that came into force on 1 April 1995, the Minister of Social Affairs
        and Employment requested the Health Council of the Netherlands to classify
        compounds toxic to reproduction. This classification is performed by the Health
        Council's Subcommittee on the Classification of Reproduction Toxic Substances
        of the Dutch Expert Committee on Occupational Safety (DECOS). The
        classification is performed according to European Union Regulation (EC) 1272/
        2008 on classification, labelling and packaging (CLP) of substances and
        mixtures. The CLP guideline is based on the Globally Harmonised System of
        Classification and Labelling of Chemicals (GHS). The Subcommittee's advice on
        the classification will be applied by the Ministry of Social Affairs and
        Employment to extend the existing list of compounds classified as reproductive
        toxicant (category 1A, 1B or 2) and compounds with effects on or via lactation.
1.2     Committee and procedure
        This present document contains the classification of tellurium by the Health
        Council's Subcommittee on the Classification of Reproduction Toxic Substances,
        hereafter called the Committee. The members of the Committee are listed in
        Scope                                                                             13
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<pre>    Annex A. The submission letter (in English) to the Minister can be found in
    Annex B.
        In 2013, the President of the Health Council released a draft of the report for
    public review. The individuals and organizations that commented on the draft
    report are listed in Annex C. The Committee has taken these comments into
    account in deciding on the final version of the report.
    The classification is based on the evaluation of published human and animal
    studies concerning adverse effects with respect to fertility and development and
    lactation of the above-mentioned compound.
    Classification for reproduction (fertility (F) and development (D)):
    Category 1                                  Known or presumed human reproductive toxicant
                                                (H360(F/D))
       Category 1A                              Known human reproductive toxicant
       Category 1B                              Presumed human reproductive toxicant
    Category 2                                  Suspected human reproductive toxicant (H361(f/d))
    No classification for effects on fertility or development
    Classification for lactation:
                                                Effects on or via lactation (H362)
                                                No labelling for lactation
    The classification and labelling of substances is performed according to the
    guidelines of the European Union (Regulation (EC) 1272/2008) presented in
    Annex D. The classification of compounds is ultimately dependent on an
    integrated assessment of the nature of all parental and developmental effects
    observed, their specificity and adversity and the dosages at which the various
    effects occur. The guideline necessarily leaves room for interpretation, dependent
    on the specific data set under consideration. In the process of using the
    regulation, the Committee has agreed upon a number of additional considerations
    (see Annex E).
1.3 Labelling for lactation
    The recommendation for classifying substances for effects on or via lactation is
    also based on Regulation (EC) 1272/2008. The guideline defines that substances
    which are absorbed by women and have been shown to interfere with lactation or
    which may be present (including metabolites) in breast milk in amounts
    sufficient to cause concern for the health of a breastfed child, shall be classified
    and labelled. Unlike the classification of substances for fertility and
 4  Tellurium
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<pre>    developmental effects, which is based on hazard identification only (largely
    independent of dosage), the labelling for effects on or via lactation is based on a
    risk characterization and therefore, it also includes consideration of the level of
    exposure of the breastfed child.
        Consequently, a substance should be labelled for effects on or via lactation
    when it is likely that the substance would be present in breast milk at potentially
    toxic levels. The Committee considers a concentration of a compound as
    potentially toxic to the breastfed child when this concentration exceeds the
    exposure limit for the general population, e.g. the acceptable daily intake (ADI).
1.4 Data
    For the present evaluation, a review on the toxic effects of tellurium and
    tellurium compounds by the Health Council’s Committee on Updating of
    Occupational Exposure Limits was available.9 The last reference concerning
    reproduction toxic effects cited in there was from 1988. Literature searches were
    conducted in the online databases XTOXLINE, MEDLINE and CAPLUS, from
    1988 up to February 2011. A final search was performed in TOXNET/TOXLINE
    in November 2012. 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. References are
    divided into literature cited and literature consulted but not cited.
        The Committee describes both the human and animal studies in the text. The
    animal data are described in more detail in Annex F as well. Of each study the
    quality of the study design (performed according to internationally
    acknowledged guidelines) and the quality of documentation are considered.
1.5 Presentation of conclusions
    The classification is given with key effects, species and references specified. In
    case a substance is not classified as toxic to reproduction, one of two reasons is
    given:
    • lack of appropriate data precludes assessment of the compound for
        reproductive toxicity
    • sufficient data show that no classification for toxic to reproduction is
        indicated.
    Scope                                                                               15
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<pre>1.6 Final remark
    The classification of compounds is based on hazard evaluation only (Niesink et
    al., 1995)16, which is one of a series of elements guiding the risk evaluation
    process. The Committee emphasizes that for derivation of health-based
    occupational exposure limits these classifications should be placed in a wider
    context. For a comprehensive risk evaluation, hazard evaluation should be
    combined with dose-response assessment, human risk characterization, human
    exposure assessment and recommendations of other organizations.
 6  Tellurium
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<pre> hapter 2
        Tellurium
2.1     Introduction
        The identity and some physicochemical properties of tellurium are given below:
        name                      : tellurium
        CAS registry number       : 13494-80-9
        EC/EINECS number          : 236-813-4
        synonyms                  : aurum paradoxum; metallum problematum; telloy
        colour and physical state : grey-white lustrous, brittle, crystalline solid, hexagonal,
                                    rhombohedral structure; or dark-grey to brown, amorphous
                                    powder with metal characteristics
        formula                   : Te
        atomic weight             : 127.6
        melting point             : 449.5-449.8 °C
        boiling point             : 988-989.9 °C
        vapour pressure           : 130 Pa at 520 °C
        density                   : 6.11-6.27 (crystalline)
        solubility                : insoluble in water
        Tellurium                                                                               17
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<pre>    use                              :   as an alloying additive in steel; as a (minor) additive in copper
                                         alloys, in lead alloys, in cast and malleable iron; in the chemical
                                         industry as a vulcanizing agent and accelerator in the processing
                                         of rubber, and as a component of catalysts for synthetic fibre
                                         production; in the production of cadmium-tellurium-based solar
                                         cells; in photoreceptor and thermoelectric electronic devices,
                                         other thermal cooling devices, as an ingredient in blasting caps,
                                         and as a pigment to produce various colours in glass and
                                         ceramics7; in the past, therapeutically, in the (intramuscular)
                                         treatment of syphilis, leprosy, trypanosomiasis (through
                                         intramuscular injections), and against excessive sweating15
    data from 3,9 unless otherwise noted.
    So far, 39 tellurium isotopes with atomic masses ranging from 105 to 143 have
    been discovered; these include eight stable, 16 neutron-deficient and 15 neutron-
    rich isotopes.12 Tellurium is a heavy element with chemical properties
    resembling those of non-metals, such as sulphur, but with more metal-like
    physical properties. Regarding properties and toxicology, it is similar to
    selenium, but tellurium is not considered to be a trace element. Biological
    functions are not yet identified.15
         The daily intake of tellurium for man was in the 1960s initially estimated to
    be 600 µg but revised to 100 µg8; based on a more recent study, an intake
    between 1 and 10 µg might be more realistic14. ‘Background’ concentrations of
    tellurium in blood, saliva and urine are <5 µg/L, <1 µg/L and <0.5 µg/L,
    respectively.14
         In human volunteers given metallic tellurium or tetra- or hexavalent
    tellurium salts, the percentage of intestinal absorption was estimated to be
    approximately 10 and 25%, respectively, based on cumulative urinary excretion
    of tellurium in the first four days after administration.13 In rats and rabbits,
    intestinal absorption ranges from 10-25 to 40%, respectively.8,13 Following
    parenteral administration, tellurium is predominantly excreted in the urine.8,13
    Small amounts (ca. 0.1%) are exhaled presumably as dimethyl telluride which
    has a characteristic garlic odour.8
2.2 Human studies
    Fertility studies
    No data are available regarding the effects of exposure to tellurium on human
    fertility.
 8  Tellurium
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<pre>    Developmental toxicity studies
    No data are available regarding the effects of exposure to tellurium on
    development in humans.
    Lactation
    No data are available regarding the excretion of tellurium in breast milk or the
    effects of exposure to tellurium on infants during the lactation period.
2.3 Animal studies
    Fertility studies
    No laboratory animal data are available regarding the effects of exposure to
    tellurium on fertility.
    Developmental toxicity studies
    Developmental toxicity studies with tellurium in laboratory animals are
    summarized in Annex F.
    Oral studies
    Garro and Pentschew (1964) fed more than 100 pregnant Long-Evans rats diets
    containing 500, 1,250 or 2,500 ppm of metallic tellurium (based on the data of
    Duckett and Johnson et al. (see below), these doses could be equal to 30, 75 and
    150 mg/kg bw/day). Dams of the two lower dose groups were treated throughout
    gestation while the high-dose animals were put on a normal diet three to five
    days before the expected delivery to avoid abortions.
        The newborn pups appeared normal although smaller than the controls.
    Hydrocephalus, that developed immediately after birth, was found in 60-90%
    and 100% of the pups of the mid- and high-dose groups, respectively, and in a
    lower, unspecified percentage at the low dose. In all dose groups, 99% of the
    affected pups died within one month.
        Garro and Pentschew stated that the amounts administered were not toxic to
    the dams tolerating the diets well and behaving normally.6
    Tellurium                                                                        19
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<pre>  Agnew et al. (1968) found no hydrocephalus in the offspring of Wistar rats (n=4/
  group) administered dietary amounts of 1,250 and 2,500 ppm of metallic
  tellurium throughout gestation (based on the data of Duckett and Johnson et al.
  (see below), these doses could be equal to 75 and 150 mg/kg bw/day).
      When given 3,300 ppm (n=10) (approximately 200 mg/kg bw, see afore),
  hydrocephalus, generally not grossly obvious until postnatal day 4 or 5, was seen
  in 8/10 litters (allowed to live 19 days or longer after birth) and in 36/77 pups.
      Data on maternal toxicity were not presented.1
  Duckett (1970) fed Wistar rats (n=20/group) 0 or 3,000 ppm (about 180 mg/kg
  bw/day*) of elemental tellurium in the diet on every gestational day (not further
  specified). On gestational day 13 and 15, foetuses (number not specified) were
  removed via the abdominal wall and after closing the abdominal wall again
  animals were allowed to terminate their pregnancy and give birth. Only the
  foetuses of tellurium-fed animals, which eventually gave birth to hydrocephalic
  animals, and foetuses of similar age from the control rats were examined and
  reported.
      The size and appearance of the tellurium and control foetuses were similar.
  No anomalies were noted in sections of the brains of the tellurium foetuses,
  stained with haematoxylin-eosin. Electron microscopic examination showed
  morphological anomalies in the cells in the ependymal layer of the tellurium
  foetuses, 13- and 15-intrauterine-days old. The ependymal layer of the normal
  foetal rat resembled that of human, rabbit and chick foetuses. On the ventricular
  surface of the ependymal cells from tellurium foetuses the normally present
  microvilli were not present and the number of mitochondria was greatly
  diminished. Mitochondria were often abnormal, smaller and darker than normal
  and showed distortion of cristae. The cells in the rest of the telencephalon
  appeared to be normal.
      No data on dams or pups were reported. Duckett only stated that from his
  experience, the dose given resulted in 50% of the rats giving birth to litters
  whose every member was hydrocephalic.4
  Duckett et al. (1971) investigated in a later study the effect of periodical or single
  dietary dosing on the occurrence of hydrocephalus. Pregnant rats (strain not
  reported) were given 2,500 ppm (about 150 mg/kg bw/day using a body weight
  of 250 g) of metallic tellurium in the diet for every gestational day (21 days) and
  Calculated based on 15 g food intake per day containing 45 mg of elemental tellurium and an average
  body weight of 250 g at the beginning of pregnancy as indicated in Duckett (1970).
0 Tellurium
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<pre>  12/20 rats gave birth to litters containing an average of eight pups, six of which
  were hydrocephalic. Subsequently, the same dose was given to three groups of
  pregnant rats (n=20/group): the first group received tellurium from gestational
  day 1 through 9, the second group on gestational day 10-15 and the third group on
  day 16-21.
      Twelve rats fed tellurium during gestational day 10-15 gave birth to
  hydrocephalic rats. The average litter numbered nine, five of which were
  hydrocephalic. No hydrocephalic pups were noted in the other two dose groups.
  Also, single doses on one gestational day were given to five rats per group per
  gestational day. Seventy-two animals gave birth to an average of eight offspring.
  No hydrocephalic pups were noted.5
      The Committee notes that the exact day of postnatal examination, the
  absence or presence of maternal toxicity and statistics were not reported.
  Johnson and co-workers (1988) performed a standard developmental toxicity
  study in rats and rabbits generally performed according to OECD Test Guideline
  414 (1981). Preliminary studies in the rat showed that gavage studies gave only
  developmental toxicity at doses ≥10,000 mg/kg bw/day while dietary intake
  resulted in effects at ≥559 mg/kg bw/day*. For the main studies, dietary
  administration was chosen.
      Pregnant Sprague-Dawley rats (n=32-33) were given 0, 30, 300, 3,000 or
  15,000 ppm of tellurium in the diet on gestational day 6-15 (equal to
  approximately 0, 2, 20, 166 and 633 mg/kg bw/day for gestational day 6-10 and
  0, 2, 18, 173 and 580 mg/kg bw/day for gestational day 11-15**). On day 20 of
  presumed gestation, approximately two-thirds of the females in each group were
  killed and foetuses were investigated. The remaining dams in each group were
  allowed to deliver and pups were observed until postnatal day 7. Heads of pups
  which were stillborn, found dead or killed on postnatal day 7 were examined.
      No effect was observed on the incidences of pregnancy, on the mean numbers
  of corpora lutea, implantations and resorptions, on the mean litter size, on the
  numbers of live and dead foetuses and on the percentages of male foetuses.
      At 15,000 ppm, mean weights of female and male foetuses were decreased
  (p≤0.05). Increased incidences of litters with variations (100%, controls: 18%;
  p≤0.01) and of foetuses with variations (41%, controls: 2.1%; p-value not
  reported), of malformed foetuses (no details presented), and of foetuses with
  delayed ossification (no details presented) were reported. The most common
  Corresponds to 7,500 ppm Te in the diet as reported in Johnson et al.
* Calculated by Johnson et al. based on quantities of feed consumed.
  Tellurium                                                                          21
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<pre>  malformation was internal hydrocephalus with dilatation of the lateral ventricles
  observed in 17 litters (85%; controls: 1 (4.6%); p≤0.05) and in 67 foetuses
  (55%; controls: 1 ( 0.7%); p≤0.05). More severely affected foetuses had also
  slight to marked dilatation of the third and/or fourth ventricles. Externally,
  hydrocephalus was noted only for two foetuses (litters not specified), one of
  which had an enlarged fontanel bordered by a haemorrhagic area. Moderate
  dilatation of the renal pelvis was also found (no details). Other malformations
  included kinked and/or stubbed tails, rotation of a hindlimb or hind foot, a
  malformed retina, malpositioned manubrium and clavicles, short radius, ulna
  and/or femur, wavy ribs and a thickened or split rib. Many of these foetuses from
  severely affected dams also showed delayed ossification of the parietals,
  interparietals, supraoccipitals, vertebral and sternal centra, pubes, ischia and/or
  ribs. At 3000 ppm, incidences of litters with variations (57%, p≤0.01) and of
  foetuses with variations (11%, p-value not reported), of malformed foetuses (no
  details presented) and of foetuses with delayed ossification (no details presented)
  were increased as well. Also in this group, the most common malformation was
  internal hydrocephalus with dilatation of the lateral ventricles observed in three
  litters (14%; not statistically significant from controls) and in 11 foetuses (55%;
  not statistically significant). Moderate dilatation of the renal pelvis was also
  found (no details). No other malformations were observed.
       Regarding the groups that were allowed to litter, there were no effects on
  duration of gestation, on the number (percentage) of dams with stillborn, on litter
  size, on the number of live pups delivered and on mean pup weights on postnatal
  day 7. In the highest dose group, the number (percentage) of pups surviving
  seven days was decreased (p≤0.01). No gross, external or visceral anomalies
  were seen, but there was a significant increase in the incidence of slight to
  extreme dilatation of the lateral ventricles in pups at the highest dose at postnatal
  day 7 (p≤0.01).
       No maternal mortality occurred. Maternal body weight gain and food
  consumption were decreased at 300 and 3,000 ppm (p≤0.01), while weight loss
  and halved food consumption were seen at 15,000 ppm (p≤0.01) during
  exposure.11
  In the same study, New Zealand white rabbits (n=17) were artificially
  inseminated and fed diets containing 0, 17.5, 175, 1750 or 5,250 ppm of
  tellurium (equal to approximately 0, 0.8, 8, 52, 97 mg/kg bw/day using average
  feed intake on gestational days 6-18 and average maternal body weight on
  gestational day 6) on gestational days 6-18. Dams were killed on gestational day
  29 and foetuses were examined.
2 Tellurium
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<pre>    The number of pregnancies varied between dose levels: 10, 15, 9, 15 and 13
at 0, 17.5, 175, 1,750 and 5,250 ppm, respectively. No effect was observed on the
incidence of abortion, mean numbers of corpora lutea, implantations,
resorptions, litter size or sex ratio (% of male foetuses/litter). At 5,250 ppm,
decreased mean foetal weight (males 84%, females 95% of control; not
statistically significant), increased incidences of litters with abnormalities (46%;
controls: 2%) of foetuses with abnormalities (12%; controls: 6.7%), malformed
foetuses (no details presented) and foetuses with delayed ossification (no details
presented) were observed (no statistics reported). In the foetuses of this group,
the following effects were reported: low incidences of hydrocephalus; enlarged
and/or irregularly shaped anterior fontanel; incomplete ossification of, or small
holes in, the frontals and parietals; frontals with thickened ossification; umbilical
hernia; fused pulmonary artery and aorta; asymmetric and/or irregularly shaped
and/or fused sternebrae; and thickened areas in the ribs. These foetuses also
tended to be smaller than normal and had fewer caudal vertebral, xiphoid and
forepaw phalangeal foetal ossification sites.
    Maternal toxicity consisted of soft or liquid faeces, alopecia, thin appearance,
and/or decreased motor activity and decreased body weight gain and food
consumption at 1,750 and 5,250 ppm (body weight gain: p≤0.01 at both doses;
food consumption: p≤0.05 at 1,750 and p≤0.01 at 5,250 ppm). 11
Intramuscular injection
In a subsequent study (see diet studies above), Agnew and Curry (1972)
investigated the precise period of teratogenic susceptibility of the rat embryo to
tellurium. Pregnant rats (n=5-10/experiment) were injected intramuscularly with
13 mg/kg bw metallic tellurium suspended in olive oil on one day of gestational
day 7 to 13; two or three pregnant controls were injected with single doses of
olive oil from gestational days 9-13. Dams were allowed to deliver and offspring
was observed for ten postnatal days, killed and examined for hydrocephalus and
other visceral defects. Only those mothers failing to deliver were autopsied and
examined for foetal resorptions the day following predicted delivery.
    Apart from foetuses with hydrocephalus observed after injection on
gestational day 7 (1/31, 3%), 9 (14/75, 19%) and 10 (10/32, 31%) (controls:
1/94, 1%), no biologically relevant effects were noted. Malformations other than
hydrocephalus were not observed.
    Data on maternal toxicity were not presented.2
Tellurium                                                                             23
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<pre>    Lactation
    Two female rats were given a diet containing 0 or 1.25% of metallic tellurium
    (about 750 mg/kg bw/day*) from postnatal day 0 until sacrifice at postnatal days
    7, 14, 21 or 28 (n=5 pups/group). Apart from a garlic odour and skin
    discoloration, no signs of toxicity were seen in the lactating dams. During the
    postnatal period, neonates from treated mothers showed effects such as garlic
    odour, skin discoloration, lethargy, hindlimb paralysis, incontinence, slow weight
    gain and smaller size. Microscopic examination of nerve tissues revealed
    hypomyelation, myelin degeneration, and Schwann cell degeneration.10
        The Committee notes the limited study design.
2.4 Conclusions
    Fertility
    No human or animal studies on fertility effects of tellurium were available.
        Therefore, the Committee proposes not to classify tellurium for effects on
    fertility due to a lack of appropriate human and animal data.
    Developmental toxicity
    No human studies on developmental toxicity effects of tellurium were available.
        In one developmental toxicity study, maternally toxic levels of tellurium
    in the diet induced increased numbers of rat foetuses with dilated ventricles/
    hydrocephalus, of rat foetuses with hydrocephalus and decreased weights and of
    rabbit foetuses with variations and malformations and delayed ossification.11 In
    other less well performed and reported diet studies in rats, tellurium caused
    increased numbers of rat pups with hydrocephalus.1,4-6 In one of the latter
    studies6, levels affecting the offspring were stated to be not toxic to the dams
    while in the other studies1,4,5, it was not reported whether effects were seen in the
    presence or absence of maternal toxicity.
        The Committee is of the opinion that the developmental effects observed
    occurred independently from maternal toxicity. Therefore, based on the data
    from laboratory animal studies, the Committee recommends classification of
    tellurium in category 1B (presumed human reproductive toxicant).
    Based on the data of Duckett and Johnson et al. (see afore).
 4  Tellurium
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<pre>Lactation
No human data and only limited animal data were available regarding the
excretion of tellurium in breast milk or the effects of exposure to tellurium on
infants during the lactation period.
     Therefore, the Committee concluded that a lack of appropriate data
precludes assessment of tellurium for effects on or via lactation.
Proposed classification for fertility
Lack of appropriate data precludes the assessment of tellurium for effects on
fertility.
Proposed classification for developmental toxicity
Category 1B; H360D.
Proposed labelling for effects on or via lactation
Lack of appropriate data precludes the assessment of tellurium for effects on or
via lactation.
Tellurium                                                                        25
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<pre>6 Tellurium</pre>

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<pre>  References
  Agnew WF, Fauvre FM, Pudenz PH. Tellurium hydrocephalus: distribution of tellurium-127m
  between maternal, fetal, and neonatal tissue of the rat. Exp Neurol. 1968;21:120-2.
  Agnew WF, Curry E. Period of teratogenic vulnerability of rat embryo to induction of hydrocephalus
  by tellurium. Experientia. 1972;28:1444-5.
  Budavari S, O’Neil M, Smith A, Heckelman P, Obenchain J, editors. Tellurium. In: The Merck Index;
  an encyclopedia of chemicals, drugs, and biologicals. Whitehouse Station NJ, USA: Merck & Co,
  Inc.; 1996.
  Duckett S. Fetal encephalopathy following ingestion of tellurium. Experientia. 1970;26:1239-41.
  Duckett S, Sandler A, Scott T. The target period during fetal life for the production of tellurium
  hydrocephalus. Experientia. 1971;27:1064-5.
  Garro F, Pentschew A. Neonatal hydrocephalus in the offspring of rats fed during pregnancy non-
  toxic amounts of tellurium. Arch Psychiatr Zeitschr Neurol. 1964; 206:272-80.
  George MW. Tellurium. [Internet]. [cited 2012 April]. Available from: http://minerals.usgs.gov/
  minerals/pubs/commodity/selenium/mcs-2012-tellu.pdf.
  Gerhardsson L. Tellurium. In: Nordberg GF, Fouler BA, Nordberg M, Friberg LT, editors. Handbook
  of the toxicology of metals. Burlington MA, USA: Academic Press; 2007. p. 815-25.
  Health Council of the Netherlands: Committee on Updating of Occupational Exposure Limits.
  Tellurium and tellurium compounds (excluding TeF6). Health-based reassessment of administrative
  occupational exposure limits. The Hague: Health Council of The Netherlands; 2002:
  2000/15OSH/055.
0 Jackson KF, Hammang JP, Worth SF, Duncan ID. Hypomyelation in the neonatal rat central and
  peripheral nervous system following tellurium intoxication. Acta Neuropathol. 1989;78:301-9.
  References                                                                                         27
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<pre>1 Johnson EM, Christian MS, Hoberman AM, DeMarco CJ, Kilpper R, Mermelstein R. Developmental
  toxicology investigation of tellurium. Fundam Appl Toxicol. 1988;11: 691-702.
2 Kathawa J, Fry C, Thoennessen M. Discovery of palladium, antimony, tellurium, iodine, and xenon
  isotopes. At Data Nucl Data Tables. 2013;99:22-52.
3 Kron T, Hansen C, Werner E. Renal excretion of tellurium after peroral administration of tellurium in
  different forms to healthy volunteers. J Trace Elem Electrolytes Health Dis. 1991;5:239-44.
4 Kron T, Hansen C, Werner E. Tellurium ingestion with foodstuffs. J Food Comp Anal. 1991;4:
  196-205.
5 Larner AJ. Biological effects of tellurium: a review. Trace Elem Electrolytes. 1995;12:26-31.
6 Niessink R, de Vries J, Hoolinger M. Toxicology principles and applications. Boca Raton FL, USA:
  CRC Press; 1995.
  Literature consulted but not cited
  Barlow SM, Sullivan FM. Tellurium and its compounds. In: Reproductive hazards of industrial
  chemicals: an evaluation of animal and human data. New York, USA: Academic Press; 1982.
  p. 515-22.
8 Tellurium
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<pre>A The Committee
B The submission letter (in English)
C Comments on the public draft
D Regulation (EC) 1272/2008 of the European Community
E Additional considerations to Regulation (EC) 1272/2008
F Developmental toxicity studies
  Annexes
                                                         29
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<pre>0 Tellurium</pre>

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<pre>nnex A
     The Committee
     •  A.H. Piersma, Chairman
        Professor of Reproductive and Developmental Toxicology, Utrecht
        University, Utrecht and National Institute of Public Health and the
        Environment, Bilthoven
     •  D. Lindhout
        Professor of Medical Genetics, Paediatrician (not practising), Clinical
        Geneticist, University Medical Centre, Utrecht
     •  N. Roeleveld
        Reproductive Epidemiologist, Radboud university medical centre, Nijmegen
     •  J.G. Theuns-van Vliet
        Reproductive Toxicologist, TNO Triskelion BV, Zeist
     •  D.H. Waalkens-Berendsen
        Reproductive Toxicologist, Zeist
     •  P.J.J.M. Weterings
        Toxicologist, Weterings Consultancy BV, Rosmalen
     •  A.S.A.M. van der Burght, Scientific Secretary
        Health Council of the Netherlands, Den Haag
     •  J.T.J. Stouten, Scientific Secretary
        Health Council of the Netherlands, Den Haag
     The first draft of this report was prepared by Dr. H.M. Barentsen, from the
     Regulatory Affairs Department of WIL Research Europe BV (Den Bosch,
     The Committee                                                               31
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<pre>  the Netherlands) by contract with the Ministry of Social Affairs and
  Employment.
  The Health Council and interests
  Members of Health Council Committees are appointed in a personal capacity
  because of their special expertise in the matters to be addressed. Nonetheless, it
  is precisely because of this expertise that they may also have interests. This in
  itself does not necessarily present an obstacle for membership of a Health
  Council Committee. Transparency regarding possible conflicts of interest is
  nonetheless important, both for the chairperson and members of a Committee
  and for the President of the Health Council. On being invited to join a
  Committee, members are asked to submit a form detailing the functions they
  hold and any other material and immaterial interests which could be relevant for
  the Committee’s work. It is the responsibility of the President of the Health
  Council to assess whether the interests indicated constitute grounds for non-
  appointment. An advisorship will then sometimes make it possible to exploit the
  expertise of the specialist involved. During the inaugural meeting the
  declarations issued are discussed, so that all members of the Committee are
  aware of each other’s possible interests.
2 Tellurium
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<pre>nnex B
     The submission letter (in English)
     Subject         : Submission of the advisory report Tellurium
     Your reference  : DGV/MBO/U-932542
     Our reference   : U-8075/HS/cn/543-H14
     Enclosed        :1
     Date            : April 3, 2014
     Dear Minister,
     I hereby submit the advisory report on the effects of tellurium on fertility and on
     the development of the progeny; it also concerns effects on lactation and on the
     progeny via lactation. This advisory report is part of an extensive series in which
     reproduction toxic substances are classified in accordance with European
     guidelines. This involves substances to which people may be exposed
     occupationally.
     The advisory report was prepared by a permanent committee of the Health
     Council of the Netherlands, the Subcommittee on the Classification of
     Reproduction Toxic Substances. The advisory report was consequently reviewed
     by the Health Council’s Standing Committee on Health and the Environment.
     The submission letter (in English)                                                  33
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<pre>  Today I sent copies of this advisory report to the State Secretary of Infrastructure
  and the Environment and to the Minister of Health, Welfare and Sport, for their
  information.
  Yours sincerely,
  (signed)
  Prof. dr. W.A. van Gool,
  President
4 Tellurium
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<pre>nnex C
     Comments on the public draft
     A draft of the present report was released in 2013 for public review. The
     following organisations and persons have commented on the draft document:
     • T.J. Lentz, K. Krajnak; National Institute for Occupational Safety and Health,
         Cincinnati OH, USA
     • K. Heitmann; UMCO Umwelt Consult GmbH, Hamburg, Germany.
     The received comments, and the replies by the Committee can be found on the
     website of the Health Council.
     Comments on the public draft                                                     35
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<pre>6 Tellurium</pre>

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<pre>nnex D
     Regulation (EC) 1272/2008 of the
     European Community
     3.7            Reproductive toxicity
     3.7.1          Definitions and general considerations
     3.7.1.1        Reproductive toxicity includes adverse effects on sexual function and fertility in adult
     males and females, as well as developmental toxicity in the offspring. The definitions presented
     below are adapted from those agreed as working definitions in IPCS/EHC Document No 225, Princi-
     ples for Evaluating Health Risks to Reproduction Associated with Exposure to Chemicals. For classi-
     fication purposes, the known induction of genetically based heritable effects in the offspring is
     addressed in Germ Cell Mutagenicity (section 3.5), since in the present classification system it is con-
     sidered more appropriate to address such effects under the separate hazard class of germ cell muta-
     genicity.
     In this classification system, reproductive toxicity is subdivided under two main headings:
     (a) adverse effects on sexual function and fertility;
     (b) adverse effects on development of the offspring.
     Some reproductive toxic effects cannot be clearly assigned to either impairment of sexual function
     and fertility or to developmental toxicity. Nonetheless, substances with these effects, or mixtures con-
     taining them, shall be classified as reproductive toxicants.
     Regulation (EC) 1272/2008 of the European Community                                                      37
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<pre>  3.7.1.2         For the purpose of classification the hazard class Reproductive Toxicity is differentiated
                  into:
  •     adverse effects
        •    on sexual function and fertility, or
        •    on development;
  •     effects on or via lactation.
  3.7.1.3         Adverse effects on sexual function and fertility
  Any effect of substances that has the potential to interfere with sexual function and fertility. This
  includes, but is not limited to, alterations to the female and male reproductive system, adverse effects
  on onset of puberty, gamete production and transport, reproductive cycle normality, sexual behaviour,
  fertility, parturition, pregnancy outcomes, premature reproductive senescence, or modifications in
  other functions that are dependent on the integrity of the reproductive systems.
  3.7.1.4         Adverse effects on development of the offspring
  Developmental toxicity includes, in its widest sense, any effect which interferes with normal devel-
  opment of the conceptus, either before or after birth, and resulting from exposure of either parent
  prior to conception, or exposure of the developing offspring during prenatal development, or postna-
  tally, to the time of sexual maturation. However, it is considered that classification under the heading
  of developmental toxicity is primarily intended to provide a hazard warning for pregnant women, and
  for men and women of reproductive capacity. Therefore, for pragmatic purposes of classification,
  developmental toxicity essentially means adverse effects induced during pregnancy, or as a result of
  parental exposure. These effects can be manifested at any point in the life span of the organism. The
  major manifestations of developmental toxicity include (1) death of the developing organism, (2)
  structural abnormality, (3) altered growth, and (4) functional deficiency.
  3.7.1.5         Adverse effects on or via lactation are also included in reproductive toxicity, but for
  classification purposes, such effects are treated separately (see Table 3.7.1 (b)). This is because it is
  desirable to be able to classify substances specifically for an adverse effect on lactation so that a spe-
  cific hazard warning about this effect can be provided for lactating mothers.
8 Tellurium
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<pre>3.7.2        Classification criteria for substances
3.7.2.1      Hazard categories
3.7.2.1.1    For the purpose of classification for reproductive toxicity, substances are allocated to
one of two categories. Within each category, effects on sexual function and fertility, and on develop-
ment, are considered separately. In addition, effects on lactation are allocated to a separate hazard cat-
egory.
Table 3.7.1(a) Hazard categories for reproductive toxicants.
Categories                      Criteria
CATEGORY 1                      Known or presumed human reproductive toxicant
                                Substances are classified in Category 1 for reproductive toxicity when
                                they are known to have produced an adverse effect on sexual function
                                and fertility, or on development in humans or when there is evidence
                                from animal studies, possibly supplemented with other information, to
                                provide a strong presumption that the substance has the capacity to
                                interfere with reproduction in humans. The classification of a sub-
                                stance is further distinguished on the basis of whether the evidence for
                                classification is primarily from human data (Category 1A) or from
                                animal data (Category 1B).
                Category 1A Known human reproductive toxicant
                                The classification of a substance in Category 1A is largely based on
                                evidence from humans.
                Category 1B Presumed human reproductive toxicant
                                The classification of a substance in Category 1B is largely based on
                                data from animal studies. Such data shall provide clear evidence of an
                                adverse effect on sexual function and fertility or on development in
                                the absence of other toxic effects, or if occurring together with other
                                toxic effects the adverse effect on reproduction is considered not to be
                                a secondary non-specific consequence of other toxic effects. However,
                                when there is mechanistic information that raises doubt about the rele-
                                vance of the effect for humans, classification in Category 2 may be
                                more appropriate.
CATEGORY 2                      Suspected human reproductive toxicant
                                Substances are classified in Category 2 for reproductive toxicity when
                                there is some evidence from humans or experimental animals, possi-
                                bly supplemented with other information, of an adverse effect on sex-
                                ual function and fertility, or on development, and where the evidence
                                is not sufficiently convincing to place the substance in Category 1. If
                                deficiencies in the study make the quality of evidence less convincing,
                                Category 2 could be the more appropriate classification.
                                Such effects shall have been observed in the absence of other toxic
                                effects, or if occurring together with other toxic effects the adverse
                                effect on reproduction is considered not to be a secondary non-specific
                                consequence of the other toxic effects.
Regulation (EC) 1272/2008 of the European Community                                                        39
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<pre>  Table 3.7.1(b) Hazard category for lactation effects.
  EFFECTS ON OR VIA LACTATION
  Effects on or via lactation are allocated to a separate single category. It is recognised that for many
  substances there is no information on the potential to cause adverse effects on the offspring via lacta-
  tion. However, substances which are absorbed by women and have been shown to interfere with lac-
  tation, or which may be present (including metabolites) in breast milk in amounts sufficient to cause
  concern for the health of a breastfed child, shall be classified and labelled to indicate this property
  hazardous to breastfed babies. This classification can be assigned on the:
  (a) human evidence indicating a hazard to babies during the lactation period; and/or
  (b) results of one or two generation studies in animals which provide clear evidence of adverse effect
  in the offspring due to transfer in the milk or adverse effect on the quality of the milk; and/or
  (c) absorption, metabolism, distribution and excretion studies that indicate the likelihood that the sub-
  stance is present in potentially toxic levels in breast milk.
  3.7.2.2        Basis of classification
  3.7.2.2.1      Classification is made on the basis of the appropriate criteria, outlined above, and an
  assessment of the total weight of evidence (see 1.1.1). Classification as a reproductive toxicant is
  intended to be used for substances which have an intrinsic, specific property to produce an adverse
  effect on reproduction and substances shall not be so classified if such an effect is produced solely as
  a non-specific secondary consequence of other toxic effects.
  The classification of a substance is derived from the hazard categories in the following order of pre-
  cedence: Category 1A, Category 1B, Category 2 and the additional Category for effects on or via lac-
  tation. If a substance meets the criteria for classification into both of the main categories (for example
  Category 1B for effects on sexual function and fertility and also Category 2 for development) then
  both hazard differentiations shall be communicated by the respective hazard statements. Classifica-
  tion in the additional category for effects on or via lactation will be considered irrespective of a clas-
  sification into Category 1A, Category 1B or Category 2.
  3.7.2.2.2      In the evaluation of toxic effects on the developing offspring, it is important to consider
  the possible influence of maternal toxicity (see section 3.7.2.4).
  3.7.2.2.3      For human evidence to provide the primary basis for a Category 1A classification there
  must be reliable evidence of an adverse effect on reproduction in humans. Evidence used for classifi-
  cation shall ideally be from well conducted epidemiological studies which include the use of appro-
  priate controls, balanced assessment, and due consideration of bias or confounding factors. Less
  rigorous data from studies in humans shall be supplemented with adequate data from studies in
  experimental animals and classification in Category 1B shall be considered.
0 Tellurium
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<pre>3.7.2.3         Weight of evidence
3.7.2.3.1       Classification as a reproductive toxicant is made on the basis of an assessment of the
total weight of evidence, see section 1.1.1. This means that all available information that bears on the
determination of reproductive toxicity is considered together, such as epidemiological studies and
case reports in humans and specific reproduction studies along with sub-chronic, chronic and special
study results in animals that provide relevant information regarding toxicity to reproductive and
related endocrine organs. Evaluation of substances chemically related to the substance under study
may also be included, particularly when information on the substance is scarce. The weight given to
the available evidence will be influenced by factors such as the quality of the studies, consistency of
results, nature and severity of effects, the presence of maternal toxicity in experimental animal stud-
ies, level of statistical significance for inter-group differences, number of endpoints affected, rele-
vance of route of administration to humans and freedom from bias. Both positive and negative results
are assembled together into a weight of evidence determination. A single, positive study performed
according to good scientific principles and with statistically or biologically significant positive results
may justify classification (see also 3.7.2.2.3).
3.7.2.3.2       Toxicokinetic studies in animals and humans, site of action and mechanism or mode of
action study results may provide relevant information which reduces or increases concerns about the
hazard to human health. If it is conclusively demonstrated that the clearly identified mechanism or
mode of action has no relevance for humans or when the toxicokinetic differences are so marked that
it is certain that the hazardous property will not be expressed in humans then a substance which pro-
duces an adverse effect on reproduction in experimental animals should not be classified.
3.7.2.3.3       If, in some reproductive toxicity studies in experimental animals the only effects
recorded are considered to be of low or minimal toxicological significance, classification may not
necessarily be the outcome. These effects include small changes in semen parameters or in the inci-
dence of spontaneous defects in the foetus, small changes in the proportions of common foetal vari-
ants such as are observed in skeletal examinations, or in foetal weights, or small differences in
postnatal developmental assessments.
3.7.2.3.4       Data from animal studies ideally shall provide clear evidence of specific reproductive
toxicity in the absence of other systemic toxic effects. However, if developmental toxicity occurs
together with other toxic effects in the dam, the potential influence of the generalised adverse effects
shall be assessed to the extent possible. The preferred approach is to consider adverse effects in the
embryo/foetus first, and then evaluate maternal toxicity, along with any other factors which are likely
to have influenced these effects, as part of the weight of evidence. In general, developmental effects
that are observed at maternally toxic doses shall not be automatically discounted. Discounting devel-
Regulation (EC) 1272/2008 of the European Community                                                         41
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<pre>  opmental effects that are observed at maternally toxic doses can only be done on a case-by-case basis
  when a causal relationship is established or refuted.
  3.7.2.3.5      If appropriate information is available it is important to try to determine whether devel-
  opmental toxicity is due to a specific maternally mediated mechanism or to a non-specific secondary
  mechanism, like maternal stress and the disruption of homeostasis. Generally, the presence of mater-
  nal toxicity shall not be used to negate findings of embryo/foetal effects, unless it can be clearly dem-
  onstrated that the effects are secondary non-specific effects. This is especially the case when the
  effects in the offspring are significant, e.g. irreversible effects such as structural malformations. In
  some situations it can be assumed that reproductive toxicity is due to a secondary consequence of
  maternal toxicity and discount the effects, if the substance is so toxic that dams fail to thrive and there
  is severe inanition, they are incapable of nursing pups; or they are prostrate or dying.
  3.7.2.4        Maternal toxicity
  3.7.2.4.1      Development of the offspring throughout gestation and during the early postnatal stages
  can be influenced by toxic effects in the mother either through non-specific mechanisms related to
  stress and the disruption of maternal homeostasis, or by specific maternally-mediated mechanisms. In
  the interpretation of the developmental outcome to decide classification for developmental effects it
  is important to consider the possible influence of maternal toxicity. This is a complex issue because
  of uncertainties surrounding the relationship between maternal toxicity and developmental outcome.
  Expert judgement and a weight of evidence approach, using all available studies, shall be used to
  determine the degree of influence that shall be attributed to maternal toxicity when interpreting the
  criteria for classification for developmental effects. The adverse effects in the embryo/foetus shall be
  first considered, and then maternal toxicity, along with any other factors which are likely to have
  influenced these effects, as weight of evidence, to help reach a conclusion about classification.
  3.7.2.4.2      Based on pragmatic observation, maternal toxicity may, depending on severity, influ-
  ence development via non-specific secondary mechanisms, producing effects such as depressed foe-
  tal weight, retarded ossification, and possibly resorptions and certain malformations in some strains
  of certain species. However, the limited number of studies which have investigated the relationship
  between developmental effects and general maternal toxicity have failed to demonstrate a consistent,
  reproducible relationship across species. Developmental effects which occur even in the presence of
  maternal toxicity are considered to be evidence of developmental toxicity, unless it can be unequivo-
  cally demonstrated on a case-by-case basis that the developmental effects are secondary to maternal
  toxicity. Moreover, classification shall be considered where there is a significant toxic effect in the
  offspring, e.g. irreversible effects such as structural malformations, embryo/foetal lethality, signifi-
  cant post-natal functional deficiencies.
2 Tellurium
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<pre>3.7.2.4.3      Classification shall not automatically be discounted for substances that produce devel-
opmental toxicity only in association with maternal toxicity, even if a specific maternally-mediated
mechanism has been demonstrated. In such a case, classification in Category 2 may be considered
more appropriate than Category 1. However, when a substance is so toxic that maternal death or
severe inanition results, or the dams are prostrate and incapable of nursing the pups, it is reasonable
to assume that developmental toxicity is produced solely as a secondary consequence of maternal
toxicity and discount the developmental effects. Classification is not necessarily the outcome in the
case of minor developmental changes, when there is only a small reduction in foetal/pup body weight
or retardation of ossification when seen in association with maternal toxicity.
3.7.2.4.4      Some of the end points used to assess maternal effects are provided below. Data on
these end points, if available, need to be evaluated in light of their statistical or biological signifi-
cance and dose response relationship.
Maternal mortality:
an increased incidence of mortality among the treated dams over the controls shall be considered evi-
dence of maternal toxicity if the increase occurs in a dose-related manner and can be attributed to the
systemic toxicity of the test material. Maternal mortality greater than 10 % is considered excessive
and the data for that dose level shall not normally be considered for further evaluation.
Mating index
(no. animals with seminal plugs or sperm/no. mated × 100) (*)
Fertility index
(no. animals with implants/no. of matings × 100)
Gestation length
(if allowed to deliver)
Body weight and body weight change:
Consideration of the maternal body weight change and/or adjusted (corrected) maternal body weight
shall be included in the evaluation of maternal toxicity whenever such data are available. The calcula-
() It is recognised that the Mating index and the Fertility index can also be affected by the male.
Regulation (EC) 1272/2008 of the European Community                                                       43
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<pre>  tion of an adjusted (corrected) mean maternal body weight change, which is the difference between
  the initial and terminal body weight minus the gravid uterine weight (or alternatively, the sum of the
  weights of the foetuses), may indicate whether the effect is maternal or intrauterine. In rabbits, the
  body weight gain may not be useful indicators of maternal toxicity because of normal fluctuations in
  body weight during pregnancy.
  Food and water consumption (if relevant):
  The observation of a significant decrease in the average food or water consumption in treated dams
  compared to the control group is useful in evaluating maternal toxicity, particularly when the test
  material is administered in the diet or drinking water. Changes in food or water consumption need to
  be evaluated in conjunction with maternal body weights when determining if the effects noted are
  reflective of maternal toxicity or more simply, unpalatability of the test material in feed or water.
  Clinical evaluations (including clinical signs, markers, haematology and clinical chemistry studies):
  The observation of increased incidence of significant clinical signs of toxicity in treated dams relative
  to the control group is useful in evaluating maternal toxicity. If this is to be used as the basis for the
  assessment of maternal toxicity, the types, incidence, degree and duration of clinical signs shall be
  reported in the study. Clinical signs of maternal intoxication include: coma, prostration, hyperactivity,
  loss of righting reflex, ataxia, or laboured breathing.
  Post-mortem data:
  Increased incidence and/or severity of post-mortem findings may be indicative of maternal toxicity.
  This can include gross or microscopic pathological findings or organ weight data, including absolute
  organ weight, organ-to-body weight ratio, or organ-to-brain weight ratio. When supported by find-
  ings of adverse histopathological effects in the affected organ(s), the observation of a significant
  change in the average weight of suspected target organ(s) of treated dams, compared to those in the
  control group, may be considered evidence of maternal toxicity.
  3.7.2.5        Animal and experimental data
  3.7.2.5.1      A number of internationally accepted test methods are available; these include methods
  for developmental toxicity testing (e.g. OECD Test Guideline 414), and methods for one or two-gen-
  eration toxicity testing (e.g. OECD Test Guidelines 415, 416).
  3.7.2.5.2      Results obtained from Screening Tests (e.g. OECD Guidelines 421 — Reproduction/
  Developmental Toxicity Screening Test, and 422 — Combined Repeated Dose Toxicity Study with
4 Tellurium
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<pre>Reproduction/Development Toxicity Screening Test) can also be used to justify classification,
although it is recognised that the quality of this evidence is less reliable than that obtained through
full studies.
3.7.2.5.3      Adverse effects or changes, seen in short- or long-term repeated dose toxicity studies,
which are judged likely to impair reproductive function and which occur in the absence of significant
generalised toxicity, may be used as a basis for classification, e.g. histopathological changes in the
gonads.
3.7.2.5.4      Evidence from in vitro assays, or non-mammalian tests, and from analogous substances
using structure-activity relationship (SAR), can contribute to the procedure for classification. In all
cases of this nature, expert judgement must be used to assess the adequacy of the data. Inadequate
data shall not be used as a primary support for classification.
3.7.2.5.5      It is preferable that animal studies are conducted using appropriate routes of administra-
tion which relate to the potential route of human exposure. However, in practice, reproductive toxic-
ity studies are commonly conducted using the oral route, and such studies will normally be suitable
for evaluating the hazardous properties of the substance with respect to reproductive toxicity. How-
ever, if it can be conclusively demonstrated that the clearly identified mechanism or mode of action
has no relevance for humans or when the toxicokinetic differences are so marked that it is certain that
the hazardous property will not be expressed in humans then a substance which produces an adverse
effect on reproduction in experimental animals shall not be classified.
3.7.2.5.6      Studies involving routes of administration such as intravenous or intraperitoneal injec-
tion, which result in exposure of the reproductive organs to unrealistically high levels of the test sub-
stance, or elicit local damage to the reproductive organs, including irritation, must be interpreted with
extreme caution and on their own are not normally the basis for classification.
3.7.2.5.7      There is general agreement about the concept of a limit dose, above which the produc-
tion of an adverse effect is considered to be outside the criteria which lead to classification, but not
regarding the inclusion within the criteria of a specific dose as a limit dose. However, some guide-
lines for test methods, specify a limit dose, others qualify the limit dose with a statement that higher
doses may be necessary if anticipated human exposure is sufficiently high that an adequate margin of
exposure is not achieved. Also, due to species differences in toxicokinetics, establishing a specific
limit dose may not be adequate for situations where humans are more sensitive than the animal
model.
3.7.2.5.8      In principle, adverse effects on reproduction seen only at very high dose levels in animal
studies (for example doses that induce prostration, severe inappetence, excessive mortality) would
Regulation (EC) 1272/2008 of the European Community                                                       45
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<pre>              not normally lead to classification, unless other information is available, e.g. toxicokinetics informa-
              tion indicating that humans may be more susceptible than animals, to suggest that classification is
              appropriate. Please also refer to the section on maternal toxicity (3.7.2.4) for further guidance in this
              area.
              3.7.2.5.9      However, specification of the actual ‘limit dose’ will depend upon the test method that
              has been employed to provide the test results, e.g. in the OECD Test Guideline for repeated dose tox-
              icity studies by the oral route, an upper dose of 1 000 mg/kg has been recommended as a limit dose,
              unless expected human response indicates the need for a higher dose level.
              3.7.3          Classification criteria for mixtures
              3.7.3.1        Classification of mixtures when data are available for all ingredients or only for some
              ingredients of the mixture
              3.7.3.1.1      The mixture shall be classified as a reproductive toxicant when at least one ingredient
              has been classified as a Category 1A, Category 1B or Category 2 reproductive toxicant and is present
              at or above the appropriate generic concentration limit as shown in Table 3.7.2 for Category 1A, Cat-
              egory 1B and Category 2 respectively.
              3.7.3.1.2      The mixture shall be classified for effects on or via lactation when at least one ingredi-
              ent has been classified for effects on or via lactation and is present at or above the appropriate generic
              concentration limit as shown in Table 3.7.2 for the additional category for effects on or via lactation.
 able 3.7.2 Generic concentration limits of ingredients of a mixture classified as reproduction toxicants or foreffects on or via
actation that trigger classification of the mixture.
 ngredient classified as:     Generic concentration limits triggering classification of a mixture as:
                              Category 1A                Category 1B               Category 2                Additional category
                              reproductive toxicant reproductive toxicant reproductive toxicant for effects on or via l
                                                                                                             actation
Category 1A                   ≥ 0,3 %
 eproductive toxicant         [Note 1]
  ategory 1B                                             ≥ 0,3 %
eproductive toxicant                                     [Note 1]
Category 2                                                                         ≥ 3,0 %
 eproductive toxicant                                                              [Note 1]
Additional category                                                                                          ≥ 0,3 %
or effects on or via                                                                                         [Note 1]
actation
  ote The concentration limits in the table above apply to solids and liquids (w/w units) as well as gases (v/v units).
  ote 1 If a Category 1 or Category 2 reproductive toxicant or a substance classified for effects on or via lactation is present in
he mixture as an ingredient at a concentration above 0,1 %, a SDS shall be available for the mixture upon request.
  6           Tellurium
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<pre>3.7.3.2        Classification of mixtures when data are available for the complete mixture
3.7.3.2.1      Classification of mixtures will be based on the available test data for the individual
ingredients of the mixture using concentration limits for the ingredients of the mixture. On a case-by-
case basis, test data on mixtures may be used for classification when demonstrating effects that have
not been established from the evaluation based on the individual components. In such cases, the test
results for the mixture as a whole must be shown to be conclusive taking into account dose and other
factors such as duration, observations, sensitivity and statistical analysis of reproduction test systems.
Adequate documentation supporting the classification shall be retained and made available for review
upon request.
3.7.3.3        Classification of mixtures when data are not available for the complete mixture:
               bridging principles
3.7.3.3.1      Subject to paragraph 3.7.3.2.1, where the mixture itself has not been tested to determine
its reproductive toxicity, but there are sufficient data on the individual ingredients and similar tested
mixtures to adequately characterise the hazards of the mixture, these data shall be used in accordance
with the applicable bridging rules set out in section 1.1.3.
3.7.4          Hazard Communication
3.7.4.1        Label elements shall be used for substances or mixtures meeting the criteria for
               classification in this hazard class in accordance with Table 3.7.3
Regulation (EC) 1272/2008 of the European Community                                                        47
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<pre> able 3.7.3 Label elements for reproductive toxicity.
 lassification              Category 1A or Category 1B              Category 2                              Additional category
                                                                                                            for effects on or via
                                                                                                            lactation
GHS Pictograms                                                                                              No pictogram
 ignal Word                 Danger                                  Warning                                 No signal word
Hazard Statement            H360: May damage fertility or the       H361: Suspected of damaging fertil-     H362: May cause
                            unborn child (state specific effect if  ity or the unborn child (state specific harm to breast-fed
                            known)(state route of exposure if it is effect if known) (state route of expo-  children.
                            conclusively proven that no other       sure if it is conclusively proven that
                            routes of exposure cause the hazard)    no other routes of exposure cause the
                                                                    hazard)
 recautionary Statement     P201                                    P201                                    P201
 revention                  P202                                    P202                                    P260
                            P281                                    P281                                    P263
                                                                                                            P264
                                                                                                            P270
 recautionary Statement     P308 + P313                             P308 + P313                             P308 + P313
 esponse
 recautionary Statement     P405                                    P405
 torage
 recautionary Statement     P501                                    P501
Disposal
 8            Tellurium
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<pre>nnex E
     Additional considerations to
     Regulation (EC) 1272/2008
     The classification and labelling of substances is performed according to the
     guidelines of the European Union (Regulation (EC)1272/2008) presented in
     Annex D. The classification of compounds is ultimately dependent on an
     integrated assessment of the nature of all parental and developmental effects
     observed, their specificity and adversity, and the dosages at which the various
     effects occur. The guideline necessarily leaves room for interpretation, dependent
     on the specific data set under consideration. In the process of using the
     regulation, the Committee has agreed upon a number of additional
     considerations:
     • if there is sufficient evidence to establish a causal relationship between
         human exposure to the substance and impaired fertility or subsequent
         developmental toxic effects in the offspring, the compound will be classified
         in category 1A, irrespective of the general toxic effects (see Annex D,
         3.7.2.2.1.)
     • adverse effects in a reproductive study, occurring without reporting the
         parental or maternal toxicity, may lead to a classification other than category
         1B, when the effects occur at dose levels which cause severe toxicity in
         general toxicity studies
     • clear adverse reproductive effects will not be disregarded on the basis of
         reversibility per se
     Additional considerations to Regulation (EC) 1272/2008                              49
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<pre>  •   the Committee dot not only use guideline studies (studies performed
      according to OECD* standard protocols) for the classification of compounds,
      but non-guideline studies are taken into consideration as well.
   Organisation for Economic Cooperation and Development.
0 Tellurium
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<pre> nnex        F
             Developmental toxicity studies
 able 1 Developmental toxicity studies with tellurium in animals.
 uthors        species         experimental            dose/route      general         developmental toxicity
                               period/design                           toxicity
Garro/         Long-Evans low/mid dose:                0, 500, 1,250,  not toxic to    pups appeared normal although smaller
 entschew      rats(n>100)     throughout gestation; 2,500 ppm         dams: dams      than controls
1964)                          high dose: throughout (ca. 30, 75,      tolerated diets hydrocephalus developed immediately
                               gestation until 3-5 d 150 mg/kg         well; behaved   after birth; incidences:
                               before expected         bw/da); diet    normally        500 ppm: unspecified increase
                               delivery                                                1,250 ppm: 60-90%
                                                                                       2,500 ppm: 99%
                                                                                       mortality: 99% of all affected pups
                                                                                       within 1 mo
Agnew et al.   Wistar rats     throughout gestation    0, 1,250,       not reported    1,250 ppm: no hydrocephalus
1968)          (n=4 low/mid                            2,500, 3,300                    500 ppm; no hydrocephalus
               dose; n=10                              ppm (ca. 75,                    3,300 ppm: hydrocephalus in 8/10 litters
               high dose)                              150, 200 mg/                    (allowed to live ≥19 d; appearing grossly
                                                       kg bw/da); diet                 after pnd 4 or 5) and in 36/77 pups
Duckett (1970) Wistar rats     daily throughout        3,000 ppm       not reported    no effect on size and appearance of
               (n=20)          gestation;              (ca. 45 mg/rat                  foetuses; no anomalies in sections of the
                               examination of foetal or 180 mg/kg                      brains of the tellurium foetuses, stained
                               brains on gd 13, 15; bw/d); diet                        with haematoxylin-eosin; electron
                               only foetuses of                                        microscopic examination: morphological
                               tellurium-fed animals,                                  anomalies in cells of ependymal layer:
                               eventually giving                                       ependymal layer of normal foetal rat
                               birth to hydrocephalic                                  resembled that of human, rabbit, and
                               animals,and foetuses                                    chick foetuses; on the ventricular surface
                               of similar age from                                     of the ependymal cells from tellurium
                               the control rats                                        foetuses. normally
             Developmental toxicity studies                                                                                    51
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<pre>                                 examined and                                           present microvilli not present and
                                 reported                                               number of mitochondria greatly
                                                                                        diminished; mitochondria often
                                                                                        abnormal, smaller and darker than
                                                                                        normal and showed distortion of cristae;
                                                                                        cells in the rest of the telencephalon
                                                                                        appeared to be normal
Duckett et al.  rats (strain not daily throughout        2,500 ppm       not reported   12 rats fed during gd 10-15 gave birth to
1971)           specified)       gestation; on gd 1-9,   (ca. 150 mg/                   hydrocephalic rats (average litter 9 with
                (n=20)           10-15, 16-21; (exact    kg bw/d); diet                 5 hydrocephalic); no hydrocephalic
                                 day of examination                                     animals during other dosing periods
                                 not reported)
Duckett et al.  rats (strain not one of gd 1-21;         2,500 ppm       3 animals died 72 animals gave birth to an average of 8
1971)           specified)       number of postnatal     (ca. 150 mg/ (not further      offspring; no hydrocephalic animals; no
                (n=5)            hydrocephalus (exact    kg bw/d); diet specified)      further information
                                 day of examination
                                 not reported)
Agnew/Curry     Long-Evans one of gd 7-13;               0, 13 mg/kg not reported       after injection on gd 8: delivery in 5/8
1972)           rats (n=5-10; sacrifice: pnd 10          bw                             after injection on gd 7, 8, 10, 11: total
                controls 2-3) examined for               (suspended in                  number of offspring/group rather low,
                                 hydrocephalus and       olive oil); im                 number of foetal resorptions increased;
                                 other visceral effects;                                after injection on gd 7, 9, 10: number of
                                 only mothers failing                                   foetuses with hydrocephalus: 1, 14, 10,
                                 to deliver were                                        resp. (vs. 1 in controls); no other
                                 autopsied and                                          malformations observed
                                 examined for foetal
                                 resorptions the day
                                 following predicted
                                 delivery
 ohnson et al.  Sprague-        gd 6-15; sacrifice: 2/3  0, 30, 300,     no mortality;  foetuses: no effect on incidence of
1988)           Dawley rats; on gd 20: foetuses          3,000, 15,000   300, 3,000,    pregnancy, mean number of corpora
                (n=32-33)       examined; 1/3 allowed    ppm (ca. 0, 2,  15,000 ppm:    lutea, implantations, live and dead
                                to deliver: pups         20, 166, 633    decreased      foetuses, resorptions, litter size, % of
                                observed until pnd 7;    mg/kg bw/d      maternal       males;
                                pup heads (stillborn,    for gd 6-10; 0, weight gain,   15,000 ppm: decreased weights of male,
                                found dead or killed)    2, 18, 173,     food           females (p≤0.05); % litters with
                                examined                 580 mg/kg       consumption    variations: 100% (controls: 18%;
                                                         bw/d for gd     (during        p≤0.01); % foetuses with variations: 41%
                                                         11-15); diet    exposure;      (controls: 2.1%; p-value not presented);
                                                                         p≤0.01 at gd   increased incidence of malformed
                                                                         6-9, gd 6-15); foetuses (no details), of foetuses with
                                                                         3,000, 15,000  delayed ossification (no details); most
                                                                         ppm: thin      common malformation: internal
                                                                         appearance);   hydrocephalus with dilatation of the
                                                                         not clear at   lateral ventricles: in 17 litters (85%) vs. 1
                                                                         which levels:  in controls (4.6%) (p≤0.05); in 67
                                                                         preparturi-    foetuses (55%) vs. 1 in controls (0.7%)
                                                                         tional vaginal (p≤0.05); also slight to marked dilatation
                                                                         bleeding,      of the third and/or fourth ventricles in
                                                                         decreased      more severely affected foetuses;
                                                                         motor activity externally hydrocephalus in 2 foetuses
                                                                                        (one had enlarged fontanelle bordered by
 2            Tellurium
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<pre>                                                                                 a haemorrhagic area); dilatation of renal
                                                                                 pelvis (no details); other malformations
                                                                                 (no further details): kinked and/or
                                                                                 stubbed tails, rotation of hind limb/foot,
                                                                                 malformed retina, malpositioned
                                                                                 manubrium and clavicles, short radius,
                                                                                 ulna and/or femur, wavy ribs, thickened/
                                                                                 split rib; delayed ossification of the
                                                                                 parietals, interparietals, supraoccipitals,
                                                                                 vertebral and sternal centra, pubes,
                                                                                 ischia, and/or ribs in many of these
                                                                                 foetuses from severely affected dams
                                                                                 3000 ppm; % litters with variations:
                                                                                 57% ( p≤0.05); % foetuses with
                                                                                 variations: 11% (p-value not presented);
                                                                                 increased incidence of malformed
                                                                                 foetuses (no details), of foetuses with
                                                                                 delayed ossification (no details); most
                                                                                 common malformation: internal
                                                                                 hydrocephalus with dilatation of the
                                                                                 lateral ventricles: in 3 litters (14%) (n.s.);
                                                                                 in 11 foetuses (8.3%) (n.s.); dilatation of
                                                                                 renal pelvis (no details); no other
                                                                                 malformations treatment had no effect on
                                                                                 duration of gestation in groups allowed
                                                                                 to litter; pups: no effect on number of
                                                                                 dams with stillbirths, litter size, of live
                                                                                 pups delivered, on mean pup weights at
                                                                                 pnd 7 15,000 ppm; decreased number
                                                                                 (%) of pups surviving 7 d (p≤0.01); % of
                                                                                 litters with dilated lateral ventricles at
                                                                                 pnd 7: 75% (controls:0) ((p≤0.01); % of
                                                                                 pups with dilated lateral ventricles at pnd
                                                                                 7: 61% (controls:0) ((p≤0.01); no (other)
                                                                                 gross, external or visceral anomalies
Johnson et al. New Zealand gd 6-18; sacrifice: gd 0, 17.5, 175,  1,750, 5,250    number of pregnancies varied between
(1988)         white rabbits 29                   1,750, 5,250   ppm:            dose levels: 10, 15, 9, 15 and 13 at 0,
               (n=17)                             ppm (ca. 0,    decreased bw    17.5, 175, 1750 or 5250 ppm,
                                                  0.8, 8, 52, 97 gain (p≤0.01),  respectively;
                                                  mg/kg bw/d     food            no effect on incidences of abortion, mean
                                                  using feed     consumption     numbers of corpora lutea, implantations,
                                                  intake gd 6-18 (p≤0.05,        resorptions, litter size, on % male
                                                  and maternal   p≤0.01, resp.), foetuses/litter;
                                                  bw on gd 6);   soft or liquid  5250 ppm: decreased foetal weight:
                                                  diet           faeces,         males 84%, females 95% of controls;
                                                                 alopecia, thin  incidence of litters with abnormalities:
                                                                 appearance,     46% (controls: 2%); of foetuses with
                                                                 and/or          abnormalities: 12% (controls: 6.7%);
                                                                 decreased       increased in malformed foetuses (no
                                                                 motor activity  details), foetuses with delayed
                                                                 (p≤0.01)        ossification (no details); low incidences
                                                                 5,250           of hydrocephalus; enlarged and/or
            Developmental toxicity studies                                                                                 53
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<pre>                                                                   ppm: adverse   irregularly shaped anterior fontanelle;
                                                                   clinical signs incomplete ossification of, or small holes
                                                                   (not further   in, the frontals and parietals; frontals
                                                                   specified)     with thickened ossification; umbilical
                                                                   (p≤0.01)       hernia; fused pulmonary artery, aorta;
                                                                                  asymmetric and/or irregularly shaped
                                                                                  and/or fused sternebrae; thickenedareas
                                                                                  in ribs; foetuses also tended to be smaller
                                                                                  than normal with fewer caudal vertebral,
                                                                                  xiphoid, forepaw phalangeal ossification
                                                                                  sites
   based on the data of Duckett (1970) and Johnson et al. (1988)
bbreviations: bw=body weight; d=day(s); gd=gestational day(s); im=intramuscular; mo=month(s); pnd=postnatal day(s).
4           Tellurium
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<pre>Health Council of the Netherlands
Advisory Reports
The Health Council’s task is to       In addition, the Health Council
advise ministers and parliament on    issues unsolicited advice that
issues in the field of public health. has an ‘alerting’ function. In some
Most of the advisory reports that     cases, such an alerting report
the Council produces every year       leads to a minister requesting
are prepared at the request of one    further advice on the subject.
of the ministers.
Areas of activity
Optimum healthcare                    Prevention                          Healthy nutrition
What is the optimum                   Which forms of                      Which foods promote
result of cure and care               prevention can help                 good health and
in view of the risks and              realise significant                 which carry certain
opportunities?                        health benefits?                    health risks?
Environmental health                  Healthy working                     Innovation and
Which environmental                   conditions                          the knowledge
influences could have                 How can employees                   infrastructure
a positive or negative                be protected against                Before we can harvest
effect on health?                     working conditions                  knowledge in the
                                      that could harm their               field of healthcare,
                                      health?                             we first need to
                                                                          ensure that the right
                                                                          seeds are sown.
www.healthcouncil.nl
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<br><br>