<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
          Theophylline
             Evaluation of the effects on reproduction,
             recommendation for classification
2013/02
</pre>

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<pre>Theophylline
    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 Theophylline
Uw kenmerk              : DGV/MBO/U-932542
Ons kenmerk             : U-7650/HS/fs/543-M13
Bijlagen                :1
Datum                   : 5 april 2013
Geachte minister,
Graag bied ik u hierbij het advies aan over de effecten van theofylline 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 Sub-
commissie Classificatie reproductietoxische stoffen. Het is vervolgens getoetst door de
Beraadsgroep Gezondheid en omgeving van de raad.
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
Te l e f o o n ( 0 7 0 ) 3 4 0 7 0 0 4                             Te l e f a x ( 0 7 0 ) 3 4 0 7 5 2 3
E - m a il : h . st o u t e n @ g r. n l                           w w w. g r. n l
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<pre></pre>

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<pre>Theophylline
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. 2013/02, The Hague, April 05, 2013
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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.
                 The Health Council of the Netherlands is a member of the International Network
                 of Agencies for Health Technology Assessment (INAHTA), an international
                 collaboration of organisations engaged with health technology assessment.
 I NA HTA
This report can be downloaded from www.healthcouncil.nl.
Preferred citation:
Health Council of the Netherlands. Theophylline. Evaluation of the effects on
reproduction, recommendation for classification. The Hague: Health Council of
the Netherlands, 2013; publication no. 2013/02.
all rights reserved
ISBN: 978-90-5549-947-2
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<pre>   Contents
   Samenvatting 9
   Executive summary 11
   Scope 13
.1 Background 13
.2 Committee and procedure 13
.3 Effects on or via lactation 14
.4 Data 15
.5 Presentation of conclusions 15
.6 Final remark 16
   Theophylline 17
.1 Properties 17
.2 Human studies 18
.3 Animal studies 22
.4 Conclusions 27
   References 29
   Contents                       7
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<pre>  Annexes 33
A The Committee 35
B The submission letter (in English) 37
C Regulation (EC) 1272/2008 of the European Community 39
D Additional considerations to Regulation (EC) 1272/2008 51
E Fertility and developmental toxicity studies 53
  Theophylline
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<pre>Samenvatting
In het voorliggende advies heeft de Gezondheidsraad theofylline onder de loep
genomen. Theofylline, een methylderivaat van xanthine, is een luchtwegverwij-
der die wordt voorgeschreven bij astma en chronische obstructieve luchtwegaan-
doeningen. 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 men-
sen tijdens de beroepsuitoefening kunnen worden blootgesteld. De Subcommis-
sie 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 vrou-
wen 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 com-
missie een voorstel voor classificatie. Voor theofylline komt de commissie tot de
volgende aanbevelingen:
• voor effecten op de fertiliteit adviseert de commissie om theofylline niet te
    classificeren wegens onvoldoende geschikte gegevens
• voor effecten op de ontwikkeling adviseert de commissie theofylline in cate-
    gorie 1B te classificeren (stoffen waarvan verondersteld wordt dat zij toxisch
    zijn voor de menselijke voortplanting ) en met H360D (kan het ongeboren
    kind schaden) te kenmerken
Samenvatting                                                                       9
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<pre>  •  voor effecten op of via lactatie adviseert de commissie om theofylline niet te
     kenmerken wegens onvoldoende geschikte gegevens.
0 Theophylline
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<pre>Executive summary
In the present report, the Health Council of the Netherlands reviewed
theophylline. Theophylline is a methylxanthine drug and used as a
bronchodilator in the therapy for respiratory diseases such as asthma and chronic
obstructive pulmonary disease (COPD). This report is part of a series, in which
the Health Council evaluates the effects of substances on reproduction, at the
request of the Minister of Social Affairs and Employment. It mainly concerns
substances to which man can be occupationally exposed. The Subcommittee on
the Classification of Reproduction Toxic Substances of the Dutch Expert
Committee on Occupational Safety 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 theophylline, these recommendations are:
• for effects on fertility, the Committee recommends not classifying
    theophylline due to a lack of appropriate data
• for effects on development, the Committee recommends classifying
    theophylline 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
    theophylline due to a lack of appropriate data.
Executive summary                                                                 11
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<pre>2 Theophylline</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 and 1B and 2) or compound with effects on or via
        lactation.
1.2     Committee and procedure
        This document contains the classification of theophylline by the Health
        Council’s Subcommittee on the Classification of Reproduction Toxic
        Substances, hereafter called the Committee. The members of the Committee are
        Scope                                                                             13
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<pre>    listed in Annex A. The submission letter (in English) to the Minister can be
    found in Annex B.
    The classification is based on the evaluation of published human and animal
    studies concerning adverse effects with respect to fertility and development as
    well as lactation of the above mentioned compound.
    Classification for reproduction (fertility (F) and development (D)):
    Category 1                                          Known or presumed human reproductive
                                                        toxicant (H360(F/D))
         Category 1A                                    Known human reproductive toxicant
         Category 1B                                    Presumed human reproductive toxicant
    Category 2                                          Suspected human reproductive toxicant
                                                        (H361(f/d))
    No classification for effects on fertility or development
    Classification for lactation:
                                                        Effects on or via lactation (H362)
                                                        No labelling for lactation
    The classification and labelling of substances is performed according to the
    guidelines of the European Union (Regulation (EC)1272/2008) presented in
    Annex C. 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 D).
    In 2012, the President of the Health Council released a draft of the report for
    public review. No comments were received.
1.3 Effects on or via 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
 4  Theophylline
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<pre>    sufficient to cause concern for the health of a breastfed child, shall be classified
    and labelled. Unlike the classification of substances for fertility and develop-
    mental effects, which is based on hazard identification only (largely independent
    of dosage), the labelling for effects on or via lactation is based on risk charac-
    terization 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 poten-
    tially toxic to the breastfed child when this concentration leads to exceeding the
    exposure limit for the general population, e.g. the acceptable daily intake (ADI).
1.4 Data
    Literature searches were conducted in the on-line databases Current Contents
    and Medline, starting from 1966 up to March 2011 and by searches on internet.
    A final search was performed in March 2012 in Pubmed. Literature was selected
    primarily on the basis of the text of the abstracts. Publications cited in the
    selected articles, but not selected during the primary search, were reviewed if
    considered appropriate. In addition, handbooks and a collection of most recent
    reviews were consulted as well as several websites regarding (publications on)
    toxicology and health. References are divided into literature cited and literature
    consulted, but not cited.
         The Committee describes both human and animal studies in the text. The
    animal data are described in more detail in Annex E as well. Of each study, the
    quality of the study design (performed according to internationally acknow-
    ledged guidelines) and the quality of documentation is considered.
         In the assessment of the potential reproduction toxic effects of theophylline,
    the Committee also used data on adverse effects related to its application as a
    therapeutic agent.
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 preclude assessment of the compound for repro-
         ductive toxicity
    Scope                                                                                15
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<pre>    •    Sufficient data show that no classification for toxic to reproduction is
         indicated.
1.6 Final remark
    The classification of compounds is based on hazard evaluation only (Niesink et
    al., 1995)13, 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  Theophylline
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<pre> hapter 2
        Theophylline
2.1     Properties
        name                      : theophylline
        IUPAC name                : 1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione
        CAS name                  : 1H-purine-2,6-dione, 3,7-dihydro-1,3-dimethyl-
        CAS registry number       : 58-55-9
        EC/EINECS number          : 200-385-7
        synonyms                  : 1,3-dimethylxanthine
        colour and physical state   white crystalline powder
        molecular formula         : C7 H 8 N 4 O 2
        structural formula        :
        molecular weight          : 180.16
        melting point             : 270-274oC
        vapour pressure           : 7x10-7 Pa (at 25oC; estimated)
        solubility in water       : 7,360 mg/L (at 25 oC)
        Log Poctanol/water        : - 0.02 (recommended: see http://logkow.cisti.nrc.ca/logkow/
                                    search.html)
        Theophylline                                                                            17
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<pre>    use                      :   theophylline is a methylxanthine drug and used as a
                                 bronchodilator in the therapy for respiratory diseases such as
                                 chronic obstructive pulmonary disease (COPD) and asthma. It
                                 is naturally found in tea and cocoa beans2;
                                 therapeutic doses of theophylline are in the range of 2-12
                                 mg/kg/day, achieving plasma levels between 4-24 µg/mL;
                                 recommended theophylline therapeutic levels are between 5
                                 and 12 µg/mL; plasma levels as low as 1.3 µg/mL have been
                                 found to be effective.18
    general toxicity         :   adverse reactions associated with theophylline are generally
                                 mild when peak serum concentrations are below 20 µg/mL,
                                 and mainly consist of transient caffeine-like adverse effects
                                 such as nausea, vomiting, headache and insomnia; however,
                                 when peak serum theophylline concentrations exceed 20
                                 µg/mL, theophylline produces a wide range of adverse
                                 reactions including persistent vomiting, cardiac arrhythmias
                                 and intractable seizures which can be lethal.2
    mechanism                :   theophylline has two distinct actions in the airways of patients
                                 with reversible obstruction: smooth muscle relaxation (i.e.
                                 bronchodilation) and suppression of the response of the
                                 airways to stimuli (i.e. non-bronchodilator prophylactic
                                 effects).2
    kinetics                 :   theophylline is rapidly and completely absorbed after oral
                                 administration in solution or immediate-release solid oral
                                 dosage form. Once theophylline enters the systemic
                                 circulation, about 40% is bound to plasma protein. Unbound
                                 distributes freely throughout body water, but poorly into body
                                 fat. An increase in the volume of distribution of theophylline,
                                 primarily due to reduction in plasma protein binding, occurs
                                 amongst others in women during the third trimester of
                                 pregnancy and in premature neonates. In such cases, the
                                 patient may show signs of toxicity at total (bound + unbound)
                                 serum concentrations of theophylline in the therapeutic range
                                 (10-20 µg/mL), due to elevated concentrations of the
                                 pharmacologically active unbound drug.2
                                 In adults and children beyond one year of age, approximately
                                 90% of the dose is metabolized in the liver. In neonates,
                                 approximately 50% of the theophylline dose is excreted
                                 unchanged in the urine. The pharmacokinetics of theophylline
                                 varies widely among similar patients.2 Theophylline passes
                                 freely the placenta and is excreted into breast milk.8
2.2 Human studies
    Fertility studies
    No studies were found regarding the effects of exposure to theophylline on
    human fertility.
 8  Theophylline
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<pre>Developmental toxicity studies
Schatz et al. evaluated the associations between the use of asthma medication
and perinatal outcomes including gestational hypertension, preterm birth, low
birth weight, small for gestational age and major congenital malformations. The
asthmatic participants recruited had completed an asthma observational cohort
study or a randomized controlled trial of beclomethasone versus theophylline for
moderate asthma during pregnancy. These studies were conducted at 16 centres
of the Maternal Fetal Medicine Units Network of the US National Institute of
Child Health and Human Development with recruitment from December 1995
through March 1999. During this time, patients with moderate asthma were first
offered entry into the randomized controlled trial and if they refused, they were
offered entry into the observational cohort study. The final cohort included 2,123
asthmatic participants, 1,739 from the observational study and 384 from the
randomized controlled trial. No differences in perinatal outcomes were found
comparing theophylline-using participants (n=273) and participants on other
types of medication (n=1,850).15
Heinonen et al. conducted an epidemiological investigation of the possible
developmental effects of drugs used in a cohort of 50,282 mother-child pairs
recruited in 12 centres in the US during the years 1959-1965. For theophylline,
117 mother-child pairs were indentified. In this group, ten children had any
malformation in relation to exposure to theophylline during the first four months
of pregnancy (hospital standardized relative risk: 1.38; survival and race
standardized relative risk: 1.29). The authors concluded that the data provided no
evidence for a teratogenic effect.7
In a prospective cohort study of 51,830 singleton pregnancies at 12 medical
centres in the US between 1959 and 1966, the association between theophylline
and stillbirth was evaluated. Theophylline use during pregnancy was not
associated with any increase in the risk of stillbirth. This applied both to
theophylline-using women who had a diagnosis of one form or another of asthma
(n=392) and to those who were not so labelled (n=814; it was not clear why
subjects without a status of asthma received medication). Details on the amount
of theophylline received were not available. Due to the low incidence of
stillbirth, the power of the study was approximately 50 % (Neff and Leviton).12
In a Finnish case-control study conducted in 1982-1990, the data of 212 pregnant
asthmatics with theophylline treatment were compared with findings in 292
Theophylline                                                                       19
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<pre>  pregnant asthmatics without theophylline treatment and 237 non-asthmatic
  pregnant control subjects. There were no differences between the groups as to
  age, height, age of onset of asthma, lung function, parity or smoking. The
  incidence of preeclampsia (15.6%) was higher in theophylline-treated subjects
  than in untreated asthmatics (10.6%) or non-asthmatic controls (6.4%). No
  differences were seen between the groups with regard to gestational age, birth
  weight, Apgar score or perinatal deaths. Theophylline treatment was not
  associated with premature contractions or premature rupture of membranes,
  haemorrhage, placenta previa, abruption of the placenta, abnormal foetus
  position, augmentation of labour, prolonged third phase of delivery or increased
  haemorrhage post-partum. Three infants with malformations were born in 121
  patients (2.5%) treated with theophylline during the first trimester and four in the
  91 patients (4%) treated with theophylline during the second and third trimester
  only. Corresponding figures in the asthmatic and healthy control group were
  three (1%) and two (0.8%), respectively. The average frequency of
  malformations in Finland was 2% at that time (Stenius-Aarniala et al.).20
  Schatz et al. performed a prospective study of 824 asthmatic pregnant women
  (receiving various types of medication) and 678 non-asthmatic pregnant women,
  followed between 1978 and 1989. The numbers of subjects exposed to
  theophylline were 292 (first trimester) and 429 (any time exposure), but exposure
  was not unique (if needed for the prevention of acute asthmatic episodes or
  symptoms interfering with sleep or normal activity, medication was administered
  sequentially in the following order 1) β-agonist; 2) theophylline and/or
  cromolyn; 3) beclomethasone, 4) prednisone). Perinatal outcomes were
  compared in theophylline-exposed versus unexposed individuals (with and
  without asthma). No associations were identified between major congenital
  malformations and first trimester exposure (prevalence: 4.5% in 292 exposed vs.
  5.3% in 1208 non-exposed) or any time exposure (prevalence: 4.7% in 429
  exposed vs. 5.3% in 1061 non-exposed) to theophylline. An association was
  found, however, between theophylline use and preterm birth (6% in exposed vs.
  3.6% in non-exposed; p=0.034). According to Schatz et al., this finding may
  have been confounded by the presence and the severity of asthma.16
  The effects of asthma or various asthma therapies were prospectively examined
  in 872 pregnant women with a diagnosis of asthma (778 of whom experienced
  asthma symptoms or took medication during pregnancy) and 1333 women
  without a diagnosis of asthma (of whom 884 had neither symptoms nor used
  medication, whereas 449 had symptoms or used medication during pregnancy).
0 Theophylline
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<pre>Asthma severity during pregnancy was determined for each subject, regardless of
a diagnosis of asthma, by cross-classifying them on their symptoms and
medication steps, to derive at four severity categories (intermittent, mild
persistent, moderate persistent, severe persistent) and a category with neither
symptoms nor treatment.
    When specific medication was considered, theophylline use was associated
with an increased risk of preterm delivery (OR= 5.0; 95%CI: 1.6-16.0) but not
with intra-uterine growth restriction. More detailed analyses showed that
theophylline use increased the risk of premature delivery by 5% (95%CI: 1-9%)
for every increase in dose per month and decreased the gestational age by 1.1
weeks (p=0.002) for once-daily use across pregnancy, adjusted for asthma
severity and other confounding factors (Bracken et al.).1
Lactation
Yurchak and Jusko studied the transfer of theophylline to breast milk following
single oral doses of theophylline of 4.25 mg/kg bw in three asthmatic patients
and following four daily doses of 200 mg aminophylline (i.e. theophylline with
ethylenediamine in 2:1 ratio) in two patients. Peak concentrations were observed
in serum at or within 30 minutes and in breast milk two to three hours after
administration and amounted in one patient to 6.8 and 4.0 mg/L, respectively.
The average milk to serum concentration was about 0.7, and milk concentration
paralleled the time-course of serum concentrations. Irritability and fretful
sleeping were observed in one infant only on days when the mother was taking
theophylline while no such effects were seen in the other infant.21
Stec et al. investigated the kinetics of transfer to breast milk in three nursing
patients following single intravenous doses of 3-5 mg/kg bw of aminophylline.
Serum and milk concentrations paralleled; the breast milk:serum concentration
ratio was about 0.7.19
Reinhardt et al. investigated the kinetics of the transfer of theophylline from
breast feeding mothers to their infants. Following administration of a dual dose
(300 mg followed by 200 mg after four hours) of theophylline to 12 lactating
mothers, breast milk:plasma ratios between 0.6-0.9 were calculated. The mean
levels obtained within one to ten hours after the first dose were approximately 6-
10 mg/L in plasma and approximately 3-7 mg/L in milk).14
Theophylline                                                                       21
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<pre>    As part of a study on the effects of pregnancy on the kinetics of theophylline
    throughout pregnancy and post-partum, Gardner et al. determined theophylline
    concentrations in breast milk samples collected prior to treatment and at three
    time points after treatment and in infant plasma samples obtained prior and after
    feeding. Concentrations in milk roughly paralleled those in plasma. The breast
    milk:plasma concentration ratios varied between 0.54 and 1.08. According to the
    authors, characterization of the theophylline acquisition by the nursing neonates
    was hampered by an inadequate number of neonatal plasma samples. In all cases,
    however, detectable levels of theophylline were present in the neonate before and
    after feeding.3
2.3 Animal studies
    Fertility and developmental toxicity studies in laboratory animals are
    summarized in Annex E.
    Fertility studies
    Theophylline was tested for its effect on fertility in Swiss CD-1 mice according
    to the Reproductive Assessment by Continuous Breeding (RACB) design used
    by the National Toxicology Program.
        The RACB (Task 2) design uses 20 rodents/sex/group (controls: 40 pairs)
    which are exposed from one week prior to cohabitation. During a subsequent
    14-week continuous exposure, the animals are housed as breeding pairs and
    normally four to five litters are delivered per adult pair. Theophylline was
    administered at 0%, 0.075%, 0.15% and 0.3% weight per volume in the feed,
    providing calculated consumptions of 0, 126, 260 and 500 mg/kg bw/day. After
    14 weeks of treatment, male mice gained nearly 7, 6, 4 and 3% of their initial
    body weights, respectively, while group mean body weights of the female mice
    varied with the gestational phase. Alopecia occurred in both sexes of all
    treatment groups (20-25% in the low-dose group and >50% in the mid- and high-
    dose groups). Three control mice and four low-dose mice died.
        In the high-dose group, the number of days to deliver each litter was
    consistently increased (three days longer for the first litter, five days longer for
    the last litter and similarly increased for all other litters).
        After the last litter had been delivered, the females were evaluated for vaginal
    cyclicity for seven days, and then the F0 mice in the control group and the high-
    dose group were killed and necropsied. There was an 11% increase in relative
    liver weight in the high-dose females. There were no changes in the length of the
 2  Theophylline
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<pre>oestrous cycle or in the percent of time spent in the various oestrus stages.
Treated male terminal body weights were reduced by 7%. Relative seminal
vesicle weight was decreased by 19% in the treatment (0.3%) group. Epididymal
sperm density was reduced by 20% in the treatment (0.3%) group. The percent
motile and the percent of abnormal morphologic forms were unchanged in the
treatment (0.3%) group (Lamb et al.)9, (Morrissey et al.)11. This study does not
allow conclusions on the effects of theophylline on reproductive performance.
Sperm morphology and vaginal cytoIogy were evaluated in F344 rats and
B6C3F1 mice as part of subchronic (13-week) toxicity studies of theophylline.
Theophylline was administered by gavage at 0, 75, 150 and 300 mg/kg bw/day
(mice) or 0, 37.6, 75 and 150 mg/kg bw/day (rats). In parallel studies, theophyl-
line was administered in the diet at levels of 0%, 0.1%, 0.2% and 0.4%. These
levels were approximately equivalent to 0, 200, 400 and 800 mg/kg bw/day
(mice) or 66, 130 and 260 mg/kg bw/day (rats).
     In the gavage studies, terminal body weights were decreased in male mice at
150 and 300 mg/kg bw/day, while absolute testis weights were decreased in high-
dose mice (300 mg/kg bw/day). In high-dose rats (150 mg/kg bw/day), testis
weights were also decreased and body weights tended to be lower. Other
reproductive endpoints, including sperm number and motility, epididymis weight
and oestrous cycle length, were not significantly affected.
     In the parallel 13-week feeding studies, terminal body weights were
decreased in mice of both sexes in all treatment groups, but not in rats. In mice,
increases were noted in epididymis weights in the mid-dose and high-dose group
and in cauda epididymis weights in the mid-dose group. In rats, the absolute
epididymis weights were increased in the mid-dose group, whereas the cauda
epididymis weights were decreased in the high-dose group. In rats, there was a
dose-related increase in abnormal sperm (significant in the high-dose group
only). Oestrus cycle length was not affected in any group (Morrissey et al.).11
Groups of male Swiss CD-1 mice (n=10/group) were exposed by gavage to 0, 20,
60 and 200 mg theophylline/kg bw/day for 17 days and then necropsied. There
were no adverse changes in clinical signs, body weights or in histology of liver
and kidneys. Weights of testes and epididymides, sperm density per cauda and
sperm motility were not affected. At the high-dose level, theophylline induced
mild changes in the testis epithelium, consisting primarily of asynchronous germ
cell development and focal loss of germ cells within individual tubules (Harris et
al.).4
Theophylline                                                                       23
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<pre>  Groups of female Swiss CD-1 mice (n=10/group) were dosed by gavage with 0,
  20, 60 and 200 mg theophylline/kg bw/day for 19 days. After seven days of
  dosing, these females were cohabited with male mice that were treated for five
  days prior to mating (until day 5 of cohabitation). After 19 days of dosing, the
  females were killed. There were no adverse clinical signs. One female in the
  high-dose group was killed moribund. Pregnancy rate was, non-significantly,
  decreased in the high-dose group (6/9 vs. 9/10 in all other groups). There were no
  effects on live, dead or total implants per female (Harris et al.).4
  Developmental toxicity studies
  Theophylline was tested for its effect on reproduction in Swiss CD-1 mice
  according to the Reproductive Assessment by Continuous Breeding (RACB)
  design used by the National Toxicology Program (see above Fertility studies).
      Significant reproductive effects were observed; fewer pups per litter were
  noted at all doses (reduced by 22%, 29% and 42% in the low-, mid- and high-
  dose group, respectively). In the high-dose group, there was a 19% reduction in
  the mean number of litters per pair and a 6% decrease in live pup weight adjusted
  for litter size.
      A crossover mating trial was performed with F0 mice to detect which sex had
  been affected. According to the RACB (Task 3) design, three groups are formed:
  control males x high-dose females, high-dose males x control females and
  controls x controls (20 pairs in each group). In this mating trial, there were no
  differences in the percent of pairs mating or delivering a live litter. However, in
  the group cohabiting control males and high-dose females, the proportion of pups
  born alive was reduced by 16% and the adjusted pup weight was reduced by 15%
  (Lamb et al.)9, (Morrissey et al.)11.
      In summary, theophylline caused adverse reproductive effects in Swiss CD-1
  mice (fewer live pups per litter at 126, 260 and 500 mg/kg bw/day, with reduced
  pup weight and fewer litters per pair at the high-dose level) in the absence of
  changes in maternal body weight.
  Theophylline was administered to groups (n=20-21/group) of pregnant Sprague-
  Dawley (CD) rats in the feed during gestational day 6 through 15. The dietary
  levels were 0%, 0.15%, 0.3% or 0.4%, providing an estimated intake of 0, 124,
  218 or 259 mg theophylline/kg bw/day . There were no maternal deaths.
  Piloerection was noted at a higher incidence in the two higher dose groups.
  Maternal body weight gain and maternal body weight on gestational day 20
  corrected for gravid uterine weight were decreased in the high-dose group.
4 Theophylline
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<pre>Maternal feed consumption was decreased in the high-dose group, and water
consumption was increased in all theophylline-treated groups. Gravid uterine
weights tended to be lower in the high-dose group, but the differences with the
controls were not significant. There were no differences among the groups in
number of implantation sites per litter, percentage pre-implantation loss, litters
with resorptions or percentage resorptions per litter. The number of live foetuses
per litter was decreased at the high-dose level and the average male and female
foetal weight per litter was decreased in the mid- and high-dose group. The
percentage of malformations per litter was not affected. External, visceral or
skeletal malformations and variations were not affected by theophylline.
Lindström et al. concluded that the NOAEL for maternal toxicity was 218 mg/kg
bw/day and for developmental toxicity 124 mg/kg bw/day (Lindström et al.).10
Theophylline was administered to groups (n=23-33/group) of pregnant Swiss
(CD-1) mice in the drinking water during gestational day 6 through 15. The
levels in the drinking water were 0%, 0.075%, 0.15% or 0.2% providing an
estimated intake of 0, 282, 372 or 396 mg theophylline/kg bw/day. There were no
maternal deaths. Piloerection was noted at a higher incidence in the two higher
dose group. Maternal body weight gain during gestation, maternal body weight
on gestational day 17 corrected for gravid uterine weight and maternal water
consumption were decreased in the mid- and high-dose group. Gravid uterine
weight was decreased in the high-dose group. The percentage of resorptions per
litter was increased in the mid- and high-dose group. There were no differences
in number of implantation sites per litter or the percentage pre-implantation loss.
The average male and female weight per litter was decreased in the mid- and
high-dose group. The number of externally malformed foetuses was slightly
increased in the mid-and high-dose group, but statistical significance was not
obtained. Visceral or skeletal malformations and variations were not affected by
theophylline.
     Lindström et al. concluded that the NOAEL for maternal and developmental
toxicity was 282 mg/kg bw/day (Lindström et al.).10
     The Committee notes that the study may have been confounded by the
decreased water intake in the mid- and high-dose group.
Groups of female Swiss CD-1 mice (n=10/group) were dosed by gavage with 0,
20, 60 and 200 mg theophylline/kg bw/day for 19 days. After seven days of
dosing, these females were cohabited with male mice that were treated for five
days prior to mating (until day 5 of cohabitation). After 19 days of dosing, the
females were killed. There were no adverse clinical signs. One female in the
Theophylline                                                                        25
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<pre>  high-dose group was killed moribund. Pregnancy rate was, non-significantly,
  decreased in the high-dose group (6/9 versus 9/10 in all other groups). There
  were no effects on live, dead, or total implants per female (Harris et al.).4
  Groups of mated female Swiss CD-1 mice (n=13-15/group) were dosed by
  gavage with 0, 20, 60 and 200 mg theophylline/kg bw/day during organogenesis
  (gestational day 8-14). The dams were allowed to deliver and litters were
  evaluated on postnatal day 0, 1 and 4. There were no effects on the number of
  females littering, number of implantations per female, number of live neonates or
  total litter weight (Harris et al.).4
  The foetal toxicity of theophylline and its relationship to maternal plasma levels
  were examined in mated rabbits (n=20/group) dosed intravenously from gesta-
  tional day 6 through 18. Theophylline was injected into the auricular vein at 0,
  15, 30 or 60 mg theophylline/kg bw/day. The Cmax of theophylline was similar on
  gestational day 6 and 18, namely 30, 56 and 106 µg/mL in the low-, mid- and
  high-dose group, respectively. The dams were sacrificed on gestational day 29.
      Decreases in body weight and in feed intake and reversible toxicity
  (accelerated respiration, sluggish startle reactions, dilation of the auricular
  vessels, polyurea) were noted in the high-dose group. One animal died and four
  animals aborted in the high-dose group.
      Foetal toxicity was observed in the high-dose group, including late foetal
  death and a tendency towards decreased foetal body weights. There were no
  differences in implantations, live foetuses or sex ratio. Cleft palate was observed
  in eight foetuses (two litters) of the high-dose group. Increased incidences of
  skeletal variations (13th rib) were noted in the high-dose group; there were no
  differences in the incidence of visceral or skeletal anomalies or of ossifications
  (Shibata et al.).17
  Lactation
  Theophylline was administered to Wistar rats (n=5 or 6/group) at 0 or 1 mg/kg
  bw/day via the drinking water throughout pregnancy up to lactational day 14.
  The dose of 1 mg/kg bw/day was stated to mimic the proportion of theophylline
  in tea. Theophylline had no effect on maternal weight and carcass fat during
  pregnancy/lactation, the volume or composition of the milk, or on litter weight.5,6
6 Theophylline
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<pre>2.4 Conclusions
    Fertility
    No studies were found regarding the effects of theophylline on human fertility.
        In animal studies, effects of theophylline on the male reproductive system
    were noted. Theophylline caused reduced relative seminal vesicle weights and
    epididymal sperm numbers in mice at 500 mg/kg bw/day9,11, lower absolute
    testis weights in mice at 300 mg/kg bw/day and in rats at 150 mg/kg bw/day11
    and increased epididymis weights in mice at 400 and 800 mg/kg bw/day11. These
    findings were accompanied by reductions in body weight. In another study in
    rats, the absolute cauda epididymis weights were decreased and abnormal sperm
    was observed at 260 mg/kg bw/day in the absence of growth retardation.11
        In a continuous breeding study, the number of days to deliver each litter was
    consistently increased after oral exposure of mice to 500 mg/kg bw/day9,11, but
    no other studies were found regarding functional effects of theophylline on
    animal fertility.
        Overall, the Committee proposes not classifying theophylline for effects on
    fertility due to a lack of appropriate human and animal data.
    Developmental toxicity
    Several studies were available on the potential effects of theophylline in pregnant
    asthmatic women. Most of the studies, that addressed various pregnancy
    outcomes, were negative but may not have had sufficient power or an adequate
    design to disentangle the roles of asthma and theophylline use.7,12,15,20 In two
    studies, use of theophylline during pregnancy was found to cause an increase in
    preterm deliveries.1,16
        The Committee concludes that the human data are not sufficient for
    classification.
    Animal studies (with oral exposure to theophylline ranging from 124-500 mg/kg
    bw/day), showed reductions in the number of pups per litter in mice9,11 and
    rats10, increased percentage of resorptions in mice10 and reduced pup weights in
    mice9-11 and rats10. Some of these effects were noted in the absence of maternal
    growth retardation. In these studies, the administration of theophylline did not
    induce visceral or skeletal malformations and variations. In an intravenous study
    in rabbits (levels up to 60 mg/kg bw/day, corresponding to maternal plasma
    Theophylline                                                                        27
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<pre>  levels up to 106 µg theophylline/mL), cleft palate and increased incidence of
  skeletal variations were noted in the presence of maternal toxicity.
      The Committee is of the opinion that the developmental effects occurred
  independently from maternal toxicity. Therefore, based on the animal data the
  Committee recommends to classify theophylline in category 1B.
  Lactation
  No human data were available for effects on or via lactation.
      In rats, administration in the drinking water of amounts of 1 mg/kg bw/day
  throughout pregnancy up to lactational day 14, no effects on maternal weight and
  carcass fat, the volume or composition of the milk, or on litter weight were
  observed.5,6
      No data were found on background concentrations of theophylline in breast
  milk or on concentrations in breast milk in women occupationally exposed to
  theophylline.
      Following oral or intravenous administration to lactating women,
  theophylline was found in breast milk.3,14,19,21
      In the absence of data on the toxicity of theophylline in breast milk, the
  Committee is not able to calculate a safe level for theophylline in human breast
  milk. Therefore, the Committee proposes not labelling theophylline for effects
  on or via lactation due to a lack of appropriate human and animal data.
  Proposed classification for fertility
  Lack of appropriate human and animal data precludes the assessment of
  theophylline for fertility.
  Proposed classification for developmental toxicity
  Category 1B; H360D
  Proposed labelling for effects on or via lactation
  Lack of appropriate human and animal data precludes the assessment of
  theophylline for effects on or via lactation.
8 Theophylline
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<pre>  References
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  References                                                                                           29
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<pre>1 Morrissey RE, Collins JJ, Lamb JC, Manus AG, Gulati DK. Reproductive effects of theophylline in
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3 Niessink RJM, de Vries J, Hoolinger MA. Toxicology principles and applications. Boca Raton FL,
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4 Reinhardt D, Richter O, Brandenburg G. Pharmakokinetik des Arzneimittelübergangs von stillenden
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5 Schatz M, Dombrowski MP, Wise R, Momirova V, Landon M, Mabie W, et al. The relationship of
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6 Schatz M, Zeiger RS, Harden K, Huffman CC, Chilingar L, Petitti D. The safety of asthma and
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7 Shibata M, Wachi M, Kawaguchi M, Kojima J, Onodera K. Teratogenic and fetal toxity following
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9 Stec GP, Greenberger P, Ruo TI, Henthorn T, Morita Y, Atkinson Jr AJ, et al. Kinetics of theophylline
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0 Stenius-Aarniala B, Riikonen S, Teramo K. Slow-release theophylline in pregnant asthmatics. Chest
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1 Yurchak AM, Jusko WJ. Theophylline secretion into breast milk. Pediatrics 1976; 57: 518-525.
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  Brandstetter Y, Kaplanski J, van CC, Ben-Zvi Z. Theophylline pharmacokinetics in pregnant and
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0 Theophylline
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References                                                                                          31
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<pre>  Park JM, Schmer V, Myers TL. Cardiovascular anomalies associated with prenatal exposure to
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  Yoshioka K, Suzuki C, Itoh S, Kikuchi K, Iwamura S, Rodriguez-Martinez H. Production of piglets
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2 Theophylline
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<pre>A The Committee
B The submission letter (in English)
C Regulation (EC) 1272/2008 of the European Community
D Additional considerations to Regulation (EC) 1272/2008
E Fertility and developmental toxicity studies
  Annexes
                                                         33
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<pre>4 Theophylline</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 Nijmegen 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 Committee                                                              35
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<pre>  The first draft of the present document was prepared by Dr. B.A.R. Lina from
  TNO Triskelion BV, Zeist, 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.
6 Theophylline
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<pre>nnex B
     The submission letter (in English)
     Subject         : Submission of the advisory report Theophylline
     Your reference  : DGV/MBO/U-932342
     Our reference   : U-7650/HS/fs/543-M13
     Enclosed        :1
     Date            : April 5, 2013
     Dear Minister,
     I hereby submit the advisory report on the effects of theophylline 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 reproductive toxic substances are classified in accordance with European
     guidelines. This involves substances to which people can be exposed while
     pursuing their occupation.
     The advisory report was prepared by the a permanent Committee of the Health
     Council of the Netherlands, the Subcommittee on the Classification of
     Reproduction Toxic Compounds. The advisory report was subsequently
     reviewed by the Health Council’s Standing Committee on Health and the
     Environment.
     The submission letter (in English)                                                  37
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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
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<pre>nnex C
     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, Principles for
     Evaluating Health Risks to Reproduction Associated with Exposure to Chemicals. For classification
     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 considered more
     appropriate to address such effects under the separate hazard class of germ cell mutagenicity.
     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
     containing them, shall be classified as reproductive toxicants.
     Regulation (EC) 1272/2008 of the European Community                                                     39
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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
  development 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
  postnatally, 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
  specific hazard warning about this effect can be provided for lactating mothers.
  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 development, are
  considered separately. In addition, effects on lactation are allocated to a separate hazard category.
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<pre>                                       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
                         substance 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
                         relevance 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,
                         possibly supplemented with other information, of an adverse effect on
                         sexual 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                                               41
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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
  lactation. However, 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 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
  substance 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
  precedence: Category 1A, Category 1B, Category 2 and the additional Category for effects on or via
  lactation. 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. Classification in the additional category for effects on or via lactation will be considered
  irrespective of a classification 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
  classification shall ideally be from well conducted epidemiological studies which include the use of
  appropriate controls, balanced assessment, and due consideration of bias or confounding factors. Less
  rigorous data from studies in humans shall be supplemented with adequate data from studies in
  experimental animals and classification in Category 1B shall be considered.
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<pre>3.7.2.3. Weight of evidence
3.7.2.3.1. Classification as a reproductive toxicant is made on the basis of an assessment of the total
weight of evidence, see section 1.1.1. This means that all available information that bears on the
determination of reproductive toxicity is considered together, such as epidemiological studies and
case reports in humans and specific reproduction studies along with sub-chronic, chronic and special
study results in animals that provide relevant information regarding toxicity to reproductive and
related endocrine organs. Evaluation of substances chemically related to the substance under study
may also be included, particularly when information on the substance is scarce. The weight given to
the available evidence will be influenced by factors such as the quality of the studies, consistency of
results, nature and severity of effects, the presence of maternal toxicity in experimental animal
studies, level of statistical significance for inter-group differences, number of endpoints affected,
relevance 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
produces 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 incidence of
spontaneous defects in the foetus, small changes in the proportions of common foetal variants 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
Regulation (EC) 1272/2008 of the European Community                                                      43
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<pre>  developmental 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
  developmental 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 maternal toxicity shall not be used to negate findings of embryo/foetal effects, unless it can be
  clearly demonstrated 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, influence
  development via non-specific secondary mechanisms, producing effects such as depressed foetal
  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
  unequivocally 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,
  significant post-natal functional deficiencies.
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<pre>3.7.2.4.3. Classification shall not automatically be discounted for substances that produce
developmental 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 significance and
dose response relationship.
Maternal mortality:
an increased incidence of mortality among the treated dams over the controls shall be considered
evidence 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
() 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                                                         45
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<pre>  calculation 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
  findings 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-
  generation 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
  Reproduction/Development Toxicity Screening Test) can also be used to justify classification,
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<pre>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 administration
which relate to the potential route of human exposure. However, in practice, reproductive toxicity
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. However,
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 injection,
which result in exposure of the reproductive organs to unrealistically high levels of the test substance,
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 production
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
guidelines 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
not normally lead to classification, unless other information is available, e.g. toxicokinetics
Regulation (EC) 1272/2008 of the European Community                                                       47
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<pre>              information 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 toxicity
              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,
              Category 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 ingredient
              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.
                                                              Table 3.7.2
   Generic concentration limits of ingredients of a mixture classified as reproduction toxicants or for effects on or via
                                        lactation 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
                                                                                                               lactation
  ategory 1A r                      ≥ 0,3 %
 productive toxicant                [Note 1]
  ategory 1B                                                 ≥ 0,3 %
eproductive toxicant                                         [Note 1]
  ategory 2                                                                            ≥ 3,0 %
eproductive toxicant                                                                   [Note 1]
Additional category for                                                                                        ≥ 0,3 %
 ffects on or via lactation                                                                                    [Note 1]
Note:     The concentration limits in the table above apply to solids and liquids (w/w units) as well as gases (v/v units).
Note 1: If a Category 1 or Category 2 reproductive toxicant or a substance classified for effects on or via lactation is
          present in the mixture as an ingredient at a concentration above 0,1 %, a SDS shall be available for the mixture
          upon request.
  8           Theophylline
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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
                                                               Table 3.7.3
                                             Label elements for reproductive toxicity
Classification                  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               H362: May cause harm to
                                unborn child (state specific effect if fertility or the unborn child (state breast-fed children.
                                known)(state route of exposure if it specific effect if known) (state
                                is conclusively proven that no other route of exposure if it is
                                routes of exposure cause the           conclusively proven that no other
                                hazard)                                routes of exposure cause the
                                                                       hazard)
 recautionary Statement         P201                                   P201                                 P201
 revention                      P202                                   P202                                 P260
                                P281                                   P281                                 P263
                                                                                                            P264
                                                                                                            P270
              Regulation (EC) 1272/2008 of the European Community                                                                     49
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<pre> recautionary Statement  P308 + P313 P308 + P313 P308 + P313
 esponse
 recautionary Statement  P405        P405
 torage
 recautionary Statement  P501        P501
Disposal
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<pre>nnex D
     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 C. 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 C,
         3.7.2.2.1.)
     • Adverse effects in a reproductive study, reported without information on 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                              51
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<pre>  •   The Committee does not only use guideline studies (studies performed
      according to OECD* standard protocols) for the classification of compounds,
      but non-guideline studies are taken into consideration as well.
   Organisation for Economic Cooperation and Development.
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<pre> nnex        E
             Fertility and developmental
             toxicity studies
Table 1 Fertility studies in laboratory animals.
authors              species             experimental period/      dose              general toxicity    effects on
                                         design                                                          reproductive organs/
                                                                                                         effects on
                                                                                                         reproduction
Morrissey et al.     Swiss CD-1 mice tested according to the 0, 0.075, 0.15,         alopecia in both    no changes in length
(1988)                                   Reproductive              0.3%; diet        sexes of all        of oestrous cycle or
Lamb et al. (1997)                       Assessment by             (equivalent to 0, treatment groups    in percent of time
                                         Continuous Breeding 126, 260, 500           (low dose: 20-25%;  spent in various
                                         (RACB) design used by mg/kg bw/d            mid/high dose:      oestrus stages’;
                                         the National                                >50%;               decreased relative
                                         Toxicology Program;                         mortality in 3      seminal vesicle
                                         In Task 2 of this RACB                      control and 4 low-  weight (by 19%) in
                                         design, 20 animals/sex/                     dose mice;          high-dose group;
                                         group (controls: 40                         11% increase in     reduced epididymal
                                         pairs) are exposed from                     relative liver      sperm density (by
                                         1 week prior to                             weight in high-dose 20%) in high-dose
                                         cohabitation; during a                      females;            group;
                                         subsequent 14 wk                            7% reduction in     no changes in percent
                                         continuous exposure,                        terminal bw and     motile and percent
                                         animals are housed as                       increased absolute  abnormal
                                         breeding pairs and                          liver weight in     morphologic forms in
                                         normally 4-5 litters are                    high-dose males     high-dose group
                                         delivered per adult pair;
                                         after delivery of last
                                         litter, females are
                                         evaluated for vaginal
                                         cyclicity for 7 d, and F0
                                         mice in control group
                                         and high-dose group
                                         killed and necropsied.
             Fertility and developmental toxicity studies                                                                   53
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<pre>Morrissey et al.     F344 rats (n=10/  sperm morphology and rat: 0, 37.6, 75, 150        gavage: decreased    gavage: decreased
(1988)               group);           vaginal cytoIogy           mg/kg bw/d             terminal bw in male  absolute testes
                     B6C3F1 mice       evaluations                mice: 0, 0.75, 150,    mice at 150 and      weight in high-dose
                     (n=10/group)                                 300 mg/kg bw/d;        300 mg/kg bw/d;      rats and mice;
                                                                  gavage                 diet: decreased      no stat. sign. effects
                                                                  0, 0.1, 0.2, 0.4%;     terminal bw in male  on other reproductive
                                                                  diet (equivalent to    and female mice in   endpoints, including
                                                                  ca. 66, 130, 260       all treatment groups sperm number, sperm
                                                                  mg/kg bw/d in rats,    (no effect in rats)  motility,
                                                                  and                                         epididymides weight,
                                                                   0, 200, 400, 800                           oestrus cycle length
                                                                  mg/kg bw/d                                  diet: rats: increased
                                                                  in mice)                                    epididymidis weights
                                                                                                              in mid-dose group;
                                                                                                              decreased cauda
                                                                                                              epididymidis weights
                                                                                                              in high-dose group;
                                                                                                              dose-related increase
                                                                                                              in abnormal sperm
                                                                                                              (stat. sign. in high-
                                                                                                              dose group only); no
                                                                                                              effect on oestrus
                                                                                                              cycle length
                                                                                                              mice: increased
                                                                                                              epididymidis weights
                                                                                                              in mid-dose and
                                                                                                              high-dose group;
                                                                                                              increased cauda
                                                                                                              epididymidis weights
                                                                                                              in mid-dose group.
Harris et al. (1992) male Swiss CD-1 mice exposed for 17 d; 0, 20, 60, 200               no adverse changes high-dose: mild
                     mice (n=10/group) then necropsied.           mg/kg bw/d;            in clinical signs,   changes in testis
                                                                  gavage                 bw, or in liver and epithelium consisting
                                                                                         kidney histology     primarily of
                                                                                                              asynchronous germ
                                                                                                              cell development and
                                                                                                              focal loss of germ
                                                                                                              cells within
                                                                                                              individual tubules.
Harris et al. (1992) Swiss CD-1 mice female mice treated for 0, 20, 60, 200              no adverse clinical high dose: decreased
                     (n=10/group)      19 d, then killed;. after mg/ kg bw/d             signs; 1 female in pregnancy rate (6/9
                                       7 d of treatment,                                 high-dose group      vs. 9/10 in all other
                                       cohabitation with male                            killed moribund.     groups; n.s.).
                                       mice that were treated                                                 no stat. sign. effect
                                       for 5 d prior to mating                                                on number of live-,
                                       (until d 5 of                                                          dead-, or total
                                       cohabitation).                                                         implants per female
bw=body weight; d=day(s); n.s.=not statistically significant; stat. sign.=statistically significant
 4            Theophylline
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<pre>Table 2a Developmental toxicity studies in laboratory animals with theophylline: oral administration
authors              species             experimental period/ dose                  general toxicity    developmental
                                         design                                                         toxicity
Morrissey et al.     Swiss CD-1 mice     tested according to 0, 0.075, 0.15,        see above Table 1.  fewer pups/ litter at
(1988)                                   RACB (Task 2)        0.3%; diet                                all doses (reduced
Lamb et al. (1997)                       design (see above (equivalent to 0,                            by 22%, 29%, 42%
                                         Table 1);            126, 260, 500                             at the low, mid, high
                                         and crossover        mg/kg bw/d)                               dose, respectively).
                                         mating trial with F0                                           high dose: 19%
                                         mice to detect which                                           reduction in the
                                         sex had been                                                   mean number of
                                         affected; according                                            litters/pair; 6%
                                         to the RACB (Task                                              decrease in live pup
                                         3) design, three                                               weight adjusted for
                                         groups are formed:                                             litter size;
                                         control males x                                                consistently greater
                                         high-dose females,                                             number of days to
                                         high-dose males x                                              deliver each litter
                                         control females, and                                           (three d longer for
                                         controls x controls                                            the first litter, 5 d for
                                         (20 pairs in each                                              the last litter, and
                                         group).                                                        similarly increased
                                                                                                        for all other litters)
                                                                                                        in the group
                                                                                                        cohabiting control
                                                                                                        males and high-dose
                                                                                                        females: reduced
                                                                                                        proportion of pups
                                                                                                        born alive (by 16%);
                                                                                                        reduced adjusted
                                                                                                        pup weight (by
                                                                                                        15%)
                                                                                                        no differences in
                                                                                                        percent of pairs
                                                                                                        mating or delivering
                                                                                                        a live litter.
Lindström et al.     Swiss (CD-1) mice gd 6-15                0, 0.075, 0.15,       no maternal deaths  decreased gravid
(1990)               (n=23-33/group)                          0.2%; drinking        decreased water     uterine weights at
                                                              water                 consumption at mid  the high dose (n.s.)
                                                              (equivalent to 0,     and high dose       decreased number of
                                                              282, 372, 396         higher incidence of live foetuses/litter at
                                                              mg/kg bw/d            piloerection at mid the high dose
                                                                                    and high dose.      decreased male and
                                                                                    decreased maternal  female foetal
                                                                                    bw gain during      weight/litter at the
                                                                                    gestation and bw on mid- and high dose
                                                                                    gd 17 corrected for no stat. sign.
                                                                                    gravid uterine      differences in
                                                                                    weight at the mid   number of
                                                                                    and high dose       implantation sites/
                                                                                    decreased maternal  litter, percentage
                                                                                    feed consumption at preimplantation
                                                                                    the high dose       loss, litters with
                                                                                                        resorptions,
                                                                                                        percentage
                                                                                                        resorptions/litter
             Fertility and developmental toxicity studies                                                                     55
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<pre>                                                                                                           no effect on
                                                                                                           percentage of
                                                                                                           malformations/ litter
                                                                                                           or on incidences of
                                                                                                           external, visceral or
                                                                                                           skeletal
                                                                                                           malformations and
                                                                                                           variations
Lindström et al.        Swiss (CD-1) mice gd 6-15.               0, 0.075, 0.15,      no maternal deaths   decreased gravid
(1990)                  (n=23-33/group)                          0.2%; drinking       decreased water      uterine weight at the
                                                                 water                consumption at mid   high dose increased
                                                                 (equivalent to 0,    and high dose        percentage of
                                                                 282, 372, 396        higher incidence of  resorptions/litter at
                                                                 mg/kg bw/d           piloerection at mid  the mid and high
                                                                                      and high dose.       dose decreased male
                                                                                      decreased maternal   and female foetal
                                                                                      bw gain during       weight/litter at the
                                                                                      gestation and bw on  mid and high dose
                                                                                      gd 17 corrected for  slightly increased
                                                                                      gravid uterine       number of
                                                                                      weight at the mid    externally
                                                                                      and high dose        malformed foetuses
                                                                                                           at the mid and high
                                                                                                           dose (n.s.)
                                                                                                           no stat.sign.
                                                                                                           differences in
                                                                                                           number of
                                                                                                           implantation sites/
                                                                                                           litter or percentage
                                                                                                           of preimplantation
                                                                                                           loss or in incidence
                                                                                                           of
                                                                                                           visceral or skeletal
                                                                                                           malformations and
                                                                                                           variations
                                                                                                           the study may have
                                                                                                           been confounded by
                                                                                                           the decreased water
                                                                                                           intake in the mid-
                                                                                                           and high-dose
                                                                                                           group.
Harris et al. (1992) Swiss CD-1 mice      see above Table 1      0, 20, 60, 200       see above Table 1    decreased
                        (n=10/group)                             mg/kg bw/d;                               pregnancy rate (6/9
                                                                 gavage                                    vs. 9/10 in all other
                                                                                                           groups; n.s.)
                                                                                                           no stat. sign. effect
                                                                                                           on number of live-,
                                                                                                           dead-, or total
                                                                                                           implants/female
Harris et al. (1992) Swiss CD-1 mice      gd 8-14;               0, 20, 60, 200       not reported         no stat. sign. effects
                        (n=13-15/group)   dams were allowed mg/kg bw/d; gavage                             on number of
                                          to deliver and litters                                           females littering,
                                          were evaluated on                                                number of
                                          pnd 0, 1, 4.                                                     implantations/
                                                                                                           female, number of
                                                                                                           live neonates, total
                                                                                                           litter weight
bw=body weight; d=day(s); gd=gestational day(s); n.s.=not statistically significant; pnd=postnatal day(s);
stat. sign.=statistically significant
 6            Theophylline
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<pre>able 2b Developmental toxicity studies in laboratory animals with theophylline: intravenous injection
uthor            species         experimental      dose                    general toxicity            developmental toxicity
                                 period/design
hibata et al.    Kbl:JW rabbits gd 6-18; sacrifice 0, 15, 30, 60 mg/kg     high dose: 1 animal         high dose: foetal toxicity
2000)            (n= 20/group)   on gd 29          bw/d; iv                died, 4 animals aborted; including late foetal
                                                   Cmax of theophylline    decreased maternal bw death and tendency
                                                   similar on gd 6 and     and feed; reversible        towards decreased foetal
                                                   gd 18, viz. 30, 56, 106 toxicity (accelerated       bw; cleft palate in
                                                   µg/mL at low, mid, high respiration, sluggish       8 foetuses (2 litters);
                                                   dose, respectively      startle reactions,          increased incidence of
                                                                           dilation of the auricular skeletal variations
                                                                           vessels, polyurea)          (13th rib)
                                                                                                       no stat. sign. differences
                                                                                                       in implantations, live
                                                                                                       foetuses or sex ratio,
                                                                                                       incidences of visceral or
                                                                                                       skeletal anomalies or
                                                                                                       ossifications.
w=body weight; d=day(s); gd=gestational day(s); iv=intravenous; stat. sign.=statistically significant.
              Fertility and developmental toxicity studies                                                                     57
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<pre>8 Theophylline</pre>

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<pre>Health Council of the Netherlands
Advisory Reports
The Health Council’s task is to       In addition, the Health Council
advise ministers and parliament on    issues unsolicited advice that
issues in the field of public health. has an ‘alerting’ function. In some
Most of the advisory opinions that    cases, such an alerting report
the Council produces every year       leads to a minister requesting
are prepared at the request of one    further advice on the subject.
of the ministers.
Areas of activity
Optimum healthcare                    Prevention                          Healthy nutrition
What is the optimum                   Which forms of                      Which foods promote
result of cure and care               prevention can help                 good health and
in view of the risks 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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