<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
          Chlorpromazine
             Evaluation of the effects on reproduction,
             recommendation for classification
2015/14
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<pre>Chlorpromazine
    Evaluation of the effects on reproduction,
    recommendation for classification
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<pre></pre>

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<pre>Aan de minister van Sociale Zaken en Werkgelegenheid
Onderwerp             : aanbieding advies Chlorpromazine
Uw kenmerk            : DGV/BMO/U-932542
Ons kenmerk           : U-8378/EvV/fs/543-F15
Bijlagen              :1
Datum                 : 20 mei 2015
Geachte minister,
Graag bied ik u hierbij het advies aan over de effecten van chloorpromazine op de vrucht-
baarheid 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 voortplan-
ting giftige stoffen worden geclassificeerd volgens richtlijnen van de Europese Unie. Het
gaat om stoffen waaraan mensen tijdens de beroepsuitoefening kunnen worden blootge-
steld.
Dit advies is opgesteld door een vaste commissie van de Gezondheidsraad, de Subcommis-
sie Classificatie reproductietoxische stoffen van de Commissie Gezondheid en beroepsma-
tige blootstelling aan stoffen. Het is vervolgens getoetst door de Beraadsgroep Gezondheid
en omgeving van de Gezondheidsraad.
Ik heb dit advies vandaag ter kennisname toegezonden aan de minister van Volksgezond-
heid, Welzijn en Sport en, eveneens ter kennisname, aan de staatssecretaris van Infrastruc-
tuur en Milieu.
Met vriendelijke groet,
prof. dr. J.L. Severens,
vicevoorzitter
Bezoekadres                                                        Postadres
Parnassusplein 5                                                   Postbus 16052
2 5 11 V X      Den Haag                                           2500 BB Den Haag
E - m a i l : p w. v a n . v l i e t @ g r. n l                    w w w. g r. n l
Te l e f o o n ( 0 7 0 ) 3 4 0 7 3 2 7
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<pre></pre>

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<pre>Chlorpromazine
Evaluation of the effects on reproduction,
recommendation for classification
Committee on the Classification of Reproduction Toxic Substances
of the Health Council of the Netherlands
to:
the Minister of Social Affairs and Employment
No. 2015/14, The Hague, May 20, 2015
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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 and Sport, Infrastructure and the Environment, Social Affairs
and Employment, and Economic Affairs. The Council can publish advisory
reports on its own initiative. It usually does this in order to ask attention for
developments or trends that are thought to be relevant to government policy.
     Most Health Council reports are prepared by multidisciplinary committees of
Dutch or, sometimes, foreign experts, appointed in a personal capacity. The
reports are available to the public.
                 The Health Council of the Netherlands is a member of the European
                 Science Advisory Network for Health (EuSANH), a network of science
                 advisory bodies in Europe.
This report can be downloaded from www.healthcouncil.nl.
Preferred citation:
Health Council of the Netherlands. Chlorpromazine - Evaluation of the effects on
reproduction, recommendation for classification. The Hague: Health Council of
the Netherlands, 2015; publication no. 2015/14.
all rights reserved
ISBN: 978-94-6281-030-3
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<pre>   Contents
   Samenvatting 9
   Executive summary 11
   Scope 13
.1 Background 13
.2 Committee and procedure 13
.3 Labelling for lactation 14
.4 Data 15
.5 Presentation of conclusions 15
.6 Final remark 16
   Chlorpromazine 17
.1 Introduction 17
.2 Human studies 19
.3 Animal studies 23
.4 Conclusion 34
   References 37
   Contents                       7
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<pre>  Annexes 45
A The Committee 47
B The submission letter (in English) 49
C Comments on the public draft 51
D Regulation (EC) 1272/2008 of the European Community 53
E Additional considerations to Regulation (EC) 1272/2008 65
F Fertility and developmental toxicity studies 67
  Chlorpromazine
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<pre>Samenvatting
In het voorliggende advies heeft de Gezondheidsraad chloorpromazine onder de
loep genomen. In Nederland kan chloorpromazine worden voorgeschreven als
middel tegen misselijkheid en braken als andere middelen zijn gecontra-indi-
ceerd, als palliatieve sedatie ter bestrijding van delirium, dyspneu en onrust en
ter bestrijding van hardnekkige hik. Dit advies past in een reeks adviezen waarin
de Gezondheidsraad op verzoek van de minister van Sociale Zaken en Werkgele-
genheid de effecten van stoffen op de voortplanting beoordeelt. Het gaat vooral
om stoffen waaraan mensen tijdens de beroepsuitoefening kunnen worden bloot-
gesteld. De Subcommissie Classificatie reproductietoxische stoffen van de Com-
missie Gezondheid en beroepsmatige blootstelling aan stoffen van de raad,
hierna aangeduid als de commissie, kijkt zowel naar effecten op de vruchtbaar-
heid van mannen en vrouwen als naar effecten op de ontwikkeling van het nage-
slacht. 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 chloorpromazine komt de commissie
tot de volgende aanbevelingen:
• voor effecten op de fertiliteit adviseert de commissie chloorpromazine te
    classificeren in categorie 1B (stoffen waarvan verondersteld wordt dat zij
    toxisch zijn voor de menselijke voortplanting) en te kenmerken met H360F
    (kan de vruchtbaarheid schaden)
Samenvatting                                                                      9
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<pre>  •  voor effecten op de ontwikkeling adviseert de commissie chloorpromazine te
     classificeren in categorie 1B (stoffen waarvan verondersteld wordt dat zij
     toxisch zijn voor de menselijke voortplanting) en te kenmerken met H360D
     (kan het ongeboren kind schaden)
  •  voor effecten op en tijdens lactatie adviseert de commissie om chloorproma-
     zine niet te kenmerken wegens onvoldoende geschikte gegevens.
0 Chlorpromazine
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<pre>Executive summary
In the present report the Health Council of the Netherlands reviewed
chlorpromazine. In the Netherlands, chlorpromazine may be prescribed in the
management of nausea and vomiting in case other medicines are contraindicated,
in palliative sedation for the relief of delirium, dyspnoea and restlessness, and in
the treatment of intractable hiccups. This report is part of a series, in which the
Health Council evaluates the effects of substances on reproduction, at request of
the Minister of Social Affairs and Employment. It mainly concerns substances to
which man can be exposed occupationally. 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 chlorpromazine, these recommendations are:
• for effects on fertility, the Committee recommends classifying
    chlorpromazine in category 1B (presumed human reproductive toxicant) and
    labelling with H360F (may damage fertility)
• for effects on development, the Committee recommends classifying
    chlorpromazine in category 1B (presumed human reproductive toxicant) and
    labelling with H360D (may damage the unborn child)
Executive summary                                                                    11
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<pre>  •  for effects on or via lactation, the Committee recommends not labelling
     chlorpromazine due to a lack of appropriate data.
2 Chlorpromazine
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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 chlorpromazine 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.
         In 2014, the President of the Health Council released a draft of the report for
    public review. The individuals and organizations that commented on the draft
    report are listed in Annex C. The Committee has taken these comments into
    account in deciding on the final version of the report. The comments received,
    and the replies by the Committee, can be found on the website of the Health
    Council.
    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 D. The classification of compounds is ultimately dependent on an
    integrated assessment of the nature of all parental and developmental effects
    observed, their specificity and adversity and the dosages at which the various
    effects occur. The guideline necessarily leaves room for interpretation, dependent
    on the specific data set under consideration. In the process of using the
    regulation, the committee has agreed upon a number of additional considerations
    (see Annex E).
1.3 Labelling for lactation
    The recommendation for classifying substances for effects on or via lactation is
    also based on Regulation (EC) 1272/2008. The guideline defines that substances
    which are absorbed by women and have been shown to interfere with lactation or
    which may be present (including metabolites) in breast milk in amounts
 4  Chlorpromazine
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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
    developmental effects, which is based on hazard identification only (largely
    independent of dosage), the labelling for effects on or via lactation is based on a
    risk characterization and therefore, it also includes consideration of the level of
    exposure of the breastfed child.
        Consequently, a substance should be labelled for effects during lactation
    when it is likely that the substance would be present in breast milk at potentially
    toxic levels. The Committee considers a concentration of a compound as
    potentially toxic to the breastfed child when this concentration exceeds the
    exposure limit for the general population, e.g. the acceptable daily intake (ADI).
1.4 Data
    Literature searches were conducted in the online databases TOXLINE,
    MEDLINE and CAPLUS, up to and including January 2012 without a starting
    date; an update was performed in TOXNET in April 2014. Publications cited in
    the selected articles, but not retrieved during the primary search, were reviewed
    if considered appropriate. In addition, handbooks and most recent reviews were
    consulted. References are divided in 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 F as well. Of each study the
    quality of the study design (performed according to internationally
    acknowledged guidelines) and the quality of documentation are considered.
        In the assessment of the potential reproduction toxic effects of
    chlorpromazine, 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 precludes assessment of the compound for
        reproductive toxicity
    • sufficient data show that no classification for reproductive toxicity is
        indicated.
    Scope                                                                                15
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<pre>1.6 Final remark
    The classification of compounds is based on hazard evaluation only (Niesink et
    al., 1995)46, 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  Chlorpromazine
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<pre> hapter 2
        Chlorpromazine
2.1     Introduction
        name                      : chlorpromazine
        CAS number                : 50-53-3
        CAS registry name         : 10H-phenothiazine-10-propanamine, 2-chloro-N,N-dimethyl-
        synonyms                  : chloropromazine; 2-chloropromazine; 2-chloro-10-[3-
                                    (dimethylamino)propyl]- phenothiazine; 2-chloro-10[3’-
                                    (dimethylamino)propyl]phenothiazine; N-(3-
                                    dimethylaminopropyl)-3-chlorophenothiazine
        colour and physical state : oily liquid; white crystalline solid
        molecular weight          : 318.6
        molecular formula         : C17H19ClN2S
        structural formula        :
        melting point             : approximately 60 oC
        boiling point             : 200-205 oC (at 0.1 KPa)
        vapour pressure           : 0.7x10-3 Pa (at 25 oC; estimated)
        Log Poctanol/water        : 5.35 (recommended value)58
        Chlorpromazine                                                                       17
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<pre>  solubility                 :    practically insoluble in water (2.6 mg/L; at 24 oC); very soluble
                                  in ethanol, ether, benzene and chloroform; soluble in dilute
                                  hydrochloric acid
  use                        :    in human medicine, for the treatment of both acute and chronic
                                  psychoses including schizophrenia, organic-induced psychoses
                                  and manic-depressive illness; it has also been used in the first
                                  trimester of pregnancy to control nausea and vomiting and to
                                  control depressions and/or psychotic behaviour as well as during
                                  labour and delivery; routes of administration are oral, rectal,
                                  intramuscular or intravenous.
                                  in veterinary medicine, as an antiemetic, a pre-anaesthetic or a
                                  muscle relaxant.
                                  In the Netherlands, chlorpromazine-containing medicines are not
                                  registered for use in human or veterinary medicine nowadays14; it
                                  is available, as a suppository, on prescription at pharmacists in
                                  the management of nausea and vomiting in case other medicines
                                  are contraindicated, in palliative sedation for the relief of
                                  delirium, dyspnoea and restlessness and in the treatment of
                                  intractable hiccups.15
  general toxicity           :    oral LD50 values were 135 and 210 mg/kg bw in mice and rats,
                                  respectively; intravenous LD50 values 20, 23-46, 16 and 30 mg/
                                  kg bw in mice, rats, rabbits and dogs, respectively;
                                  intraperitoneal LD50 values 115-136 mg/kg bw and 71 mg/kg bw
                                  in mice and rats, respectively33
  mechanism                  :    Chlorpromazine is a phenothiazine derivative and acts as an
                                  effective antagonist on different postsynaptic receptors (e.g.
                                  dopamine receptors, serotonin receptors, histamine receptors, α1-
                                  and α2-adrenergic receptors and on M1 and M2 muscarinic
                                  acetylcholine receptors).
  kinetics                   :    Chlorpromazine is highly lipophilic and rapidly binds to plasma
                                  protein after administration; it is rapidly distributed throughout
                                  the body and highest concentrations of this drug are found in
                                  organs that need a high supply of blood (e.g. brain, lung etc.). It
                                  is metabolized mainly in the liver by cytochrome-P450 family
                                  enzymes, usually CYP2D6. The major metabolic pathways of the
                                  drugs are hydroxylation and conjugation with glucuronic acid.
                                  Due to its high lipophilicity, high membrane- and protein
                                  binding, the elimination half-life of chlorpromazine is 16-30
                                  hours. Approximately 10-12 metabolites are generated by the
                                  hepatic pathway, which may be detected in the urine for several
                                  months after discontinuation of use.33 Considerably longer
                                  plasma elimination half-lives (rapid phase: 1.46 days; slow
                                  phase: 3.19 days) were described in an infant whose mother was
                                  treated with chlorpromazine the last trimester of pregnancy.45
                   44
  Data from HSDB , unless otherwise noted.
8 Chlorpromazine
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<pre>2.2   Human studies
2.2.1 Fertility studies
      Giarola et al. studied 54 patients treated with chlorpromazine (100-600 mg) or
      meprobamates daily for several months and reported persisting amenorrhoea in
      74% of the patients while 59% of the patients showed anovulation.22
           Similar effects were also reported by Whitelaw72 and Sulman et al.65
2.2.2 Developmental toxicity studies
      Numerous studies evaluated the use of chlorpromazine in obstetrics to relieve
      pain in labour (e.g.1,11-13,16,26,27,30,35,41,42,47,59,60). In the majority of the studies
      however, chlorpromazine was used in combination with one or more other drugs,
      no untreated control groups were included, and effects on newborn were
      described in general terms. In combination with the exposure period, i.e. a few
      hours just before and during parturition, the Committee considers these studies of
      little relevance in assessing the developmental toxic effects of chlorpromazine
      and will not present them here in further detail.
      A prospective survey was described by Rumeau-Rouquette et al., which included
      12,764 women in 12 University hospitals in Paris. Four out of 57 women
      exposed to chlorpromazine during the first three months of pregnancy gave birth
      to malformed infants: syndactyly; microcephaly, clubfoot/hand, muscular
      abdominal aplasia (also exposed to acetylpromazine); endocardial fibroelastosis,
      brachymesophalangy, clinodactyly (also exposed to pipamazine); and
      microcephaly (also exposed to promethazine). However, the study did not take
      into account confounders such as concomitant medical conditions and concurrent
      medication, alcohol or smoking.55
      Farkas and Farkas performed a prospective study which included 906 women
      who had hyperemesis gravidarum in the first trimester of pregnancy and
      delivered between September 1, 1963 and August 31, 1968 in a hospital in Cluj,
      Romania. In the group of 152 women hospitalized and treated with
      chlorpromazine alone, three gave birth to infants with (not specified)
      malformations (2%), whereas no malformed infants were seen in a similarly
      treated group of 102 ambulatory patients. The malformation rates in the group of
      Chlorpromazine                                                                             19
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<pre>  906 patients and in the group of 84 ambulatory patients receiving a placebo were
  3.9 and 2.4%, respectively.20
  Sobel et al. found 52 records of women who were treated with chlorpromazine
  during pregnancy and delivered in eight different New York State mental
  hospitals from 1949 through 1958. In four cases, foetal damage (miscarriage,
  stillbirth, developmental delay) occurred after treatment with chlorpromazine
  (100-400 mg/day during gestation), the prevalence (8%) being comparable with
  foetal damage (7%) found in a control group of 202 non-treated women.
  However, babies from three women who were treated with 500-600 mg
  chlorpromazine daily in the later part of pregnancy were born with respiratory
  distress and cyanosis and required oxygen over a sustained period. One of the
  babies died. No respiratory distress was observed in the 49 cases treated with a
  lower concentration of chlorpromazine.64
  Ayd reported on 27 women treated with chlorpromazine pre-pregnancy, at the
  time of conception and during gestation (n=16) or starting some time after the
  first trimester (n=11). All women delivered full-term healthy babies with normal
  birth weights. Nine of the infants were breast-fed for varying lengths of time with
  no apparent adverse effects. In addition, no intellectual or behavioural problems
  were reported during follow-up periods up to 7 years.3
  In order to study the effects of psychotropic drugs on infant behaviour, Auerbach
  et al. recruited 54 women during the last trimester of pregnancy in the period
  1973-1977. Four of these women received chlorpromazine alone. The behaviour
  of their infants was assessed at postnatal days 3 (n=2) and 14 (n=4) using the
  Brazelton Neonatal Behavioral Assessment Scale. At postnatal day 3, behavioral
  signs including hypertonia and startles were observed in one infant. At postnatal
  day 14, mild or extreme hypertonia was seen in all four infants, as well as poor
  motor maturity in two, tremulousness in one, and startles in one infant.
  According to Auerbach et al., it was not clear whether these effects should be
  interpreted as symptoms of neonatal abstinence or withdrawal or as
  extrapyramidal signs associated with drug toxicity, or whether exposure via
  breast milk could have been involved.2
  Several cases of infants from mothers treated during (a part of) their pregnancy
  with chlorpromazine mostly in combination with other drugs or other kinds of
  therapy were reported.4,7,18,19,24,28,40,43,45,48,49,66 These reports described a variety
  of effects among which neurological effects, including extrapyramidal
0 Chlorpromazine
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<pre>      symptoms, and intestinal effects and one stillbirth with malformations. In one of
      these cases, severe neurological depression slowly abating during the first nine
      postnatal days was accompanied by steadily decreasing plasma chlorpromazine
      levels.45
      Kris and Carmichael reported on 12 women receiving chlorpromazine before,
      during and after pregnancy or during and after pregnancy. No infant born showed
      signs of abnormality at birth, and all infants (aged five to 16 months at the time
      of publication) showed normal behaviour and development.37 In a subsequent
      report, Kris stated that over a period of ten years 52 children were born to
      mothers maintained on psychopharmacotherapy (probably chlorpromazine)
      throughout pregnancy, parturition and postpartum. They all seemed normal at the
      time of birth and no indications of the presence of any problems of behaviour or
      any emotional or mental disturbances were seen during the mostly undefined
      follow-up period.36
2.2.3 Lactation
      Kris et al. reported normal development of seven breast-fed infants whose
      mothers received chlorpromazine (50-150 mg/day) during pregnancy and
      postnatally.37
      Blacker et al. measured levels of chlorpromazine in plasma 30, 60, 90 and 180
      minutes and in milk 60, 120 and 180 minutes following administration of 1,200
      mg to one woman hospitalized four days postpartum. Peak levels amounted to
      750 µg/L (at 90 minutes) and 290 µg/L (at 120 minutes) in plasma and milk,
      respectively. During the 18-day treatment period in hospital, she breast-fed her
      infant without effects on its growth, activity or development. Blacker et al.
      estimated that the mother’s dose of 1,200 mg (20 mg/kg bw) would have resulted
      in a dose of 3 µg/kg bw in the child. They stated that they could not detect
      chlorpromazine in blood or in breast milk of other patients following oral doses
      of 600 mg.9
      Ayd reported on 27 pregnant women treated with chlorpromazine) prior to and
      during pregnancy or starting some time after the first trimester. All women
      delivered full-term healthy babies with normal birth weights. Nine of the infants
      were breast-fed for varying lengths of time with no apparent adverse effects. No
      intellectual or behavioural problems were reported during follow-up periods up
      to 7 years.3
      Chlorpromazine                                                                     21
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<pre>  Uhlir and Ryznar examined breast milk of 15 patients. Metabolites of
  chlorpromazine were found in one to four fractions of 27 samples from 12
  patients. Uhlir and Ryznar stated that the daily dose of chlorpromazine should
  exceed 200 mg in order to enter into the breast milk.67
  Vorherr presented breast milk levels of 300 µg/L and stated that the percentage of
  administered dose in breast milk was 0.07%/day. No more details were given.69
  Using a modified gas chromatographic method, Wiles et al. measured
  chlorpromazine in samples of breast milk from four mothers (concentrations
  ranged from 7-98 µg/L), two of whom breast-fed their babies. One of these
  infants was found drowsy and lethargic after ingestion of chlorpromazine in the
  breast milk (92 µg/L), whereas the other infant (concentration in breast milk of
  7 µg/L) showed no effects.73
  Ohkubo et al. developed a high-performance liquid chromatographic (HPLC)
  assay for the determination of chlorpromazine in serum and blood and used the
  method in four patients receiving oral chlorpromazine doses of 40, 100, 120 or 2
  00 mg. In the patient receiving 40 mg, the concentration in milk was 5.5 µg/L,
  while no results were reported for the other patients. Levels in plasma were 5.0, 7.5
  and 12.0 µg/L at 100, 120 and 200 mg, respectively; no results were available for
  the patient receiving 40 mg. The limit of detection of the method was 0.5 µg/L.50
  Yoshida et al. used a HPLC method to determine, amongst others, chlorpromazine
  concentrations in maternal milk and plasma and an enzyme immunoassay for
  concentrations in maternal plasma, urine and milk and in infant’s plasma and
  urine. Twelve women were monitored, one woman receiving daily doses of 50 mg
  chlorpromazine alone during eight weeks breast-feeding, three women receiving
  doses of 200-600 mg during six to nine weeks breast-feeding in combination with
  haloperidol, and eight haloperidol or trifluoperazine. Using HPLC, concentrations
  of chlorpromazine up to 271 µg/L were measured and with the immunoassay, that
  presumably included metabolites as well, up to 568 µg/L. In a total of four urine
  and three plasma samples obtained from two infants, chlorpromazine (plus
  metabolites) levels were ≤1,4 µg/L and ≤0.7 µg/L, respectively.
      Repeated clinical and developmental assessments of the breast-fed infants
  carried out up to 30 months of age showed a decline in developmental scores
  from the first to second assessment at 12-18 months in three infants from
  mothers treated with both chlorpromazine and haloperidol. No effects were
  observed in the other infants, among which one from a mother treated with
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<pre>      chlorpromazine alone, or at other ages (1-4 months, 5-11 months, 19-30
      months).75
      The Committee notes that the more recent studies50,73,75 used more sensitive and
      specific methods for the determination of chlorpromazine in plasma, urine and
      breast milk.
2.3   Animal studies
      Fertility and developmental toxicity studies in laboratory animals are
      summarized in Annex F.
2.3.1 Fertility studies
      Oral administration
      Saigo et al. administered oral (gavage) doses of chlorpromazine of 0, 12.5, 25, 50
      or 100 mg/kg bw/day to male and female Sprague-Dawley rats (n=10 and 17-25,
      respectively) for nine weeks prior to mating and evaluated the effects for over
      three generations. One third of the pregnant rats was sacrificed on gestational day
      14, one third on gestational day 21, while the remaining one third was allowed to
      deliver.
          Maternal toxicity observed included generally dose-dependent decreases in
      body weight gain, water and food consumption, sedation and inhibited
      spontaneous locomotion, and at 100 mg/kg bw/day blepharitis (starting after
      about four to six weeks of treatment). At 12.5 and 25 mg/kg bw/day the body
      weight gain was decreased in the final third of the treatment period. At 50 and
      100 mg/kg bw/day the body weight gain was decreased from the beginning of
      treatment onwards. Statistics were not reported.
          In the groups receiving 50 and 100 mg/kg bw, oestrus cycles were 5-13 days,
      compared with 4-10 days prior to administration and at 12.5 mg/kg bw and 4-11
      days at 25 mg/kg bw. The percentages of females inseminated were 100, 86 and
      84% at 0, 50 and 100 mg/kg bw, respectively, and of females being pregnant 94,
      81, 72 and 57%* at 0, 25, 50 and 100 mg/kg bw, respectively (*p<0.05). At
      gestational day 14 or 21, post-mortem gross observations did not reveal external
      uterine or ovarian abnormalities.
          In the groups which were allowed to litter, treatment did not affect pregnancy
      length.56
      Chlorpromazine                                                                      23
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<pre>  Yokoya treated groups of ten-week-old male and female Sprague-Dawley rats
  (n=10-22/sex/group) with oral (gavage) doses of chlorpromazine of 0, 12.5, 25,
  50 or 100 mg/kg bw/day for two weeks prior to mating. Half of the pregnant
  mothers were sacrificed on gestational day 14 while the remaining dams were
  allowed to deliver (F1 generation). The male and remaining female F0 rats were
  sacrificed at 14 and 20 weeks of age, respectively. Maternal toxicity included
  dose-related decreases in body weight gain and food consumption, sedation and
  inhibited spontaneous locomotion. Supporting data for these statements were not
  reported.
      The percentages of females inseminated were 100 and 82% at 0 and 100 mg/kg
  bw, respectively (difference not statistically significant), and of females being
  pregnant 95, 75, 72*, 71* and 61%* at 0, 12.5, 25, 50 and 100 mg/kg bw,
  respectively (*p<0.05). At autopsy of male animals treated with 100 mg/kg
  bw/day, relative weights of pituitary and prostate glands were 6-10% and of
  adrenals more than 10% higher than those of controls; in females, relative weights
  of ovaries and adrenals were more than 10% and 6-10% higher and those of
  pituitary gland and uterus more than 6% lower compared to controls. No effect of
  chlorpromazine was found on gestation length and delivery.74
  Izumi et al. administered oral (gavage) doses of chlorpromazine of 0, 3, 10 or
  30 mg/kg bw/day to female Crl:CD(SD) rats (n=10/group) for two or four weeks.
  Animals were sacrificed after the treatment period. During the two-week
  treatment period, no mortality or changes in body weight (gain) or food
  consumption were observed. At 10 and 30 mg/kg bw, ptosis was observed and at
  30 mg/kg bw, decreased locomotor activity, prone position and lachrymation.
      At 10 and 30 mg/kg bw, all animals had irregular oestrus cycles compared to
  0/10 in controls (p<0.01). At necropsy, there were no gross pathological changes.
  No changes were observed in the absolute ovary and pituitary weights but uterus
  weights were decreased at 30 mg/kg bw (p<0.01). Microscopic examinations
  revealed the presence of large atretic follicles in 0, 1, 2 and 6 animals and of
  alveolar hyperplasia of the mammary gland in 0, 1, 1 and 5 animals, respectively.
      When treated for four weeks, results for mortality, clinical signs, body
  weight, food consumption and gross pathology were similar to those in the two-
  week study.
      At 30 mg/kg bw/day, 10/10 animals had irregular oestrus cycles compared to
  3/10, 0/10 and 7/10 at 0, 3 and 10 mg/kg bw/day, respectively. Weights of ovaries
  and uterus were statistically significantly decreased at 10 and 30 mg/kg bw, those
  of the pituitary at 30 mg/kg bw. Microscopic examinations revealed the presence
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<pre>of large atretic follicles in 0, 0, 3 and 3 animals and of alveolar hyperplasia of the
mammary gland in 0, 0, 2 and 7 animals, respectively.32
Izumi et al. also administered oral (gavage) doses of chlorpromazine of 0, 3, 10
or 30 mg/kg bw/day to female Crl:CD(SD) rats (n=10/group) from two weeks
before mating through gestational day 6. Animals were sacrificed at gestational
day 13. During the experimental period, no mortality occurred. Decreased motor
activity and ptosis were seen at 10 and 30 mg/kg bw and at 30 mg/kg bw,
respectively. Body weight gains were affected during the treatment period in the
highest dose group; at gestational day 13, body weights were decreased (p<0.05)
in the two higher dose groups.
    All animals treated with 10 or 30 mg/kg bw/day had irregular oestrus cycles
compared to 1/10 in the control group. At 30 mg/kg bw, a fertility index of 70%
(vs. 89% in controls; not statistically significant) and a prolonged mean
copulatory interval of 7.1 days (vs. 2.3 days; p<0.05) were observed. Treatment
did not affect the mean numbers of corpora lutea and implantations and the mean
percentages pre-implantation loss.32
Hoekstra et al. treated female Charles River CD rats with oral (gavage) doses of
chlorpromazine of 4 mg/kg bw/day for one day or of 45 mg/kg bw/day for seven
or 14 days. Vehicle served as a control. No data on general toxicity were
presented. After a single dose of chlorpromazine, ovulation was blocked in pro-
oestrus rats, which was reversed by coitus. After multiple dosing, the inhibition
of ovulation was increased. Again, the ovulation inhibition was reversed by
coitus.31
Saillenfait and Vannier did not observe effects on gestation length in pregnant
Sprague-Dawley rats (number not reported) receiving daily oral (gavage) doses
of chlorpromazine of 20 mg/kg bw from gestational day 6 to 20, when compared
to vehicle. Treatment did not affect maternal body weight.57
Hafs et al. treated male goats (mixed breeding: Saanen and Togenburg;
n=3/group) with daily oral doses of chlorpromazine of 0 or 90 mg for eight
weeks. Chlorpromazine treatment did not affect body weight gains. There were
no statistically significant effects on semen characteristics. At post-mortem
examinations of the testes, epididymides, seminal vesicles, thyroid glands and
pituitary glands, no effects on their weights or histological changes were
observed.23
Chlorpromazine                                                                         25
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<pre>  Subcutaneous administration
  Bhargava and Jaitly found that in female albino mice (n=12), the average
  duration of the oestrus cycle during a ten-day treatment with subcutaneous doses
  of chlorpromazine of 10 mg/kg bw was increased when compared to the duration
  before treatment. No data were presented on general toxicity but it was stated
  that experiments were repeated with lower doses in case a dose proved to be fatal
  or significantly reduced body weight.8
  Intramuscular administration
  Banik et al. treated four-day cyclic female Sprague-Dawley rats (n=7-23/group)
  one day before the expected pro-oestrus and on the day of pro-oestrus with
  chlorpromazine (0 or 4 mg/kg bw) intramuscularly. No data on general toxicity
  were presented. Chlorpromazine given at the day of pro-oestrus blocked
  ovulation. Ovulation could be induced in rats treated with chlorpromazine after
  injection with human chorionic gonadotropin.5
  Lescoat and Chambon measured the effect of chlorpromazine on pituitary
  concentrations of gonadotropin and prolactin in pregnant rats. Pregnant female
  rats were injected intramuscularly with 0 or 10 mg chlorpromazine/kg bw every
  eight hours during 72 hours from gestational day 1 to 4. No data on general
  toxicity were presented. Chlorpromazine induced decreases in luteinizing
  hormone from gestational day 0 to 3, decreases in follicle-stimulating hormone
  from gestational day 1 to 3 and increases in prolactin from gestational day 1
  to 4.39
  Hafs et al. treated male goats (mixed breeding: Saanen and Togenburg;
  n=3/group) with daily intramuscular doses of chlorpromazine of 0 and 90 mg
  for eight weeks. Chlorpromazine treatment caused tranquilization in 2/3 goats.
  There was no effect on body weight gain. Of the semen characteristics examined,
  semen volume was increased (p=0.08) and sperm motility decreased (p=0.04).
  Post-mortem examination of the testes, epididymides, seminal vesicles, thyroid
  glands and pituitary glands did not reveal organ weight or histological changes.23
  Land injected five ewes per group intramuscularly with 0 or 10 mg
  chlorpromazine/kg bw twice daily for six different three-day periods during the
  oestrus cycle. Apart from an increase (by about 9%) at treatment days 3-5 and a
  decrease (by about 9%) at treatment days 12-14, body weights did not differ
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<pre>      between groups. Results indicated that the ovulation rate was not depressed by
      any of the treatments. Treatment during the luteal phase of the cycle raised the
      subsequent mean ovulation rate slightly (2.70 versus 2.27 eggs).38
2.3.2 Developmental toxicity studies
      Oral administration
      Saigo et al. administered chlorpromazine (0, 12.5, 25, 50, 100 mg/kg bw/day)
      daily by gavage to both male and female Sprague-Dawley rats (n=10 and n=17-
      25, respectively) for nine weeks prior to mating and evaluated the effects for over
      three generations. Maternal toxicity observed included a generally dose-
      dependently decreased body weight gain, decreased water and food
      consumption, accompanied by sedation and inhibited spontaneous locomotion,
      and at 100 mg/kg bw/day blepharitis (starting after about four to six weeks of
      treatment). At 12.5 and 25 mg/kg bw/day the body weight gain was decreased in
      the final third of the treatment period. At 50 and 100 mg/kg bw/day the body
      weight gain was decreased from the beginning of treatment onwards. Statistics
      were not reported.
          In the animals sacrificed at gestational days 14 and 21, statistically
      significant decreases were seen in the number of live foetuses/litter at 100 mg/kg
      bw and at 12.5, 25 and 100 mg/kg bw, respectively, and in the average foetal
      weights at 25, 50 and 100 mg/kg bw in both groups.
          In the groups allowed to litter, statistically significant decreases were noted
      with respect to the numbers of live pups/litter (at 100 mg/kg bw), the average
      pup weights at 48 hours (at 25, 50, 100 mg/kg bw) and the percentages of live
      pups at postnatal day 22 (at 50, 100 mg/kg bw). Especially the weights of the
      pups of the two higher dose groups did not reach those of the controls during the
      lactation period. At postnatal week 10, average body weights and oestrus cycle
      lengths did not differ between groups. No abnormal behaviour was noted, and no
      visible external abnormalities were seen upon gross observations.
          When F1 males and females were allowed to mate for an F2 generation, the
      percentages of females inseminated or being pregnant did not differ between
      groups. At sacrifice at gestational day 14, the numbers of live foetuses/litter in
      F1 groups from exposed parents were not different from those in the controls but
      average foetal weights were statistically significantly decreased in the groups
      from parents treated with 12.5, 25 and 100 mg/kg bw. There were no uterine or
      ovarian abnormalities upon gross observations. In the groups that were allowed
      to deliver, there were no differences between groups with respect to gestation
      Chlorpromazine                                                                      27
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<pre>  length, number of live pups/litter, average pup weight at 48 hours (apart from
  those descendant from F0 rats treated with 12.5 mg/kg bw) and pup survival at
  day 22. F2 pups descendant from treated F0 rats gained more weight up to
  weaning than controls. Gross observations of the F2 pups did not reveal
  abnormalities.
      Recording of wet weights of major organs of F0 and F1 rats showed effects at
  100 mg/kg bw only, including increased weights of the liver, kidney, adrenal,
  pituitary, testis and prostate in males and kidney, adrenal gland and ovary in
  females, and decreased weights of the pituitary and the uterus in females.56
  Yokoya et al. treated both male and female Sprague-Dawley rats of the F0
  generation (n=10-22/sex/group) daily with chlorpromazine (0, 12.5, 25, 50, 100
  mg/kg bw/day) by gavage two weeks prior to mating. The effects of
  chlorpromazine administered in the F0 generation were evaluated on
  developmental parameters over three generations. Maternal toxicity included
  dose-related decreases in body weight gain and food consumption, sedation and
  inhibited spontaneous locomotion. Supporting data for these statements were not
  reported.
      No effect of chlorpromazine was found on gestation length and delivery.
  The survival of foetuses and pups, and the live foetal and pup weights decreased
  dose-dependently in F0 rats receiving at doses ≥25 mg/kg bw. In the F1 rats,
  the number of live foetuses decreased after exposure of the F0 rats to 50 and
  100 mg/kg bw/day chlorpromazine. No effect was observed on the number of live
  F2 pups, but the average pup weight was statistically significantly increased after
  exposure of the F0 rats to more than 12.5 mg/kg/day chlorpromazine.74
  Izumi et al. did not observe effects on mean numbers of live and dead embryos
  and on mean percentages of postimplantation loss in female Crl:CD(SD)
  rats (n=10/group) given oral (gavage) doses of chlorpromazine of 0, 3, 10 or
  30 mg/kg bw/day from two weeks before mating through gestational day 6 (see
  2.3.1 Fertility studies).32
  Beall et al. administered daily oral (gavage) doses of chlorpromazine of 0, 5, 25
  or 35 mg/kg bw to pregnant rats (n=19-24/group, CAW; CFE (SD) spf strain) on
  days 6 through 15 after mating. On gestational day 21, foetuses were removed
  and examined for gross, visceral and skeletal abnormalities. Three dams of the
  high-dose group died during the study.
      Treatment did not affect the number of implantations. At 25 and 35 mg/kg
  bw/day, statistically significant increases in the percentages of dams with
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<pre>resorptions (45% and 63%, respectively; controls: 17%) and in the percentages of
resorptions (7% and 20%, respectively; controls: 2%) were found. At 35 mg/kg
bw/day, the average litter size was decreased (10.5±1.0 vs. 13.6±0.4 in controls;
p<0.05). Apart from one foetus in the low-dose group showing absence of the tail
and lumbar vertical malformations, no gross, skeletal or visceral abnormalities
were seen.6
Saillenfait and Vannier administered oral (gavage) doses of chlorpromazine of 0
or 20 mg/kg bw to pregnant Sprague-Dawley rats (number not reported) received
daily from gestational day 6 to 20. Dams were weighed regularly up to postnatal
day 21. At parturition, litters were examined for litter size, sex distribution,
weight and number of dead or malformed offspring. Within 15 hours after birth,
all treated litters were cross-fostered to control females. At postnatal day 21,
litters were weaned and littermates were separated and housed by sex until
completion of the study at postnatal day 84. During the postnatal period,
offspring (12 litters/group) was examined for physical landmarks, neuromotor
development and behaviour.
     Treatment did not cause statistically significant effects on maternal body
weights, litter size, sex distribution within litters, offspring mortality or
externally visible malformations. No statistically significant effects of
chlorpromazine on parental body weights, litter size, sex distribution within
litters, offspring mortality, external examination or physical offspring
development or postweaning neurobehavioural tests were observed. However in
preweaning behavioural tests, i.e. negative geotaxis (at postnatal days 8, 10, 12),
swimming development (at postnatal day 6, 8, 10, 12) and surface righting reflex
(at postnatal days 3 to 6), the only changes observed were statistically
significantly better performances (compared to controls) in the surface righting
reflex test at postnatal day 6 and in swimming development test at postnatal days
6 and 8.57
Druga et al. treated female rats (n=5; Wistar/H-Riop) with single oral doses of 0
or 3.7x10-4 M/kg bw (119 mg/kg bw) of chlorpromazine, on gestational day 13,
14 or 15. On gestational day 21, females were sacrificed and resorptions, live and
dead foetuses, foetal weight and external malformations were recorded. Data on
maternal toxicity were not presented. Treatment caused higher foetal mortality
(p<0.05) and decreased foetal weights (p<0.05). There was no effect on the
femur index (length: thickness) or the number of foetuses with cleft palate and
micromelia.17
Chlorpromazine                                                                      29
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<pre>  Robertson et al. treated female CD rats (n=20/group) with oral (gavage) doses of
  chlorpromazine of 0, 1, 3 or 9 mg/kg bw/day from gestational day 6 to 15. One
  half of the dams was sacrificed at gestational day 21 for uterine content and
  foetal examinations. The other half was allowed to litter for offspring growth,
  morphologic and reflex development and reproductive performance evaluations.
  Maternal toxicity was limited to the dams receiving 9 mg/kg bw/day, and
  consisted of decreased activity two to four hours after dosing and a statistically
  significant decrease in maternal weight gain.
      No treatment-related effects were observed on the number of implants,
  resorptions, live and dead foetuses per litter, foetal weight and external, visceral,
  and skeletal abnormalities. In addition, no effects were found on gestation length,
  number of live and dead pups at birth, pup weights, organ weights, physical and
  reflex development of the pups and histomorphologic and morphometric
  examinations of their brains. In the post-weaning period there were significant
  increases in open field activity and decreases in latency time in male offspring at
  3 and 9 mg/kg bw compared to the pooled controls. Mating performance of
  offspring prenatally exposed to chlorpromazine was unaffected.53
  Ordy et al. administered oral (gavage) doses of 0, 4 and 16 mg/kg bw to female
  inbred C57BL/10 mice (n=20/group) throughout pregnancy. There was no effect
  on dam body weight gains but the high dose produced statistically significant
  decreases in activity in an open field test one to five hours after administration.
  Treatment caused statistically significant increases in the number of days
  between mating and birth (22.35, 23.85, 28.80 days, respectively) and
  statistically significant decreases in mean litter sizes (8.0, 7.9, 5.8, respectively)
  and mean litter weights (1.41, 1.33, 1.17 g, respectively).51
  In a second study, Ordy et al. evaluated the effects of prenatally administered
  doses of chlorpromazine on pregnancy and behaviour of the dams, hepatocellular
  alterations in relation to mortality, postnatal survival and changes in behaviour of
  the offspring in female inbred C57BL/10 mice. Groups of 30 to 56 mice were
  treated with oral (gavage) doses of chlorpromazine of 0, 4 and 16 mg/kg bw from
  six days after mating until birth. Maternal effects included dose-related increases
  in the number of days between mating and birth, decreases in body weight gains
  and reduced activity in open field behaviour. The changes in duration between
  mating and birth and in body weight gain were observed at the highest dose (both
  p<0.001). The reduced activity in open field behaviour had the same p-value,
  though whether that applies to both doses, or to the highest one, was not
  mentioned.
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<pre>    Treatment induced decreases in mean litter sizes (7.6±0.32, 6.8±0.33,
5.8±0.30 (p<0.001), respectively) and mean litter weights (1.41±0.01 g,
1.36±0.02 g, 1.22±0.02 g (p<0.001), respectively) and increases in percentages
of mortality at birth (1.5±0.14%, 3.4±0.23% (p<0.001), 11.9±0.33% (p<0.0001).
Effects of chlorpromazine on offspring behaviour included: fewer avoidances in
shock-elicted escape-avoidance learning, less traversing of squares in open field
exploration, longer open field latencies and fewer wheel revolutions than the
placebo offspring. Chlorpromazine also affected liver enzyme levels in the
offspring (viz. increases in leucine aminopeptidase activities, decreases in
alkaline phosphatase activities and depletion of glycogen). The percentage of
postnatal survival at 60 days was lower after prenatal treatment with
chlorpromazine and was lowest in the female offspring, independent of cross-
fostering.52
Intraperitoneal administration
Singh et al. treated pregnant CF rats (n=5-9) intraperitoneally with single doses
of chlorpromazine of 100 mg/kg bw on gestational day 14. On gestational days
16, 17, 18, 19 and 20, foetuses were collected by Caesarean section and
examined for abnormalities. No data on maternal toxicity were presented.
    Chlorpromazine treatment caused intrauterine growth retardation, increased
foetal mortality (19-30%; controls (vehicle): 0-3%), increased percentages of
malformed foetuses (91-98%; controls: 0-4%) and a delay of one to three days in
the ossification of the centres of the long bones of the extremities, scapulae,
ilium and skull bones. No ossification of the ischium and pubis was observed at
gestational day 20. Although no abnormal ossification was found in the
sternebrae, only 6.5% of the treated foetuses showed all six sternebrae as
compared with 98% of the controls.61-63
Furukawa et al. injected single intraperitoneal doses of chlorpromazine of 0,
50 and 100 mg/kg bw into Wistar Hannover Gallas rats (n=16-22/group) at
gestational day 14. Animals were sacrificed at gestational day 14.5, 15, 17 and
21 for foetal and histopathological placental examinations. Decreased body
weight gain (based on the body weight at gestational day 14) was seen at
50 mg/kg bw during gestational day 15 to 18 (p<0.01 or p<0.05) and at
100 mg/kg bw during gestational day 15 to 21 (p<0.01 at all timepoints). Clinical
signs such as prone position, hypothermia, loss or decrease of locomotor activity,
vaginal haemorrhage, eye discharge and incontinence of urine were seen
Chlorpromazine                                                                     31
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<pre>  disappearing by gestational day 17 at 50 mg/kg bw and by gestational day 19
  at 100 mg/kg bw at the latest.
       On gestational day 17, the percentages of dams with complete foetal
  resorptions was 20% and on gestational day 21, 20% and 44% at 50 mg/kg bw
  and 100 mg/kg bw, respectively. In the other groups, there were no litters with
  complete resorption. Reduced weights of embryos/foetuses were observed at 5
  0 mg/kg bw at gestational days 15 and 17 and at 100 mg/kg bw at gestational
  days 15-21, and of placentas 50 mg/kg bw at gestational days 17 and at 100 mg/
  kg bw at gestational days 14.5-21. No external malformations were seen
  following macroscopic examinations of foetuses at gestational day 21,
  Histological placental examination showed tropoblast apoptosis in the labyrinth
  zone, leading to labyrinth zone hypoplasia, and glycogen cell apoptosis in the
  basal zone, ultimately leading to metrial gland apoptosis.21
  Subcutaneous administration
  Hironaka et al. administered daily subcutaneous doses of chlorpromazine of
  0, 8 or 16 mg/kg bw to Sprague-Dawley rats (n=13/group) from gestational days
  17 to day 21. At the day of parturition, the total number of offspring, including
  the number of dead, were recorded. Generally, five male and five female pups/
  litter were randomly selected and allowed to be reared by nontreated foster
  mothers. Pup body weights were recorded regularly. At weaning (postnatal day
  21), male offspring was randomly selected for a learning experiment (lever press;
  light-dark discrimination) initiated at five weeks of age. No data on maternal
  toxicity were presented.
       No differences in the number of offspring per dam were observed. Treatment
  resulted in statistically significant decreases in male pup body weights at birth in
  both dose groups and in statistically significantly increased pup mortality at birth
  and during the lactation period in the high-dose group. There was no effect on the
  acquisition of lever press responses and on the original discrimination learning.
  However, reversal learning acquisition was impaired.29
  Umemura et al. evaluated the effects of chlorpromazine on spontaneous motor
  activity level and learning behaviour of light-dark discrimination in the offspring
  of female Jcl:SD rats (n=9-11 rats/group) subcutaneously treated with 2 mg/kg
  bw/day (once daily) or with 8 mg/kg bw/day (twice daily 4 mg/kg bw) from
  gestational day 17 through postnatal day 21. Vehicle served as control. In the
  maternal animals, sedation, slowed motion and eye-closing were observed
  during treatment with doses of 2 and 8 mg/kg bw. At 8 mg/kg bw/day, nursing
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<pre>behaviour was absent because of cataleptic manifestations. At this high dose, the
mean maternal body weights and water and food intakes tended to be lower than
at 2 or 0 mg/kg bw/day, but there were no statistically significant differences
among groups.
     At 8 mg/kg bw/day, mortality of pups during lactation was statistically
significantly increased and pup weights were statistically significantly lower on
postnatal day 14 and 21. No influence of the treatment was observed on the
activity level at six to seven weeks of age and on learning behaviours of the
continuous food reinforcement and light-dark discrimination. In some offspring
from treated females, the reversal learning of the light-dark discrimination was
impaired.68
West et al. treated pregnant Crl:CD(SD)BR rats (n=28) subcutaneously with 0 or
1 mg chlorpromazine/kg bw on gestational days 14, 16, and 18. An olfactory
discrimination test was performed in pups on postnatal day 9 and 10. Treatment
did not affect maternal body weights or food and water consumption.
Chlorpromazine treatment slowed the response toward the dam but did not affect
the response to the empty goal box. This may indicate a possible deficit in
olfactory discrimination.71
Intramuscular administration
Hannah et al. treated pregnant Long-Evans hooded rats with intramuscular
injections of chlorpromazine doses of 0 and 15 mg/kg bw/day from gestational
day 18 onwards. In postnatal week 1, 3 and 24, whole litters were euthanized
(3 litters/time point) and concentrations of noradrenaline, dopamine and
serotonin in the cerebellum and hippocampus were determined. Data on maternal
toxicity were not presented.
     At postnatal week 1, increased levels of dopamine and serotonin were found
in both brain regions while at postnatal week 24, all three monoamines were
decreased in the cerebellum and increased in the hippocampus.25
Walker et al. intramuscularly injected single doses of 50 mg chlorpromazine/kg
bw into pregnant mice (A/J and C3H strains) on gestational day 14. Mice were
killed on gestational day 17 and the foetuses were evaluated for foetal palate
morphology. Following treatment, dams were heavily sedated for more than nine
to often more than 18 hours (probably depending on the tranquilizer tested).
     Retardation of foetal development (presence of a heartbeat, but
morphological rating equivalent to a younger foetus) was encountered in high
Chlorpromazine                                                                    33
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<pre>      frequency after treatment with chlorpromazine in A/J mice only. Treatment
      caused cleft lip with cleft palate in foetuses of the A/J strain (13%) only
      (spontaneous incidence in the A/J strain: 6-16.7%34,54). Isolated cleft palate was
      found in 21.3% of foetuses of the A/J strain and in 3.2% of foetuses of the C3H
      strain (spontaneous incidences: 0.25%-1%34,54 and <1%10, respectively).70
2.3.3 Lactation
      No relevant experimental animal data were available on the effects of
      chlorpromazine on or via lactation.
2.4   Conclusion
2.4.1 Fertility
      The Committee concludes that the human data are not sufficient for classification
      of chlorpromazine for effects on fertility.22,65,72 Based on the findings in oral
      studies in rats5,31,32,56,74 the Committee proposes to classify chlorpromazine for
      effects on fertility in Category 1B (presumed human reproductive toxicant). This
      is supported by findings in a subcutaneous study in mice8 and an intramuscular
      study in rats5.
2.4.2 Developmental toxicity
      The Committee concludes that the human data are not sufficient for classification
      of chlorpromazine for effects on development.3,4,7,18-20,24,28,36,37,40,43,45,48,49,55,64,66
      Based on the developmental toxicity found in oral studies in rats and mice6,17,51-
      53,56,57,74 that was considered to be independent of maternal toxicity, the
      Committee proposes to classify chlorpromazine for effects on development in
      category 1B (presumed human reproductive toxicant). This conclusion is
      supported by findings in intraperitoneal21,61-63 and subcutaneous29,68,71 studies.
2.4.3 Lactation
      No studies were found regarding the effects of chlorpromazine on or via lactation
      in animals.
           Following oral administration to lactating women, chlorpromazine was found
      in breast milk.3,9,50,67,69,73,75 However, there was insufficient information on the
      relation between these levels and the possible adverse effects in infants. In
 4    Chlorpromazine
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<pre>addition, there is no information about a safe/acceptable daily intake of
chlorpromazine. Therefore, the Committee cannot calculate a safe level for
chlorpromazine in human breast milk.
    The Committee proposes not labelling chlorpromazine for effects on or via
lactation due to a lack of appropriate human and animal data.
Proposed classification for fertility
Category 1B, H360F.
Proposed classification for developmental toxicity
Category 1B, H360D.
Proposed labelling for effects on and via lactation
Lack of appropriate human and animal data precludes assessment of
chlorpromazine for effects on or via lactation.
Chlorpromazine                                                                35
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<pre>6 Chlorpromazine</pre>

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<pre>  References
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  Gynecol 1956; 71: 1242-1246.
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<pre>2 Bryans CI Jr, Mulherin CM. The use of chlorpromazine in obstetrical analgesia. Am J Obstet
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  References                                                                                           39
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0 Chlorpromazine
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  References                                                                                           41
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2 Chlorpromazine
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<pre>Szkilnik R, Brus R, Felinska W, Juraszczyk Z, Pyka U, Piechocka J, et al. Effect of chlorpromazine
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References                                                                                           43
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<pre>4 Chlorpromazine</pre>

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<pre>A The Committee
B The submission letter (in English)
C Comments on the public draft
D Regulation (EC) 1272/2008 of the European Community
E Additional considerations to Regulation (EC) 1272/2008
F Fertility and developmental toxicity studies
  Annexes
                                                         45
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<pre>6 Chlorpromazine</pre>

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<pre>nnex A
     The Committee
     •  A.H. Piersma, Chairman
        Professor of Reproductive and Developmental Toxicology, Utrecht
        University, Utrecht and National Institute of Public Health and the
        Environment, Bilthoven
     •  D. Lindhout
        Professor of Medical Genetics; Paediatrician (not practising), Clinical
        Geneticist, University Medical Centre, Utrecht
     •  N. Roeleveld
        Reproductive Epidemiologist, Radboud university medical center, 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 till June 1, 2014
        Health Council of the Netherlands, Den Haag
     •  P.W. van Vliet, Scientific Secretary from June 1, 2014
        Health Council of the Netherlands, Den Haag
     The Committee                                                               47
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<pre>  The first draft of the present document was prepared by D.H. Waalkens-
  Berendsen and M.J.W. van de Hoven (TNO Quality of Life, Zeist) 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.
8 Chlorpromazine
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<pre>nnex B
     The submission letter (in English)
     Subject         : Submission of the advisory report Chlorpromazine
     Your reference : DGV/BMO/U-932542
     Our reference : U-8379/EvV/fs/543-E15
     Enclosure(s) : 1
     Date            : 20 May, 2015
     Dear Minister,
     I hereby submit the advisory report on the effects of Chlorpromazine on fertility
     and on the development of the progeny; it also concerns effects on lactation and
     on the progeny via lactation.
     This advisory report is part of an extensive series in which reproduction toxic
     substances are classified in accordance with European guidelines. This involves
     substances to which people may be exposed occupationally.
     The advisory report was prepared by a permanent committee of the Health
     Council of the Netherlands, the Subcommittee on the Classification of
     Reproduction Toxic Substances of the Dutch Expert Committee on Occupational
     Safety (DECOS). The advisory report was consequently reviewed by the Health
     Council’s Standing Committee on Health and the Environment.
     The submission letter (in English)                                                49
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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. J.L. Severens,
  Vice President
0 Chlorpromazine
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<pre>nnex C
     Comments on the public draft
     A draft of the present report was released in 2014 for public review. The
     following organization and persons have commented on the draft document:
     • T.J. Lentz, PhD, J. O’Callaghan, PhD, National Institute for Occupational
         Safety and Health (NIOSH), Cincinnati, OH, USA
     The comments received, and the reply by the Committee can be found on the
     website of the Health Council.
     Comments on the public draft                                                51
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<pre>2 Chlorpromazine</pre>

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<pre>nnex D
     Regulation (EC) 1272/2008 of the
     European Community
     3.7            Reproductive toxicity
     3.7.1          Definitions and general considerations
     3.7.1.1        Reproductive toxicity includes adverse effects on sexual function and fertility in adult
     males and females, as well as developmental toxicity in the offspring. The definitions presented
     below are adapted from those agreed as working definitions in IPCS/EHC Document No 225, Princi-
     ples for Evaluating Health Risks to Reproduction Associated with Exposure to Chemicals. For classi-
     fication purposes, the known induction of genetically based heritable effects in the offspring is
     addressed in Germ Cell Mutagenicity (section 3.5), since in the present classification system it is con-
     sidered more appropriate to address such effects under the separate hazard class of germ cell muta-
     genicity.
     In this classification system, reproductive toxicity is subdivided under two main headings:
     (a) adverse effects on sexual function and fertility;
     (b) adverse effects on development of the offspring.
     Some reproductive toxic effects cannot be clearly assigned to either impairment of sexual function
     and fertility or to developmental toxicity. Nonetheless, substances with these effects, or mixtures con-
     taining them, shall be classified as reproductive toxicants.
     Regulation (EC) 1272/2008 of the European Community                                                      53
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<pre>  3.7.1.2         For the purpose of classification the hazard class Reproductive Toxicity is differentiated
                  into:
  •     adverse effects
        •    on sexual function and fertility, or
        •    on development;
  •     effects on or via lactation.
  3.7.1.3         Adverse effects on sexual function and fertility
  Any effect of substances that has the potential to interfere with sexual function and fertility. This
  includes, but is not limited to, alterations to the female and male reproductive system, adverse effects
  on onset of puberty, gamete production and transport, reproductive cycle normality, sexual behaviour,
  fertility, parturition, pregnancy outcomes, premature reproductive senescence, or modifications in
  other functions that are dependent on the integrity of the reproductive systems.
  3.7.1.4         Adverse effects on development of the offspring
  Developmental toxicity includes, in its widest sense, any effect which interferes with normal devel-
  opment of the conceptus, either before or after birth, and resulting from exposure of either parent
  prior to conception, or exposure of the developing offspring during prenatal development, or postna-
  tally, to the time of sexual maturation. However, it is considered that classification under the heading
  of developmental toxicity is primarily intended to provide a hazard warning for pregnant women, and
  for men and women of reproductive capacity. Therefore, for pragmatic purposes of classification,
  developmental toxicity essentially means adverse effects induced during pregnancy, or as a result of
  parental exposure. These effects can be manifested at any point in the life span of the organism. The
  major manifestations of developmental toxicity include (1) death of the developing organism, (2)
  structural abnormality, (3) altered growth, and (4) functional deficiency.
  3.7.1.5         Adverse effects on or via lactation are also included in reproductive toxicity, but for
  classification purposes, such effects are treated separately (see Table 3.7.1 (b)). This is because it is
  desirable to be able to classify substances specifically for an adverse effect on lactation so that a spe-
  cific hazard warning about this effect can be provided for lactating mothers.
4 Chlorpromazine
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<pre>3.7.2        Classification criteria for substances
3.7.2.1      Hazard categories
3.7.2.1.1    For the purpose of classification for reproductive toxicity, substances are allocated to
one of two categories. Within each category, effects on sexual function and fertility, and on develop-
ment, are considered separately. In addition, effects on lactation are allocated to a separate hazard cat-
egory.
Table 3.7.1(a) Hazard categories for reproductive toxicants.
Categories                      Criteria
CATEGORY 1                      Known or presumed human reproductive toxicant
                                Substances are classified in Category 1 for reproductive toxicity when
                                they are known to have produced an adverse effect on sexual function
                                and fertility, or on development in humans or when there is evidence
                                from animal studies, possibly supplemented with other information, to
                                provide a strong presumption that the substance has the capacity to
                                interfere with reproduction in humans. The classification of a sub-
                                stance is further distinguished on the basis of whether the evidence for
                                classification is primarily from human data (Category 1A) or from
                                animal data (Category 1B).
                Category 1A Known human reproductive toxicant
                                The classification of a substance in Category 1A is largely based on
                                evidence from humans.
                Category 1B Presumed human reproductive toxicant
                                The classification of a substance in Category 1B is largely based on
                                data from animal studies. Such data shall provide clear evidence of an
                                adverse effect on sexual function and fertility or on development in
                                the absence of other toxic effects, or if occurring together with other
                                toxic effects the adverse effect on reproduction is considered not to be
                                a secondary non-specific consequence of other toxic effects. However,
                                when there is mechanistic information that raises doubt about the rele-
                                vance of the effect for humans, classification in Category 2 may be
                                more appropriate.
CATEGORY 2                      Suspected human reproductive toxicant
                                Substances are classified in Category 2 for reproductive toxicity when
                                there is some evidence from humans or experimental animals, possi-
                                bly supplemented with other information, of an adverse effect on sex-
                                ual function and fertility, or on development, and where the evidence
                                is not sufficiently convincing to place the substance in Category 1. If
                                deficiencies in the study make the quality of evidence less convincing,
                                Category 2 could be the more appropriate classification.
                                Such effects shall have been observed in the absence of other toxic
                                effects, or if occurring together with other toxic effects the adverse
                                effect on reproduction is considered not to be a secondary non-specific
                                consequence of the other toxic effects.
Regulation (EC) 1272/2008 of the European Community                                                        55
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<pre>  Table 3.7.1(b) Hazard category for lactation effects.
  EFFECTS ON OR VIA LACTATION
  Effects on or via lactation are allocated to a separate single category. It is recognised that for many
  substances there is no information on the potential to cause adverse effects on the offspring via lacta-
  tion. However, substances which are absorbed by women and have been shown to interfere with lac-
  tation, or which may be present (including metabolites) in breast milk in amounts sufficient to cause
  concern for the health of a breastfed child, shall be classified and labelled to indicate this property
  hazardous to breastfed babies. This classification can be assigned on the:
  (a) human evidence indicating a hazard to babies during the lactation period; and/or
  (b) results of one or two generation studies in animals which provide clear evidence of adverse effect
  in the offspring due to transfer in the milk or adverse effect on the quality of the milk; and/or
  (c) absorption, metabolism, distribution and excretion studies that indicate the likelihood that the sub-
  stance is present in potentially toxic levels in breast milk.
  3.7.2.2        Basis of classification
  3.7.2.2.1      Classification is made on the basis of the appropriate criteria, outlined above, and an
  assessment of the total weight of evidence (see 1.1.1). Classification as a reproductive toxicant is
  intended to be used for substances which have an intrinsic, specific property to produce an adverse
  effect on reproduction and substances shall not be so classified if such an effect is produced solely as
  a non-specific secondary consequence of other toxic effects.
  The classification of a substance is derived from the hazard categories in the following order of pre-
  cedence: Category 1A, Category 1B, Category 2 and the additional Category for effects on or via lac-
  tation. If a substance meets the criteria for classification into both of the main categories (for example
  Category 1B for effects on sexual function and fertility and also Category 2 for development) then
  both hazard differentiations shall be communicated by the respective hazard statements. Classifica-
  tion in the additional category for effects on or via lactation will be considered irrespective of a clas-
  sification into Category 1A, Category 1B or Category 2.
  3.7.2.2.2      In the evaluation of toxic effects on the developing offspring, it is important to consider
  the possible influence of maternal toxicity (see section 3.7.2.4).
  3.7.2.2.3      For human evidence to provide the primary basis for a Category 1A classification there
  must be reliable evidence of an adverse effect on reproduction in humans. Evidence used for classifi-
  cation shall ideally be from well conducted epidemiological studies which include the use of appro-
  priate controls, balanced assessment, and due consideration of bias or confounding factors. Less
  rigorous data from studies in humans shall be supplemented with adequate data from studies in
  experimental animals and classification in Category 1B shall be considered.
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<pre>3.7.2.3         Weight of evidence
3.7.2.3.1       Classification as a reproductive toxicant is made on the basis of an assessment of the
total weight of evidence, see section 1.1.1. This means that all available information that bears on the
determination of reproductive toxicity is considered together, such as epidemiological studies and
case reports in humans and specific reproduction studies along with sub-chronic, chronic and special
study results in animals that provide relevant information regarding toxicity to reproductive and
related endocrine organs. Evaluation of substances chemically related to the substance under study
may also be included, particularly when information on the substance is scarce. The weight given to
the available evidence will be influenced by factors such as the quality of the studies, consistency of
results, nature and severity of effects, the presence of maternal toxicity in experimental animal stud-
ies, level of statistical significance for inter-group differences, number of endpoints affected, rele-
vance of route of administration to humans and freedom from bias. Both positive and negative results
are assembled together into a weight of evidence determination. A single, positive study performed
according to good scientific principles and with statistically or biologically significant positive results
may justify classification (see also 3.7.2.2.3).
3.7.2.3.2       Toxicokinetic studies in animals and humans, site of action and mechanism or mode of
action study results may provide relevant information which reduces or increases concerns about the
hazard to human health. If it is conclusively demonstrated that the clearly identified mechanism or
mode of action has no relevance for humans or when the toxicokinetic differences are so marked that
it is certain that the hazardous property will not be expressed in humans then a substance which pro-
duces an adverse effect on reproduction in experimental animals should not be classified.
3.7.2.3.3       If, in some reproductive toxicity studies in experimental animals the only effects
recorded are considered to be of low or minimal toxicological significance, classification may not
necessarily be the outcome. These effects include small changes in semen parameters or in the inci-
dence of spontaneous defects in the foetus, small changes in the proportions of common foetal vari-
ants such as are observed in skeletal examinations, or in foetal weights, or small differences in
postnatal developmental assessments.
3.7.2.3.4       Data from animal studies ideally shall provide clear evidence of specific reproductive
toxicity in the absence of other systemic toxic effects. However, if developmental toxicity occurs
together with other toxic effects in the dam, the potential influence of the generalised adverse effects
shall be assessed to the extent possible. The preferred approach is to consider adverse effects in the
embryo/foetus first, and then evaluate maternal toxicity, along with any other factors which are likely
to have influenced these effects, as part of the weight of evidence. In general, developmental effects
that are observed at maternally toxic doses shall not be automatically discounted. Discounting devel-
Regulation (EC) 1272/2008 of the European Community                                                         57
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<pre>  opmental effects that are observed at maternally toxic doses can only be done on a case-by-case basis
  when a causal relationship is established or refuted.
  3.7.2.3.5      If appropriate information is available it is important to try to determine whether devel-
  opmental toxicity is due to a specific maternally mediated mechanism or to a non-specific secondary
  mechanism, like maternal stress and the disruption of homeostasis. Generally, the presence of mater-
  nal toxicity shall not be used to negate findings of embryo/foetal effects, unless it can be clearly dem-
  onstrated that the effects are secondary non-specific effects. This is especially the case when the
  effects in the offspring are significant, e.g. irreversible effects such as structural malformations. In
  some situations it can be assumed that reproductive toxicity is due to a secondary consequence of
  maternal toxicity and discount the effects, if the substance is so toxic that dams fail to thrive and there
  is severe inanition, they are incapable of nursing pups; or they are prostrate or dying.
  3.7.2.4        Maternal toxicity
  3.7.2.4.1      Development of the offspring throughout gestation and during the early postnatal stages
  can be influenced by toxic effects in the mother either through non-specific mechanisms related to
  stress and the disruption of maternal homeostasis, or by specific maternally-mediated mechanisms. In
  the interpretation of the developmental outcome to decide classification for developmental effects it
  is important to consider the possible influence of maternal toxicity. This is a complex issue because
  of uncertainties surrounding the relationship between maternal toxicity and developmental outcome.
  Expert judgement and a weight of evidence approach, using all available studies, shall be used to
  determine the degree of influence that shall be attributed to maternal toxicity when interpreting the
  criteria for classification for developmental effects. The adverse effects in the embryo/foetus shall be
  first considered, and then maternal toxicity, along with any other factors which are likely to have
  influenced these effects, as weight of evidence, to help reach a conclusion about classification.
  3.7.2.4.2      Based on pragmatic observation, maternal toxicity may, depending on severity, influ-
  ence development via non-specific secondary mechanisms, producing effects such as depressed foe-
  tal weight, retarded ossification, and possibly resorptions and certain malformations in some strains
  of certain species. However, the limited number of studies which have investigated the relationship
  between developmental effects and general maternal toxicity have failed to demonstrate a consistent,
  reproducible relationship across species. Developmental effects which occur even in the presence of
  maternal toxicity are considered to be evidence of developmental toxicity, unless it can be unequivo-
  cally demonstrated on a case-by-case basis that the developmental effects are secondary to maternal
  toxicity. Moreover, classification shall be considered where there is a significant toxic effect in the
  offspring, e.g. irreversible effects such as structural malformations, embryo/foetal lethality, signifi-
  cant post-natal functional deficiencies.
8 Chlorpromazine
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<pre>3.7.2.4.3      Classification shall not automatically be discounted for substances that produce devel-
opmental toxicity only in association with maternal toxicity, even if a specific maternally-mediated
mechanism has been demonstrated. In such a case, classification in Category 2 may be considered
more appropriate than Category 1. However, when a substance is so toxic that maternal death or
severe inanition results, or the dams are prostrate and incapable of nursing the pups, it is reasonable
to assume that developmental toxicity is produced solely as a secondary consequence of maternal
toxicity and discount the developmental effects. Classification is not necessarily the outcome in the
case of minor developmental changes, when there is only a small reduction in foetal/pup body weight
or retardation of ossification when seen in association with maternal toxicity.
3.7.2.4.4      Some of the end points used to assess maternal effects are provided below. Data on
these end points, if available, need to be evaluated in light of their statistical or biological signifi-
cance and dose response relationship.
Maternal mortality:
an increased incidence of mortality among the treated dams over the controls shall be considered evi-
dence of maternal toxicity if the increase occurs in a dose-related manner and can be attributed to the
systemic toxicity of the test material. Maternal mortality greater than 10 % is considered excessive
and the data for that dose level shall not normally be considered for further evaluation.
Mating index
(no. animals with seminal plugs or sperm/no. mated × 100) (*)
Fertility index
(no. animals with implants/no. of matings × 100)
Gestation length
(if allowed to deliver)
Body weight and body weight change:
Consideration of the maternal body weight change and/or adjusted (corrected) maternal body weight
shall be included in the evaluation of maternal toxicity whenever such data are available. The calcula-
() It is recognised that the Mating index and the Fertility index can also be affected by the male.
Regulation (EC) 1272/2008 of the European Community                                                       59
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<pre>  tion of an adjusted (corrected) mean maternal body weight change, which is the difference between
  the initial and terminal body weight minus the gravid uterine weight (or alternatively, the sum of the
  weights of the foetuses), may indicate whether the effect is maternal or intrauterine. In rabbits, the
  body weight gain may not be useful indicators of maternal toxicity because of normal fluctuations in
  body weight during pregnancy.
  Food and water consumption (if relevant):
  The observation of a significant decrease in the average food or water consumption in treated dams
  compared to the control group is useful in evaluating maternal toxicity, particularly when the test
  material is administered in the diet or drinking water. Changes in food or water consumption need to
  be evaluated in conjunction with maternal body weights when determining if the effects noted are
  reflective of maternal toxicity or more simply, unpalatability of the test material in feed or water.
  Clinical evaluations (including clinical signs, markers, haematology and clinical chemistry studies):
  The observation of increased incidence of significant clinical signs of toxicity in treated dams relative
  to the control group is useful in evaluating maternal toxicity. If this is to be used as the basis for the
  assessment of maternal toxicity, the types, incidence, degree and duration of clinical signs shall be
  reported in the study. Clinical signs of maternal intoxication include: coma, prostration, hyperactivity,
  loss of righting reflex, ataxia, or laboured breathing.
  Post-mortem data:
  Increased incidence and/or severity of post-mortem findings may be indicative of maternal toxicity.
  This can include gross or microscopic pathological findings or organ weight data, including absolute
  organ weight, organ-to-body weight ratio, or organ-to-brain weight ratio. When supported by find-
  ings of adverse histopathological effects in the affected organ(s), the observation of a significant
  change in the average weight of suspected target organ(s) of treated dams, compared to those in the
  control group, may be considered evidence of maternal toxicity.
  3.7.2.5        Animal and experimental data
  3.7.2.5.1      A number of internationally accepted test methods are available; these include methods
  for developmental toxicity testing (e.g. OECD Test Guideline 414), and methods for one or two-gen-
  eration toxicity testing (e.g. OECD Test Guidelines 415, 416).
  3.7.2.5.2      Results obtained from Screening Tests (e.g. OECD Guidelines 421 — Reproduction/
  Developmental Toxicity Screening Test, and 422 — Combined Repeated Dose Toxicity Study with
0 Chlorpromazine
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<pre>Reproduction/Development Toxicity Screening Test) can also be used to justify classification,
although it is recognised that the quality of this evidence is less reliable than that obtained through
full studies.
3.7.2.5.3      Adverse effects or changes, seen in short- or long-term repeated dose toxicity studies,
which are judged likely to impair reproductive function and which occur in the absence of significant
generalised toxicity, may be used as a basis for classification, e.g. histopathological changes in the
gonads.
3.7.2.5.4      Evidence from in vitro assays, or non-mammalian tests, and from analogous substances
using structure-activity relationship (SAR), can contribute to the procedure for classification. In all
cases of this nature, expert judgement must be used to assess the adequacy of the data. Inadequate
data shall not be used as a primary support for classification.
3.7.2.5.5      It is preferable that animal studies are conducted using appropriate routes of administra-
tion which relate to the potential route of human exposure. However, in practice, reproductive toxic-
ity studies are commonly conducted using the oral route, and such studies will normally be suitable
for evaluating the hazardous properties of the substance with respect to reproductive toxicity. How-
ever, if it can be conclusively demonstrated that the clearly identified mechanism or mode of action
has no relevance for humans or when the toxicokinetic differences are so marked that it is certain that
the hazardous property will not be expressed in humans then a substance which produces an adverse
effect on reproduction in experimental animals shall not be classified.
3.7.2.5.6      Studies involving routes of administration such as intravenous or intraperitoneal injec-
tion, which result in exposure of the reproductive organs to unrealistically high levels of the test sub-
stance, or elicit local damage to the reproductive organs, including irritation, must be interpreted with
extreme caution and on their own are not normally the basis for classification.
3.7.2.5.7      There is general agreement about the concept of a limit dose, above which the produc-
tion of an adverse effect is considered to be outside the criteria which lead to classification, but not
regarding the inclusion within the criteria of a specific dose as a limit dose. However, some guide-
lines for test methods, specify a limit dose, others qualify the limit dose with a statement that higher
doses may be necessary if anticipated human exposure is sufficiently high that an adequate margin of
exposure is not achieved. Also, due to species differences in toxicokinetics, establishing a specific
limit dose may not be adequate for situations where humans are more sensitive than the animal
model.
3.7.2.5.8      In principle, adverse effects on reproduction seen only at very high dose levels in animal
studies (for example doses that induce prostration, severe inappetence, excessive mortality) would
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<pre>              not normally lead to classification, unless other information is available, e.g. toxicokinetics informa-
              tion indicating that humans may be more susceptible than animals, to suggest that classification is
              appropriate. Please also refer to the section on maternal toxicity (3.7.2.4) for further guidance in this
              area.
              3.7.2.5.9      However, specification of the actual ‘limit dose’ will depend upon the test method that
              has been employed to provide the test results, e.g. in the OECD Test Guideline for repeated dose tox-
              icity studies by the oral route, an upper dose of 1 000 mg/kg has been recommended as a limit dose,
              unless expected human response indicates the need for a higher dose level.
              3.7.3          Classification criteria for mixtures
              3.7.3.1        Classification of mixtures when data are available for all ingredients or only for some
              ingredients of the mixture
              3.7.3.1.1      The mixture shall be classified as a reproductive toxicant when at least one ingredient
              has been classified as a Category 1A, Category 1B or Category 2 reproductive toxicant and is present
              at or above the appropriate generic concentration limit as shown in Table 3.7.2 for Category 1A, Cat-
              egory 1B and Category 2 respectively.
              3.7.3.1.2      The mixture shall be classified for effects on or via lactation when at least one ingredi-
              ent has been classified for effects on or via lactation and is present at or above the appropriate generic
              concentration limit as shown in Table 3.7.2 for the additional category for effects on or via lactation.
 able 3.7.2 Generic concentration limits of ingredients of a mixture classified as reproduction toxicants or foreffects on or via
actation that trigger classification of the mixture.
 ngredient classified as:     Generic concentration limits triggering classification of a mixture as:
                              Category 1A                Category 1B               Category 2                Additional category
                              reproductive toxicant reproductive toxicant reproductive toxicant for effects on or via l
                                                                                                             actation
Category 1A                   ≥ 0,3 %
 eproductive toxicant         [Note 1]
  ategory 1B                                             ≥ 0,3 %
eproductive toxicant                                     [Note 1]
Category 2                                                                         ≥ 3,0 %
 eproductive toxicant                                                              [Note 1]
Additional category                                                                                          ≥ 0,3 %
or effects on or via                                                                                         [Note 1]
actation
  ote The concentration limits in the table above apply to solids and liquids (w/w units) as well as gases (v/v units).
  ote 1 If a Category 1 or Category 2 reproductive toxicant or a substance classified for effects on or via lactation is present in
he mixture as an ingredient at a concentration above 0,1 %, a SDS shall be available for the mixture upon request.
  2           Chlorpromazine
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<pre>3.7.3.2        Classification of mixtures when data are available for the complete mixture
3.7.3.2.1      Classification of mixtures will be based on the available test data for the individual
ingredients of the mixture using concentration limits for the ingredients of the mixture. On a case-by-
case basis, test data on mixtures may be used for classification when demonstrating effects that have
not been established from the evaluation based on the individual components. In such cases, the test
results for the mixture as a whole must be shown to be conclusive taking into account dose and other
factors such as duration, observations, sensitivity and statistical analysis of reproduction test systems.
Adequate documentation supporting the classification shall be retained and made available for review
upon request.
3.7.3.3        Classification of mixtures when data are not available for the complete mixture:
               bridging principles
3.7.3.3.1      Subject to paragraph 3.7.3.2.1, where the mixture itself has not been tested to determine
its reproductive toxicity, but there are sufficient data on the individual ingredients and similar tested
mixtures to adequately characterise the hazards of the mixture, these data shall be used in accordance
with the applicable bridging rules set out in section 1.1.3.
3.7.4          Hazard Communication
3.7.4.1        Label elements shall be used for substances or mixtures meeting the criteria for
               classification in this hazard class in accordance with Table 3.7.3
Regulation (EC) 1272/2008 of the European Community                                                        63
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<pre> able 3.7.3 Label elements for reproductive toxicity.
 lassification              Category 1A or Category 1B              Category 2                              Additional category
                                                                                                            for effects on or via
                                                                                                            lactation
GHS Pictograms                                                                                              No pictogram
 ignal Word                 Danger                                  Warning                                 No signal word
Hazard Statement            H360: May damage fertility or the       H361: Suspected of damaging fertil-     H362: May cause
                            unborn child (state specific effect if  ity or the unborn child (state specific harm to breast-fed
                            known)(state route of exposure if it is effect if known) (state route of expo-  children.
                            conclusively proven that no other       sure if it is conclusively proven that
                            routes of exposure cause the hazard)    no other routes of exposure cause the
                                                                    hazard)
 recautionary Statement     P201                                    P201                                    P201
 revention                  P202                                    P202                                    P260
                            P281                                    P281                                    P263
                                                                                                            P264
                                                                                                            P270
 recautionary Statement     P308 + P313                             P308 + P313                             P308 + P313
 esponse
 recautionary Statement     P405                                    P405
 torage
 recautionary Statement     P501                                    P501
Disposal
 4            Chlorpromazine
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<pre>nnex E
     Additional considerations to
     Regulation (EC) 1272/2008
     The classification and labelling of substances is performed according to the
     guidelines of the European Union (Regulation (EC)1272/2008) presented in
     Annex D. The classification of compounds is ultimately dependent on an
     integrated assessment of the nature of all parental and developmental effects
     observed, their specificity and adversity, and the dosages at which the various
     effects occur. The guideline necessarily leaves room for interpretation, dependent
     on the specific data set under consideration. In the process of using the
     regulation, the Committee has agreed upon a number of additional
     considerations:
     • If there is sufficient evidence to establish a causal relationship between
         human exposure to the substance and impaired fertility or subsequent
         developmental toxic effects in the offspring, the compound will be classified
         in category 1A, irrespective of the general toxic effects (see Annex D,
         3.7.2.2.1.).
     • Adverse effects in a reproductive study, occurring without reporting the
         parental or maternal toxicity, may lead to a classification other than category
         1B, when the effects occur at dose levels which cause severe toxicity in
         general toxicity studies.
     • Clear adverse reproductive effects will not be disregarded on the basis of
         reversibility per se.
     Additional considerations to Regulation (EC) 1272/2008                              65
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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.
6 Chlorpromazine
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<pre> nnex       F
            Fertility and developmental
            toxicity studies
able 1 Fertility effects with chlorpromazine in animals: oral administration.
uthors          species         experimental dose              general toxicity                  effects on reproductive organs/
                                period/design                                                    effects on reproduction
aigo            Sprague-        male and       0, 12.5, 25,    generally dose-dependently        oestrus cycle length: 4-10 d, 4-
1990)           Dawley rats female rats        50, 100 mg/kg decreased bw gain, decreased        11 d, 5-13 d, 5-13 d at 12.5, 25,
                (males: n=10/ treated 9 wk bw/d; gavage water, food consumption; after           50, 100 mg/kg bw/d, resp.; 4-
                group;          prior to                       every chlorpromazine              10 d prior to treatment
                females:        mating;                        administration: animals           number of females inseminated
                n=17-25/        1/3 of                         sedated, spontaneous              (%): 100, 100, 94, 86, 84, at 0,
                group)          pregnant rats                  locomotion inhibited,             12.5, 25, 50, 100 mg/kg bw,
                                sacrificed at                  symptoms persisting for up to     resp.
                                gd 14, 1/3 at                  several hr with dose-dependent    number of females pregnant
                                gd 21, 1/3                     intensity and duration; after the (%): 94, 95, 81, 72, 57*, resp.
                                allowed to                     2nd wk of administration: the     no effect on gestation length
                                deliver                        durations of the symptoms         post-mortem gross examination
                                                               following administration          at gd 14 or 21: no external
                                                               shortened slightly; at 100 mg/    uterine or ovarian
                                                               kg bw/d, about 4-6 wk after the   abnormalities
                                                               beginning of the treatment:
                                                               blepharitis in 25% of the
                                                               animals (more severe in males
                                                               than in females).
                                                               At 12.5 and 25 mg/kg bw/day
                                                               the body weight gain was
                                                               decreased in the final third of
                                                               the treatment period. At 50 and
                                                               100 mg/kg bw/day the body
                                                               weight gain was decreased
            Fertility and developmental toxicity studies                                                                       67
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<pre>                                                        from the beginning of
                                                       treatment onwards. Statistics
                                                       were not reported.
 okoya        Sprague-     male and      0, 12.5, 25,  dose-relatedly decreased bw    number of females inseminated
1990)         Dawley rats female rats    50, 100 mg/kg gain, decreased water, food    (%): 100, 100, 90, 90, 82, resp.
              (males:      treated 2 wk bw/d; gavage consumption; marked              number of females pregnant
              n=10/group; before mating;               decreased bw gain in males at  (%): 95, 75, 72*, 71*, 61*,
              females:     1/2 of                      100 mg/kg bw/d; about 5-10     resp.
              n=19-22/     pregnant rats               min after administration:      no effect on gestation length
              group)       sacrificed at               spontaneous locomotion of all  post-mortem examination at
                           gd 14, 1/2                  chlorpromazine-treated groups  wk 14 (males) and wk 20
                           allowed to                  inhibited, animals sedated,    (females): at 100 mg/kg bw/d:
                           deliver                     symptoms persisting from 30    increased male adrenal,
                                                       min to several hr with dose-   pituitary, prostate gland wt
                                                       dependent intensity and        (>10%); increased female
                                                       duration; Supporting data for  adrenal gland, ovary wt
                                                       these statements were not      (>10%); decreased female
                                                       reported.                      pituitary, uterus wt (>6%)
                                                       Post-mortem examination at
                                                       wk 14 (males) and wk 20
                                                       (females): at 100 mg/kg bw/d:
                                                       increased male and female
                                                       liver, kidney wt (>10%)
zumi et al.   female       2 wk          0, 3, 10, 30  no mortality or changes in bw  number of animals with
2009)         Crl:CD(SD)                 mg/kg bw/d; (gain) or food consumption; at   irregular oestrus cycle: 0, 1,
              rats                       gavage        10 and 30 mg/kg bw: ptosis; at 9**, 10**, resp.
              (n=10/group)                             30 mg/kg bw: decreased         post-mortem examinations:
                                                       locomotor activity, prone      mean uterus wt (mg): 396±164,
                                                       position, lachrymation         487±159, 323±100, 230±45**,
                                                                                      resp.; no effect on absolute
                                                                                      ovary and pituitary wt;
                                                                                      no gross pathological changes;
                                                                                      microscopically: large atretic
                                                                                      follicles in 0, 1, 2, 6 animals,
                                                                                      resp.; alveolar mammary gland
                                                                                      hyperplasia in 0, 1, 1, 5
                                                                                      animals, resp.
zumi et al.   female       4 wk          0, 3, 10, 30  no mortality or changes in bw number of animals with
2009)         Crl:CD(SD)                 mg/kg bw/d;   (gain) or food consumption; at irregular oestrus cycle: 3, 0, 7,
              rats (n=10/                gavage        10 and 30 mg/kg bw: ptosis; at 10**, resp.
              group)                                   30 mg/kg bw: decreased         post-mortem examinations:
                                                       locomotor activity, prone      mean ovary wt (mg):
                                                       position, lachrymation         78.0±11.7, 71.8±6.7,
                                                                                      64.1±7.3**, 58.9±12.7**,
                                                                                      resp.; mean pituitary wt (mg):
                                                                                      11.5±0.8, 11.6±1.1, 9.6±1.8**,
                                                                                      9.2±1.3**, resp.; mean uterus
                                                                                      wt (mg): 384±159, 367±132,
                                                                                      279±42**, 272±50**, resp.;
                                                                                      no gross pathological changes;
                                                                                      microscopically: large atretic
                                                                                      follicles in 0, 0, 3, 3 animals,
 8          Chlorpromazine
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<pre>                                                                                           resp.; alveolar mammary gland
                                                                                           hyperplasia in 0, 0, 2, 7
                                                                                           animals, resp.
zumi et al.     female       2 wk before 0, 3, 10, 30      no mortality; during treatment: number of animals with
2009)           Crl:CD(SD) mating            mg/kg bw/d; decreased bw gain at 30 mg/kg irregular oestrus cycle: 1, 1,
                rats (n=10/  through gd 6 gavage           bw; at gd 13 at 10 and 30 mg/ 10**, 10**, resp.; fertility
                group        sacrifice: gd                 kg bw: decreased bw*            index (%): 89, 100, 90, 70,
                             13                            decreased motor activity and    resp.; copulatory interval (d):
                                                           ptosis at 10 and 30 mg/kg bw 2.2, 3.0, 2.0, 7.1*, resp.; no
                                                           and at 30 mg/kg bw, resp.       effect on mean numbers of
                                                                                           corpora lutea, mean number of
                                                                                           implantations, mean
                                                                                           percentages preimplantation
                                                                                           loss
Hoekstra et al. female CD    1 (day of pro- 0, 4 mg/kg     no effect on bw                 After a single injection
1984)           rats n=3/    oestrus) , 7 or bw, for 1 d;                                  ovulation was blocked in pro-
                group)       14 d; females 0, 45 mg/kg                                     oestrus rats, which was
                             mated after     bw/d for 7 or                                 reversed by coitus. After
                             last day of     14 d; gavage                                  multiple dosing, the inhibition
                             dosing                                                        of ovulation was increased.
                                                                                           Again, the ovulation inhibition
                                                                                           was reversed by coitus
Hafs/Williams male goats     8 wk            0, 90 mg/kg no effect on bw or heart rate     no effect on pH of fresh sperm,
1964)           (mixed       semen           bw/d;         (measured 30 min after          semen/ejaculate, sperm
                breeding:    collected at    spansules     administration); no signs of    motility, % motile sperm,
                Saanen and   2-wk                          lethargy or paralysis           sperm/mL semen, total sperm/
                Togenburg;   intervals, 5                                                  ejaculate, motile sperm/
                n=3/group)   times before                                                  ejaculate
                             treatment, 5                                                  post-mortem examinations: no
                             times during                                                  organ wt or macro/microscopic
                             treatment                                                     changes in testes,
                                                                                           epididymides, seminal vesicles,
                                                                                           thyroid glands, pituitary
                                                                                           glands
 w=body weight; d=day(s); gd=gestational day(s); wk=week(s); wt=weight(s); *: p<0.05; **: p<0.001.
             Fertility and developmental toxicity studies                                                                69
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<pre> able 2 Fertility effects with chlorpromazine in animals: parental administration.
 uthors          species         experimental dose             general toxicity        effects on reproductive organs/effects
                                 period/design                                         on reproduction
  hargava/       female albino 10 d              10 mg/kg      no effect on bw         average duration of oestrus cycle
 aitly           mice (n=12) vaginal             bw/d; sc                              before treatment (d): 4.58±0.76
1964)                            smears                                                average duration of oestrus cycle
                                 recorded for                                          during treatment (d): 8.44±2.4**
                                 10 d before
                                 treatment and
                                 during
                                 treatment
  anik/Herr      female          the day         0, 4 mg/kg    not reported            Inhibition of ovulation and no
1968)            Sprague-        before, the     bw; im                                alteration of the estrogenic effects
                 Dawley rats day of
                 (n=7-23/        expected pro-
                 group)          oestrus.
 escoat/         female Wistar 3 times/d; gd 0, 30 mg/kg not reported                  FSH: statistically significantly lower
  hambon         rats            0-3;            bw/d; im                              on gd 1, 2, 3 compared to controls
1983)            (n=unknown) sacrifice at gd                                           LH: statistically significantly on gd 1,
                                 1, 2, 3, or 4;                                        2, 3, 4
                                 pituitary                                             prolactine: statistically significantly
                                 concentrations                                        higher at on gd 1, 2, 3, 4
                                 of FSH, LH,
                                 prolactine
                                 measured
Hafs/Williams male goats         8 wk            0, 90 mg/kg no effect on bw gain;     average semen volume: 2.0 vs. 1.6 in
1964)            (mixed          semen           bw/d; im      slight lethargy in 3/3; controls (p=0.08); average sperm/mL
                 breeding:       collected at                  limb paralysis in 2/3   fresh semen (x109): 1.65 vs. 2.13
                 Saanen and      2-wk                          (starting after about 2 (p=0.04)
                 Togenburg;      intervals,                    wk of treatment)        no effect on pH of fresh sperm, sperm
                 n=3/group)      5 times before                                        motility, % motile sperm, total sperm/
                                 treatment,                                            ejaculate, motile sperm/ejaculate
                                 5 times during                                        post-mortem examinations: no organ
                                 treatment                                             wt or macro/microscopic changes in
                                                                                       testes, epididymides, thyroid glands,
                                                                                       pituitary glands
 and (1973)      Finn-Dorset 2 times/d;          0, 20 mg/kg increased bw (by about bw (kg): d 0-2: 61.05; d 3-5: 65.25; d
                 ewes (n=5/      6 different 3-d bw/d; im      9%) at treatment d 3-5; 6-8: 61.15; d 9-11: 60.15; d 12-14:
                 group)          periods of                    decreased bw (by about 55.15; d 15-17: 60.55; controls: 60.16
                                 oestrus cycle                 9%) at treatment d12-14 ovulation (CL): d 0-2: 2.20; d 3-5:
                                                                                       2.60; d 6-8: 2.80; d 9-11: 2.60; d 12-
                                                                                       14: 2.80; d 15-17: 2.20; controls: 2.27
                                                                                       oestrus cycle length (d): d 0-2: 16.9; d
                                                                                       3-5: 17.7; d 6-8: 17.5; d 9-11: 17.7; d
                                                                                       12-14: 18.7; d 15-17: 17.8; controls:
                                                                                       17.4
 w=body weight; d=day(s); FSH=follicle-stimulating hormone; gestational day(s); im=intramuscular(ly); LH=luteinizing
 ormone; pnd=postnatal day(s); sc=subcutaneous(ly); wk=week(s); wt=weight(s); *: p<0.05; **: p<0.001.
  0          Chlorpromazine
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<pre>able 3 Developmental toxicity studies with chlorpromazine in animals: oral (gavage) administration.
uthors        species        experimental       dose          general toxicity                developmental toxicity
                             period/design
aigo          Sprague-       male and female 0, 12.5, 25,     generally dose-dependently sacrifice at gd 14:
1990)         Dawley rats rats treated 9 wk 50, 100 mg/kg decreased bw gain, decreased mean number of live foetuses/
              (males: n=10/ prior to mating; bw/d             water, food consumption;        litter: 12.2±1.2, 11.5±0.8,
              group;         1/3 of pregnant                  after every chlorpromazine 13.2±1.2, 12.0±1.0, 9.7±0.8*,
              females:       rats sacrificed at               administration: animals         at 0, 12.5, 25, 50, 100 mg/kg
              n=17-25/       gd 14, 1/3 at gd                 sedated, spontaneous            bw/d, resp.; average live foetal
              group)         21, 1/3 allowed                  locomotion inhibited,           wt (g): 2.68±0.02, 2.65±0.03,
                             to deliver F1                    symptoms persisting for up 2.48±0.02*, 2.39±0.05**,
                             pups which were                  to several hr with dose-        2.12±0.04**
                             either sacrificed                dependent intensity and         sacrifice at gd 21:
                             after weaning or                 duration; after the 2nd wk of mean number of live foetuses/
                             mated at pnw 10                  administration: the durations litter: 12.7±0.2, 11.7±0.1*,
                             to obtain an F2                  of the symptoms following 10.8±0.1*, 12.2±0.4, 9.3±1.3*,
                             generation                       administration shortened        resp.; average live foetal wt
                                                              slightly; at 100 mg/kg bw/d, (g): 5.03±0.03, 5.34±0.04**,
                                                              about 4-6 wk after the          5.21±0.05*, 4.94±0.17,
                                                              beginning of the treatment: 3.84±0.26**, resp.
                                                              blepharitis in 25% of the       F1 generation:
                                                              animals (more severe in         mean number of live pups/
                                                              males than in females). At      litter: 13.0±0.9, 12.0±0.6,
                                                              12.5 and 25 mg/kg bw/day        11.3±0.9, 11.4±0.9, 9.0±0.9*,
                                                              the body weight gain was        resp.; average pup wt at 48 hr
                                                              decreased in the final third of (g): 6.38±0.05, 6.42±0.03,
                                                              the treatment period. At 50 6.04±0.04*, 5.65±0.36*,
                                                              and 100 mg/kg bw/day the        5.48±0.36*, resp.; pup survival
                                                              body weight gain was            at pnd 22 (%): 94, 96, 100, 80*,
                                                              decreased from the beginning 81*, resp.
                                                              of treatment onwards.           at pnw 10: no effect on oestrus
                                                              Statistics were not reported cycle length, average bw; no
                                                                                              abnormal behaviour seen; no
                                                                                              visible external abnormalities
                                                                                              upon gross observations.
                                                                                              mating F1:
                                                                                              no effect on percentages of
                                                                                              females inseminated or being
                                                                                              pregnant
                                                                                              sacrifice at gd 14:
                                                                                              no effects on mean number of
                                                                                              live foetuses/litter; average live
                                                                                              foetal wt (g): 2.56±0.01,
                                                                                              2.48±0.03*, 2.46±0.02*,
                                                                                              2.45±0.05**, 2.23±0.06*
                                                                                              no uterine, ovarian
                                                                                              abnormalities upon gross
                                                                                              observations
                                                                                              F2 generation:
                                                                                              no effect on gestation length,
                                                                                              mean number of live pups/
          Fertility and developmental toxicity studies                                                                       71
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<pre>                                                                                      litter, average pup wt at 48 hr;
                                                                                      pup survival at pnd 22; F2 pups
                                                                                      descendant from treated F0 rats
                                                                                      gained more weight up to
                                                                                      weaning than controls; no
                                                                                      visible abnormalities upon
                                                                                      gross observations
                                                                                      recording of wet organ wt of F0
                                                                                      and F1 rats: only effects at 100
                                                                                      mg/kg bw/d: increases in wt of
                                                                                      the liver, kidney, adrenal,
                                                                                      pituitary, testis, prostate in
                                                                                      males, in kidney, adrenal gland,
                                                                                      ovary in females, decreases in
                                                                                      wt of pituitary, the uterus in
                                                                                      females
 okoya   Sprague-       male and female 0, 12.5, 25,    dose-relatedly decreased bw   sacrifice at gd 14:
1990)    Dawley rats    rats treated 2 wk 50, 100 mg/kg gain, decreased water, food   mean number of live foetuses/
         (n=10-22/ sex/ before mating; bw/d             consumption; marked           litter: 12.4±0.7, 9.1±0.7*,
         group)         1/2 of pregnant                 decreased bw gain in males    9.9±0.7*, 8.8±0.5*, 8.0±0.7*,
                        rats sacrificed at              at 100 mg/kg bw/d; about 5-   at 0, 12.5, 25, 50, 100 mg/kg
                        gd 14, 1/2                      10 min after administration:  bw/d, resp.; average live foetal
                        allowed to                      spontaneous locomotion of     wt (g): 2.72±0.02, 2.62±0.01*,
                        deliver                         all chlorpromazine-treated    2.30±0.03**, 1.98±0.08**,
                                                        groups inhibited, animals     2.04±0.05**
                                                        sedated, symptoms persisting  F1 generation:
                                                        from 30 min to several hr     mean number of live pups/
                                                        with dose-dependent           litter: 12.4±0.8, 9.7±0.7*,
                                                        intensity and duration;       8.8±1.1*, 8.3±1.0*, 8.0±1.0*,
                                                        Supporting data for these     resp.;
                                                        statements were not reported. average pup wt (g) at 48 hr,
                                                        Post-mortem examination at    males: 6.85±0.05, 6.10±0.14*,
                                                        wk 14 (males) and wk 20       6.17±0.36*, 5.12±0.54*,
                                                        (females): at 100 mg/kg bw/   5.07±0.84*, resp.; females:
                                                        d: males: increased adrenal,  6.83±0.06, 6.05±0.13*,
                                                        pituitary, prostate gland wt  5.95±0.32*, 5.16±0.45*,
                                                        (>10%); females: increased    5.05±0.65*, resp.; at pnd 7,
                                                        ovary wt (>10%), decreased    males: 14.83±0.58,
                                                        pituitary, uterus wt (>6%)    13.46±0.65, 11.34±0.71*,
                                                                                      10.64±0.84*, 10.34±0.71*,
                                                                                      resp.; females: 14.80±0.67,
                                                                                      13.47±0.56, 11.40±0.86*,
                                                                                      10.08±0.72*, 10.28±0.54*,
                                                                                      resp.; at pnd 14, males:
                                                                                      25.32±0.84, 24.68±0.73,
                                                                                      23.04±0.56, 22.35±0.93*,
                                                                                      23.45±1.30, resp.; females:
                                                                                      24.06±0.75, 23.34±0.64,
                                                                                      22.67±0.36, 22.36±0.83*,
                                                                                      23.06±0.93*, resp.; at pnd 21,
                                                                                      males: 42.34±1.04,
 2     Chlorpromazine
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<pre>                                             37.65±0.81*, 32.46±1.32*,
                                             30.03±2.34*, 30.18±2.65*,
                                             resp.; females: 41.06±1.10,
                                             36.64±0.94*, 32.00±1.06*,
                                             29.18±1.84*, 29.07±2.03*,
                                             resp.
                                             pup survival at pnd 22 (%): 99,
                                             93, 75*, 58**, 46**, resp.
                                             mating F1:
                                             no effect on percentages of
                                             females inseminated or being
                                             pregnant
                                             sacrifice at gd 14:
                                             mean number of live foetuses/
                                             litter: 11.6±0.5, 11.6±0.8,
                                             10.0±1.1, 10.0±0.3*,
                                             10.01±0.3*, resp.; average live
                                             foetal wt (g): 2.61±0.02,
                                             2.58±0.04, 2.52±0.02*,
                                             2.64±0.08, 2.43±0.06*
                                             no effect on F1 male and
                                             female wet organ wt at post-
                                             mortem examinations at wk 3,
                                             12 (males), 18 (females)
                                             F2 generation:
                                             no effect on gestation length,
                                             mean number of live pups/
                                             litter; average pup wt (g) at 48
                                             hr, males: 5.73±0.08,
                                             7.14±0.29*, 6.39±0.15*,
                                             6.77±0.21*, 7.17±0.27*, resp.;
                                             females: 5.89±0.06,
                                             6.93±0.18*, 6.41±0.34*,
                                             6.59±0.68*, 7.03±0.34*, resp.;
                                             at pnd 7, males: 14.87±0.23,
                                             16.10±0.38*, 16.14±0.86*,
                                             10.52±0.75*, 18.36±0.53*,
                                             resp.; females: 14.79±0.41,
                                             16.00±0.44*, 16.08±0.76*,
                                             16.50±0.87*, 18.19±0.44*,
                                             resp.; at pnd 14, males:
                                             23.15±0.92, 28.94±0.64*,
                                             27.77±0.73*, 27.61±0.32*,
                                             30.23±0.51, resp.; females:
                                             23.26±0.93, 28.89±0.56*,
                                             27.75±0.74, 27.56±0.81*,
                                             30.33±0.56*, resp.; at pnd 21,
                                             males: 34.14±0.10,
                                             42.63±0.84*, 22.34±1.34*,
                                             41.07±1.46*, 45.89±1.63*,
                                             resp.; females: 33.04±0.11,
                                             41.52±0.65*, 41.36±1.36*,
                                             40.84±0.96*, 44.08±1.34*,
Fertility and developmental toxicity studies                               73
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<pre>                                                                                               resp. pup survival at pnd 22
                                                                                               (%): 100, 89, 100, 68**, 50**,
                                                                                               resp.
                                                                                               no effect on F2 male and
                                                                                               female wet organ wt at post-
                                                                                               mortem examinations at pnw 3
zumi et al.    female          2 wk before         0, 3, 10, 30 no mortality; during           no effect on mean numbers of
2009)          Crl:CD(SD)      mating through      mg/kg bw/d   treatment: decreased bw gain live and dead embryos, on
               rats (n=10/     gd 6                             at 30 mg/kg bw; at gd 13 at mean percentages of
               group           sacrifice: gd 13                 10 and 30 mg/kg bw:            postimplantation loss
                                                                decreased bw*
                                                                decreased motor activity and
                                                                ptosis at 10 and 30 mg/kg bw
                                                                and at 30 mg/kg bw, resp.
Beall (1970)   female          gd 6-15             0, 5, 25, 35 not reported, but mortality in number of dams with
               CAW;CFE(S       gd 21: foetuses     mg/kg bw/d   3/22 dams at 35 mg/kg bw/d resorptions: 4 (17%), 7 (37%),
               D)              removed and                                                     9 (45%)*, 12 (63%)**, at 0, 5,
               spf rats (n=19- examined for                                                    25, 35 mg/kg bw/d, resp.;
               24/group)       gross, visceral                                                 number of resorptions: 6
                               and skeletal                                                    (1.8%), 13 (6%), 17 (7%)**, 51
                               abnormalities                                                   (20%)**, resp.; mean litter
                                                                                               size: 13.6±0.4, 11.5±0.8,
                                                                                               13.3±0.5, 10.5±1.0*
                                                                                               no effect on the number of
                                                                                               implantations
                                                                                               mean foetal bw (g): 5.36±0.03,
                                                                                               5.16±0.06**, 5.05±0.03**,
                                                                                               5.32±0.03, resp.
                                                                                               number of abnormal foetuses:
                                                                                               0, 1 (with absence of tail, 3
                                                                                               posterior lumbar vertebrae;
                                                                                               split ossification centre first
                                                                                               lumbar vertebra; prematurely
                                                                                               fused second lumbar arch), 0,
                                                                                               0, resp.
 aillenfait/   female          gd 6-20             0, 20 mg/kg  no effect on maternal bw       no effect on gestation length,
  annier       Sprague-        at parturition,     bw/d                                        litter size, litter sex
 1988)         Dawley rats     litters examined:                                               distribution, mortality
               (n=31/group)    litter size, sex                                                mean offspring wt (g):
                               distribution,                                                   preweaning: pnd 1: 6.2±0.14,
                               number of dead                                                  6.2±0.16 at 0, 20 mg/kg bw,
                               or malformed                                                    resp.; pnd 3: 7.8±0.25,
                               offspring;                                                      8.5±0.17*, resp.; pnd 6:
                               15 hr after birth,                                              11.6±0.41, 12.7±0.30*; pnd 9:
                               all treated litters                                             16.2±0.54, 18.2±0.54, resp.;
                               were cross-                                                     pnd 12: 21.9±0.79, 23.2±0.52*,
                               fostered to                                                     resp.; pnd 15: 26.3±0.76,
                               control females;                                                28.3±0.67, resp.; pnd 18:
                               offspring                                                       31.1±1.04, resp.; pnd 21:
                               observed for                                                    38.0±1.30, 43.2±1.04*, resp.;
                               physical                                                        postweaning: pnd 28: 66±2.2,
                               landmarks                                                       73±1.8*, resp., pnd 35:
  4          Chlorpromazine
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<pre>                (pinna                       111±3.5, 120±2.7*, resp.; pnd
                detachment,                  42: 166±3.4, 166±3.7, resp.;
                incisor eruption,            pnd 49: 217±4.0, 222±3.8,
                eye opening),                resp.; pnd 56: 268±5.0,
                behaviour: pre-              275±4.1, resp.; pnd 63:
                weaning: surface             304±6.2,309±5.1, resp.
                righting reflex,             no malformations upon
                swimming                     external examination
                development                  no effect on physical
                (angle                       landmarks
                assessment, limb             pre-weaning behavioural
                usage), negative             testing:
                geotaxis, open               surface righting reflex (% of
                field                        pups righted <2 s): pnd 3:
                (ambulation,                 trial1: 37, 40, resp., trial 2: 41,
                rearing); post-              45, resp.; pnd 4: trail 1: 59, 68,
                weaning:                     resp., trial 2: 71, 70, resp.; pnd
                rotarod, open                5: trial 1: 77, 89, resp., trial 2:
                field                        79, 90, resp.; pnd 6: trial 1: 93,
                (ambulation,                 99**, resp., trial 2: 94, 100**,
                rearing),                    resp.; swimming development:
                pupillary reflex,            angle assessment: pnd 6:
                water maze                   1.2±0.09, 1.3±0.06*, resp.; pnd
                (learning,                   8: 2.5±0.09, 3.4±0.10**, resp.;
                retention),                  pnd 10: 3.8±0.09, 3.7±0.10,
                nocturnal                    resp.; pnd 12: 4.3±0.08,
                activity, auditory           4.5±0.06*, resp.; no effect on
                startle reflex; in           limb usage
                males only,                  no effect on negative geotaxis
                neurohistology               no effect on open field
                and                          performance on pnd 18
                measurement of               post-weaning behavioural
                chatecholamine               testing:
                (noradrenaline,              rotarod test on pnd 22 (s)
                dopamine) and                males: trial1: 81±62, 63±64,
                DNA                          resp.; trial 2: 96±66, 82±70*,
                concentrations;              resp.; trial 3: 119±71, 107±73,
                sacrifice: males:            resp.; trial 4: 131±67, 102±73,
                pnw 9, 11 or 12,             resp.; no effect in females;
                females: pnw 9               open field performance:
                                             ambulation: pnd 35: males:
                                             13.9±5.5, 14.6±7.3, resp. ;
                                             females: 17.8±6.0, 20.4±6.3*,
                                             resp.; no effect on rearing in
                                             males and females on pnd 35,
                                             on rearing or ambulation in
                                             males (females not tested) on
                                             pnd 56 compared to controls,
                                             lower** nocturnal activity
                                             no effect on pupillary reflex,
                                             water maze performance,
                                             auditory startle response DNA
                                             (µg/g brain): 973±59,
Fertility and developmental toxicity studies                                  75
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<pre>                                                                                              DNA (µg/g brain): 973±59,
                                                                                              467±51**, resp.; no effect on
                                                                                              cathecholamine concentrations
                                                                                              no histological brain changes
Druga et al.   female Wistar/ gd 13, 14 or 15    0, 119 mg/kg   not reported                  treatment on gd 14: foetal
 1980)         H-Riop rats    sacrifice: gd 21   bw                                           mortality (%): 7.6±0.9,
               (n≥5/group) for foetal                                                         24.5±7.9**, at 0, 119 mg/kg
                              examinations                                                    bw, resp.; mean foetal wt (g):
                                                                                              3.5±0.06, 3.2±.10**, resp. (no
                                                                                              data concerning treatment on
                                                                                              gd 13 or 15)
                                                                                              no effect on femur-index value
                                                                                              (length: thickness), on
                                                                                              incidence of foetuses with cleft
                                                                                              palate or micromelia at
                                                                                              treatment on gd 13, 14 or 15
Robertson et   female         gd 6-15            0, 1, 3, 9 mg/ at 9 mg/kg bw: decreased      sacrifice at gd 21: no effect on
 l. (1980)     Charles River  ½ of pregnant      kg bw/d; 2     activity 2-4 hr after dosing; total number of implantations,
               CD rats        animals            control groups statistically significantly   resorptions, live and dead
               (n=20/group)   sacrificed at gd   included       decreased bw gain             foetuses /litter, on foetal
                              21 for foetal                                                   weights; no external, visceral,
                              examinations;                                                   skeletal abnormalities.
                              other ½ allowed                                                 F1 generation:
                              to deliver ; on gd                                              no effect on gestation length
                              1, treated                                                      pre-weaning:
                              animals cross-                                                  pnd 1: average pup wt/litter (g):
                              fostered with                                                   6.5, 6.5, 6.2, 6.1**, 6.2** at 0,
                              controls; ½ of                                                  0, 1, 3, 9 mg/kg bw, resp.; no
                              the offspring                                                   effect on sex distribution,
                              selected for                                                    number of live and dead pups,
                              physical                                                        number of live pups/litter
                              landmarks                                                       pnd 7, 14, 21:
                              (pinna                                                          no effect on number of live
                              detachment,                                                     pups, number of dead pups
                              lower incision                                                  during d 2-7, 8-14, 15-21,
                              eruption, hair                                                  resp., average pup wt/litter
                              growth, eye                                                     postweaning: no effect on
                              opening, vaginal                                                average male and female bw on
                              canalization,                                                   pnd 21, 42, 84, 105;
                              testis descent),                                                mean bw gain (g): pnd 21-42:
                              behavioural                                                     females: 115±1.5, 111±1.7*,
                              testing (surface                                                112±1.6, 110±1.8* at 0
                              righting reflex,                                                (pooled), 1, 3, 9 mg/kg bw,
                              horizontal                                                      resp.; males: 156±2.1, 151±1.6,
                              movement,                                                       149±1.5, 142±2.6*, resp.; pnd
                              auditory startle                                                42-84: females: 116±1.6,
                              reflex, open field                                              109±1.8, 108±1.5, 116±1.7,
                              activity,                                                       resp.; males: 255±3.1, 254±3.0,
                              rotarod),                                                       245±3.5*, 251±3.3*, resp.; pnd
                              reproductive                                                    21-105: females: 228±2.7,
                              performance;                                                    229±3.2, 226±4.3, 227±3.7;
                              other ½                                                         males: 440±5.1, 450±6.4,
                              sacrificed at pnw                                               424±7.2, 423±6.3, resp.
  6          Chlorpromazine
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<pre>                             15 or 16 for                                                   pnw 3: decreased*** latency
                            weighing organs                                                 time at 3, 9 mg/kg bw; pnw 7:
                            and, in control                                                 increased*** open-field
                            and high-dose                                                   activity at 9 mg/kg bw; pnw 13:
                            animals,                                                        increased*** open-field
                            histological                                                    activity at 3 mg/kg bw;
                            brain                                                           decreased*** latency time at 9
                            examination                                                     mg/kg bw;
                                                                                            no effect on physical
                                                                                            development, righting and
                                                                                            auditory startle reflex,
                                                                                            reproductive performance
                                                                                            no effect on organ wt, no
                                                                                            histomorphologic and
                                                                                            morphometric changes in
                                                                                            brains
Ordy et al.   female inbred 6 d after mating 0, 4, 16 mg/kg no effect on bw gain; at 16     mean d between mating and
1963)         C57BL/10      until delivery     bw/d         mg/kg bw, decreased activity    birth: 22.35, 23.85, 28.80*** at
              mice                                          in an open field test           0, 4, 16 mg/kg bw/d, resp.;
              (n=20/group;                                  (p<0.001) 1-5 hr after          mean litter size: 8.0, 7.9, 5.8*,
              controls:                                     administration                  resp. ; mean litter wt (g): 1.41,
              n=40)                                                                         1.33, 1.17****
Ordy et al.   female inbred 6 d after mating 0, 4, 16 mg/kg mean bw gain (g): 15.1±0.48,    mortality at birth (%):
1966)         C57BL/10      until delivery     bw/d         13.4±0.57, 10.3±0.52*** at      1.5±0.14, 3.4±0.23****,
              mice          after delivery,                 0, 4, 16 mg/kg bw, resp.;       11.9±***** at 0, 4, 16 mg/kg
              (n=30-56/     offspring cross-                mean duration between           bw, resp.; mean litter size:
              group)        fostered                        mating and birth (d):           7.6±0.32, 6.8±0.33, 5.8±0.30,
                            examinations:                   22.7±0.64, 25.4±1.3,            resp.; mean litter wt (g):
                            leucine                         30.8±1.3***, resp.; impaired    1.41±0.01, 1.36±0.02,
                            aminopeptidase,                 open-field behaviour***         1.22±0.02****, resp.;
                            alkaline                        (whether statistical result     mortality at pnd 60: 35% in
                            phosphatase                     applies to both doses or to the control offspring, 49% in
                            activity,                       highest one, not mentioned)     treated offspring**; no
                            glycogen in liver                                               differences in sex ratio of
                            homogenates at                                                  postnatal mortality between
                            birth and pnd 75;                                               offspring from untreated
                            open-field                                                      mothers raised by untreated
                            exploration,                                                    mothers (males: 47%, females:
                            locomotor                                                       53%) or raised by treated
                            activity (not at                                                mothers (males: 47%, females:
                            pnd 20), shock-                                                 53%); differences in sex ratio
                            elicited escape-                                                of postnatal mortality in
                            avoidance                                                       offspring from treated mothers
                            conditioning at                                                 raised by untreated mothers
                            pnd 20 and 60;                                                  (males: 33%, females: 67%)**
                            hexobarbital-                                                   or raised by treated mothers
                            induced loss of                                                 (males: 38%, females: 62%)*;
                            righting reflex at                                              in liver homogenates: at birth:
                            pnd 30 and 60                                                   increased leucine
                            (at 4 mg/kg bw                                                  aminopeptidase activity**,
                            only)                                                           decreased alkaline phosphatase
                                                                                            activity** at 16 mg/kg bw,
                                                                                            decreased glycogen** at 4 and
            Fertility and developmental toxicity studies                                                                   77
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<pre>                                                                                         16 mg/kg bw; at pnd 75:
                                                                                         increased leucine
                                                                                         aminopeptidase activity**,
                                                                                         increased alkaline phosphatase
                                                                                         activity** (glycogen not
                                                                                         determined);
                                                                                         hexobarbital-induced loss of
                                                                                         righting reflex: differences in
                                                                                         duration of hexobarbital action
                                                                                         at pnd 30 and 60 between
                                                                                         treated and control offspring**,
                                                                                         between pnd 30 and pnd 60 test
                                                                                         replication**, between males
                                                                                         and females**
                                                                                         behavioural tests: (generally
                                                                                         dose-related) fewer avoidances
                                                                                         in shock-elicted escape-
                                                                                         avoidance learning, less
                                                                                         traversing of squares in open
                                                                                         field exploration, longer open
                                                                                         field latencies and fewer wheel
                                                                                         revolutions in treated offspring
w=body weight(s); d=day(s); hr=hour(s); pnd=postnatal day(s); pnw=postnatal week(s); wk=week(s); wt=weight(s);
=p<0.05; **=p<0.01; ***=p<0.005; ****=p<0.001; *****=p<0.0001.
8          Chlorpromazine
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<pre>able 4 Developmental toxicity studies with chlorpromazine in animals: parental administration
uthors         species        experimental dose/route        general toxicity                 developmental toxicity
                              period/design
ingh et al.    female CF rats gd 14           0, 100 mg/kg not described                      foetal mortality: 19-30% in
1978, 1978,    (n=5-9;        sacrifice: gd bw; ip                                            treated groups vs. 0-3% in
979)           controls n=3- 16, 17, 18,19,                                                   controls;
               4);            20 for foetal                                                   no. of malformations: 91-98%
                              skeletal                                                        in treated groups vs. 0-4% in
                              examinations                                                    controls;
                                                                                              foetal wt, crown-rump length,
                                                                                              tail length decreased**** in
                                                                                              treated groups at all time points
                                                                                              of sacrifice;
                                                                                              delayed ossification (by 1-3 d)
                                                                                              of long bones of extremities,
                                                                                              scapulae, ilium, skull bones; no
                                                                                              ossification of ischium, pubis;
                                                                                              decreased number/ range of
                                                                                              ossified vertebral bodies and
                                                                                              arches
urukawa et al. female Wistar gd 14            0, 50, 100 mg/ based on bw at gd 14,            gd 14.5: no litters with
2014)          Hannover       sacrifice: gd kg bw; ip        decreased bw gain during gd      completed resorptions; no
               Gallas rats    14.5, 15, 17,                  15-18 and gd 15-21 at 50 and effect on number living
               (n=16-22/      21 for foetal                  100 mg/kg bw, resp.; clinical foetuses/litter (as mean of
               group)         and                            signs: prone position,           individual litter values), %
                              histological                   hypothermia, loss/decrease of foetal mortality, mean foetal wt
                              placental                      locomotor activity, vaginal      (as mean of individual litter
                              examinations                   haemorrhage, eye discharge,      values); mean placental wt (g)
                                                             incontinence of urine,           (as mean of individual litter
                                                             disappearing by gestational day values): 0.243±0.035,
                                                             17 at 50 mg/kg bw and by         0.208±0.028, 0.199±0.035*, at
                                                             gestational day 19 at 100 mg/ 0, 50, 100 mg/kg bw, resp.
                                                             kg bw at the latest              gd 15: no litters with completed
                                                                                              resorptions; no effect on
                                                                                              number living foetuses/litter, %
                                                                                              foetal mortality, mean foetal wt
                                                                                              (g): 0.268 ± 0.021, 0.229 ±
                                                                                              0.022*, 0.177 ± 0.004**, resp.;
                                                                                              mean placental wt (g): 0.229 ±
                                                                                              0.038, 0.187 ± 0.032, 0.147 ±
                                                                                              0.026*, resp.
                                                                                              gd 17: no effect on number
                                                                                              living foetuses/litter, % foetal
                                                                                              mortality, % litters with
                                                                                              completed resorptions: 0, 20,
                                                                                              20, resp.; mean foetal wt (g):
                                                                                              0.770 ± 0.023, 0.553 ±
                                                                                              0.065**, 0.517 ± 0.066**,
                                                                                              resp.; mean placental wt (g):
                                                                                              0.317 ± 0.018, 0.254 ± 0.022*,
                                                                                              0.228 ± 0.034**, resp.
            Fertility and developmental toxicity studies                                                                     79
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<pre>                                                                                             gd 19: no effect on number
                                                                                             living foetuses/litter, % foetal
                                                                                             mortality, mean foetal wt, %
                                                                                             litters with completed
                                                                                             resorptions: 0, 20, 44, resp.;
                                                                                             mean placental wt (g): 0.449 ±
                                                                                             0.035, 0.434 ± 0.035, 0.375 ±
                                                                                             0.031*, resp.
                                                                                             histopathology: tropoblast
                                                                                             apoptosis in the labyrinth zone,
                                                                                             leading to labyrinth zone
                                                                                             hypoplasia; glycogen cell
                                                                                             apoptosis in the basal zone,
                                                                                             ultimately leading to metrial
                                                                                             gland apoptosis
Umemura et al. female Jcl:SD gd 17-pnd 21    0, 2 mg/kg     sedation, slowed motion, eye-    no effect on mean litter size;
1983)          rats (n=9-11/ sacrifice: pnd  bw/d (once     closing in dams of both dosing   male, female mean pup wt at
               group)        22: dams,       daily); 8 mg/  groups; no nursing behaviour     birth; mortality at birth: 1
                             female          kg bw/d        in many dams of the high-dose    (0.8%), 5 (4%), 9 (7%), 16
                             offspring, part (twice daily 4 group due to cataleptic          (12%) at 0 (untreated), 0
                             of male         mg/kg bw); sc  manifestations;                  (vehicle), 2 mg/kg bw, 4 mg/kg
                             offspring                      mean bw at 8 mg/kg bw tended     bw, resp.
                             behavioural                    to be lower than at 2 or 0 mg/kg pnd 14: mean pup wt (g), male:
                             testing in                     bw, but no statistically         31.6±1.5, 33.1±2.9, 31.7±2.2,
                             selected male                  significant difference among     29.7±3.5*, resp.; female:
                             offspring at                   groups; low water and food       31.6±1.3, 32.0±2.8, 31.1±2.4,
                             pnw 5                          intake at 8 mg/kg bw             28.8±2.7, resp.
                             (learning), 6-7                                                 pnd 21: mortality (pnd1-21): 0,
                             (motor                                                          0, 2 (2%), 22 (20%)*; mean
                             activity), 15                                                   pup wt (g), male: 53.4±2.3,
                             (learning)                                                      54.9±3.9, 53.6±3.7, 48.5±5.8*,
                                                                                             resp.; female: 52.8±2.2,
                                                                                             52.8±3.9, 51.7±4.1, 47.7±4.0*,
                                                                                             resp.
                                                                                             pnw 5: no effect on lever
                                                                                             pressing (continuous food
                                                                                             reinforcement), light-dark
                                                                                             discrimination learning,
                                                                                             impaired reversal
                                                                                             discrimination learning at 2 and
                                                                                             8 mg/kg bw
                                                                                             pnw 6-7: no effect on motor
                                                                                             activity
                                                                                             pnw 15: no effect on lever
                                                                                             pressing, light-dark
                                                                                             discrimination learning,
                                                                                             impaired reversal
                                                                                             discrimination learning at 8
                                                                                             mg/kg bw
 0         Chlorpromazine
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<pre>Hironaka et al. female        gd 17-21        0, 8, 16 mg/kg not reported.                  no effect on mean litter size;
1988)           Sprague       at parturition, bw/d; sc                                      total number of deaths at birth:
                Dawley rats   pups from                                                     2, 10, 25** at 0, 8, 16 mg/kg
                (n=13-14/     treated                                                       bw, resp.; total number of
                group)        mothers                                                       deaths during lactation period:
                              transferred to                                                0, 18, 60**, resp.;
                              non-treated                                                   mean pup wt at birth (g): male:
                              mothers;                                                      6.4±0.3, 5.9±0.4*, 5.4±0.3*,
                              behavioural                                                   resp.; female: 6.1 ±0.4,
                              testing started                                               5.3±1.2, 5.1±0.3, resp.; no
                              at pnw 5                                                      effect on mean male and
                                                                                            female pup bw at pnd 21
                                                                                            pnw 5: retarded reversal
                                                                                            learning acquisition; no effect
                                                                                            on acquisition of lever press
                                                                                            responses and on original
                                                                                            discrimination learning
West et al.     female        gd 14, 16, 18   0, 1 mg/kg     no effect on maternal bw, food no effect on pup bw, litter size,
1986)           Crl:CD(SD)B   olfactory       bw/d; sc       and water consumption          sex ratio
                R rats (n=6/  discrimination                                                decreased response toward
                group;        test                                                          dams; no effect on response to
                controls:     performed in                                                  the empty goalbox
                n=14).        pups on pnd 9
                              and 10
Hannah et al.   female Long- gd 18-pnd 21     15 mg/kg bw/ not reported                     pnw 1: increased levels of
1987)           Evans rats    sacrifice of    d; im                                         dopamine* and serotonin** in
                (n=9 /group) whole litters                                                  cerebellum and hippocampus
                              (n=3/sample                                                   pnw 21: no effect on
                              time point) at                                                monoamine levels
                              pnw 1, 3 and                                                  pnw 24: decreased levels of
                              24 for                                                        noradrenaline*, dopamine*,
                              examination                                                   serotonin* in cerebellum;
                              of monoamine                                                  increased levels of
                              levels in                                                     noradrenaline*, dopamine*,
                              cerebellum                                                    serotonin* in hippocampus
                              and
                              hippocampus
Walker/         female A/J    gd 14           50 mg/kg bw; heavily sedation for 9-18 hr     A/J mice: number of foetuses
 atterson       (n=21), C3H sacrifice: gd     im                                            resorbing: 51; number of
1974)           (n=6) mice    17; foetal                                                    foetuses retarded (heart
                              palate                                                        beating, but morphological
                              morphology                                                    rating equivalent to a younger
                              evaluated                                                     foetus): 39; number of foetuses
                                                                                            maturing (heart beating,
                                                                                            morphological rating consistent
                                                                                            with chronological age): 61;
                                                                                            foetuses with cleft lip and cleft
                                                                                            palate occurring together: 13%;
                                                                                            foetuses with isolated cleft
                                                                                            palate: 21%
              Fertility and developmental toxicity studies                                                                81
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<pre>                                                                                            C3H mice: number of foetuses
                                                                                            resorbing: 4; number of
                                                                                            foetuses retarded (heart
                                                                                            beating, but morphological
                                                                                            rating equivalent to a younger
                                                                                            foetus): 0; number of foetuses
                                                                                            maturing (heart beating, but
                                                                                            morphological rating consistent
                                                                                            with chronological age): 31;
                                                                                            foetuses with cleft lip and cleft
                                                                                            palate occurring together: 0%;
                                                                                            foetuses with isolated cleft
                                                                                            palate: 3%
w=body weight(s); d=day(s); gd=gestational day(s); hr=hour(s); im=intramuscular; ip=intraperitoneal; pnd=postnatal day(s);
nw=postnatal week(s); sc=subcutaneous; wk=week(s); wt=weight(s); *=p<0.05; **=p<0.01; ***=p<0.005; ****=p<0.001;
****=p<0.0001.
2         Chlorpromazine
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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                  realise significant                 which carry certain
and opportunities?                    health benefits?                    health risks?
Environmental                         Healthy working                     Innovation and
health                                conditions                          the knowledge
Which environmental                   How can employees                   infrastructure
influences could have                 be protected against                Before we can harvest
a positive or negative                working conditions                  knowledge in the
effect on health?                     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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