<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
          Triamcinolone
          Triamcinolone acetonide
             Evaluation of the effects on reproduction,
             recommendation for classification
2013/03
</pre>

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

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<pre></pre>

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<pre>Aan de minister van Sociale Zaken en Werkgelegenheid
Onderwerp             : aanbieding advies Triamcinolone and Triamcinolone acetonide
Uw kenmerk            : DGV/MBO/U-932542
Ons kenmerk           : U-7651/HS/fs/543-N13
Bijlagen              :1
Datum                 : 5 april 2013
Geachte minister,
Graag bied ik u hierbij het advies aan over de effecten van triamcinolon en triamcinolonace-
tonide op de vruchtbaarheid en het nageslacht; het betreft ook effecten op de lactatie en via
de moedermelk op de zuigeling. Dit advies maakt deel uit van een uitgebreide reeks waarin
voor de voortplanting giftige stoffen worden geclassificeerd volgens richtlijnen van de
Europese Unie. Het gaat om stoffen waaraan mensen tijdens de beroepsuitoefening kunnen
worden blootgesteld.
Dit advies is opgesteld door een vaste commissie van de Gezondheidsraad, de Subcommis-
sie Classificatie reproductietoxische stoffen. Het is vervolgens getoetst door de Beraads-
groep Gezondheid en omgeving van de raad.
Ik heb dit advies vandaag ter kennisname toegezonden aan de staatssecretaris van Infra-
structuur en Milieu en aan de minister van Volksgezondheid, Welzijn en Sport.
Met vriendelijke groet,
prof. dr. W.A. van Gool,
voorzitter
Bezoekadres                                                          Postadres
Rijnstraat 50                                                        Postbus 16052
2515 XP Den              Haag                                        2500 BB Den     Haag
E - m a il : h . st o u t e n @ g r. n l                             w w w. g r. n l
Te l e f o o n ( 0 7 0 ) 3 4 0 7 0 0 4
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<pre></pre>

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<pre>Triamcinolone
Triamcinolone acetonide
Evaluation of the effects on reproduction,
recommendation for classification
Subcommittee on the Classification of Reproduction Toxic Substances
A Committee of the Health Council of the Netherlands
to:
the Minister of Social Affairs and Employment
No. 2013/03, The Hague, Aprll 5, 2013
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<pre>The Health Council of the Netherlands, established in 1902, is an independent
scientific advisory body. Its remit is “to advise the government and Parliament on
the current level of knowledge with respect to public health issues and health
(services) research...” (Section 22, Health Act).
     The Health Council receives most requests for advice from the Ministers of
Health, Welfare & Sport, Infrastructure & the Environment, Social Affairs &
Employment, Economic Affairs, and Education, Culture & Science. The Council
can publish advisory reports on its own initiative. It usually does this in order to
ask attention for developments or trends that are thought to be relevant to
government policy.
     Most Health Council reports are prepared by multidisciplinary committees of
Dutch or, sometimes, foreign experts, appointed in a personal capacity. The
reports are available to the public.
                 The Health Council of the Netherlands is a member of the European
                 Science Advisory Network for Health (EuSANH), a network of science
                 advisory bodies in Europe.
                 The Health Council of the Netherlands is a member of the International Network
                 of Agencies for Health Technology Assessment (INAHTA), an international
                 collaboration of organisations engaged with health technology assessment.
 I NA HTA
This report can be downloaded from www.healthcouncil.nl.
Preferred citation:
Health Council of the Netherlands. Triamcinolone/Triamcinolone acetonide. The
Hague: Health Council of the Netherlands, 2013; publication no. 2013/03.
all rights reserved
ISBN: 978-90-5549-946-5
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<pre>   Contents
   Samenvatting 9
   Executive summary 11
   Scope 13
.1 Background 13
.2 Committee and procedure 13
.3 Effects on or via lactation 14
.4 Data 15
.5 Presentation of conclusions 15
.6 Final remark 16
   Triamcinolone and triamcinolone acetonide 17
.1 Introduction 17
.2 Human studies 20
.3 Animal studies 21
.4 Conclusion 31
   References 35
   Contents                                     7
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<pre>  Annexes 39
A The Committee 41
B The submission letter (in English) 43
C Regulation (EC) 1272/2008 of the European Community 45
D Additional considerations to Regulation (EC) 1272/2008 57
E Fertility and developmental toxicity studies in animals 59
  Triamcinolone/Triamcinolone acetonide
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<pre>Samenvatting
In het voorliggende advies heeft de Gezondheidsraad triamcinolon en triamcino-
lonacetonide onder de loep genomen. Triamcinolon en triamcinolonacetonide
zijn glucocorticoide geneesmiddelen en werkzaam als systemische en lokale ont-
stekingsremmer. Dit advies past in een reeks adviezen waarin de Gezondheids-
raad op verzoek van de Minister van Sociale Zaken en Werkgelegenheid de
effecten van stoffen op de voortplanting beoordeelt. Het gaat vooral om stoffen
waaraan mensen tijdens de beroepsuitoefening kunnen worden blootgesteld. De
Subcommissie Classificatie reproductietoxische stoffen van de Commissie
Gezondheid en beroepsmatige blootstelling aan stoffen van de raad, hierna aan-
geduid als de commissie, kijkt naar effecten op de vruchtbaarheid van mannen en
vrouwen zowel als op de ontwikkeling van het nageslacht. Daarnaast worden
effecten op de lactatie en via de moedermelk op de zuigeling beoordeeld.
Op basis van Verordening (EG) 1272/2008 van de Europese Unie doet de com-
missie een voorstel voor classificatie. Voor triamcinolon komt de commissie tot
de volgende aanbevelingen:
• voor effecten op de fertiliteit adviseert de commissie om triamcinolon niet te
    classificeren wegens onvoldoende geschikte gegevens
• voor effecten op de ontwikkeling adviseert de commissie triamcinolon in
    categorie 1B te classificeren (stoffen waarvan verondersteld wordt dat zij
    toxisch zijn voor de menselijke voortplanting) en met H360D (kan het onge-
    boren kind schaden) te kenmerken
Samenvatting                                                                     9
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<pre>  •   voor effecten op of via lactatie adviseert de commissie om triamcinolon niet
      te kenmerken wegens onvoldoende geschikte gegevens.
  Voor triamcinolonacetonide komt de commissie tot de volgende aanbevelingen:
  • voor effecten op de fertiliteit adviseert de commissie om triamcinolonaceto-
      nide niet te classificeren wegens onvoldoende geschikte gegevens
  • voor effecten op de ontwikkeling adviseert de commissie triamcinolonaceto-
      nide in categorie 1B te classificeren (stoffen waarvan verondersteld wordt
      dat zij toxisch zijn voor de menselijke voortplanting) en met H360D (kan het
      ongeboren kind schaden) te kenmerken
  • voor effecten op of via lactatie adviseert de commissie om triamcinolonace-
      tonide niet te kenmerken wegens onvoldoende geschikte gegevens.
0 Triamcinolone/Tramcinolone acetonide
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<pre>Executive summary
In the present report the Health Council of the Netherlands reviewed
triamcinolone and triamcinolone acetonide. Triamcinolone and triamcinolone
acetonide are glucocorticoid drugs applied for systemic and local anti-
inflammatory activity. This report is part of a series, in which the Health Council
evaluates the effects of substances on reproduction, at request of the Minister of
Social Affairs and Employment. It mainly concerns substances to which man can
be occupationally exposed. The Subcommittee on the Classification of
Reproduction Toxic Substances of the Dutch Expert Committee on Occupational
Safety of the Health Council, hereafter called the Committee, evaluates the
effects on male and female fertility and on the development of the progeny.
Moreover, 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 triamcinolone, these recommendations are:
• for effects on fertility, the Committee recommends not classifying
    triamcinolone due to a lack of appropriate data
• for effects on development, the Committee recommends classifying
    triamcinolone in category 1B (presumed human reproductive toxicant) and
    labelling with H360D (may damage the unborn child)
• for effects on or via lactation, the Committee recommends not labelling
    triamcinolone due to a lack of appropriate data.
Executive summary                                                                   11
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<pre>  For triamcinolone acetonide, these recommendations are:
  • for effects on fertility, the Committee recommends not classifying
      triamcinolone acetonide due to a lack of appropriate data
  • for effects on development, the Committee recommends classifying
      triamcinolone acetonide in category 1B (presumed human reproductive
      toxicant) and labelling with H360D (may damage the unborn child)
  • for effects on or via lactation, the Committee recommends not labelling
      triamcinolone acetonide due to a lack of appropriate data.
2 Triamcinolone/Tramcinolone acetonide
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<pre> hapter 1
        Scope
1.1     Background
        As a result of the Dutch regulation on registration of compounds toxic to
        reproduction that came into force on 1 April 1995, the Minister of Social Affairs
        and Employment requested the Health Council of the Netherlands to classify
        compounds toxic to reproduction. This classification is performed by the Health
        Council’s Subcommittee on the Classification of Reproduction Toxic Substances
        of the Dutch Expert Committee on Occupational Safety (DECOS). The
        classification is performed according to European Union Regulation (EC) 1272/
        2008 on classification, labelling and packaging (CLP) of substances and
        mixtures. The CLP guideline is based on the Globally Harmonised System of
        Classification and Labelling of Chemicals (GHS). The subcommittee’s advice on
        the classification will be applied by the Ministry of Social Affairs and
        Employment to extend the existing list of compounds classified as reproductive
        toxicant (category 1A, 1B or 2) and compounds with effects on or via lactation.
1.2     Committee and procedure
        This present document contains the classification of triamcinolone and
        triamcinolone acetonide by the Health Council’s Subcommittee on the
        Classification of Reproduction Toxic Substances. The members of the
        Scope                                                                             13
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<pre>    Committee are listed in Annex A. The submission letter (in English) to the
    Minister can be found in Annex B.
    The classification is based on the evaluation of published human and animal
    studies concerning adverse effects with respect to fertility and development and
    lactation of the above mentioned compound.
    Classification for reproduction (fertility (F) and development (D):
    Category 1                    Known or presumed human reproductive toxicant (H360(F/D))
      Category 1A                 Known human reproductive toxicant
      Category 1B                 Presumed human reproductive toxicant
    Category 2                    Suspected human reproductive toxicant (H361(f/d)
    No classification for effects on fertility or development
    Classification for lactation:
                                  Effects on or via lactation (H362)
                                  No labelling for lactation
    The classification and labelling of substances is performed according to the
    guidelines of the European Union (Regulation (EC) 1272/2008) presented in
    Annex C. The classification of compounds is ultimately dependent on an
    integrated assessment of the nature of all parental and developmental effects
    observed, their specificity and adversity, and the dosages at which the various
    effects occur. The guideline necessarily leaves room for interpretation, dependent
    on the specific data set under consideration. In the process of using the
    regulation, the Committee has agreed upon a number of additional considerations
    (see Annex D).
    In 2012, the President of the Health Council released a draft of the report for
    public review. No comments were received.
1.3 Effects on or via lactation
    The recommendation for classifying substances for effects on or via lactation is
    also based on Regulation (EC) 1272/2008. The guideline defines that substances
    which are absorbed by women and have been shown to interfere with lactation or
    which may be present (including metabolites) in breast milk in amounts
    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
 4  Triamcinolone/Tramcinolone acetonide
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<pre>    risk characterization and therefore, it also includes consideration of the level of
    exposure of the breastfed child.
    Consequently, a substance should be labelled for effects on or via lactation when
    it is likely that the substance would be present in breast milk at potentially toxic
    levels. The Committee considers a concentration of a compound as potentially
    toxic to the breastfed child when this concentration exceeds the exposure limit
    for the general population, e.g. the acceptable daily intake (ADI).
1.4 Data
    Literature searches were conducted in the on-line databases XTOXLINE,
    MEDLINE and CAPLUS, up to January 2011 without a starting date. The final
    search was performed in PubMed in May 2012. Literature was selected primarily
    on the basis of the text of the abstracts. Publications cited in the selected articles,
    but not selected during the primary search, were reviewed if considered
    appropriate. References are divided in literature cited and literature consulted but
    not cited.
    The Committee describes both the human and animal studies in the text. The
    animal data are described in more detail in Annex E as well. Of each study the
    quality of the study design (performed according to internationally
    acknowledged guidelines) and the quality of documentation are considered for
    evaluation.
         In the assessment of the potential reproduction toxic effects of triamcinolone
    and triamcinolone acetonide, 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 toxic to reproduction is
         indicated.
    Scope                                                                                   15
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<pre>1.6 Final remark
    The classification of compounds is based on hazard evaluation only (Niesink
    et al., 199522), 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  Triamcinolone/Tramcinolone acetonide
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<pre>  hapter        2
                Triamcinolone and triamcinolone
                acetonide
2.1             Introduction
                The identity and some physicochemical properties of triamcinolone and
                triamcinolone acetonide are given below.
 hemical name                     : triamcinolone
  AS registry number              : 124-94-7
  C/EINECS number                 : 204-718-7
UPAC name                         : (11β,16α)-9-fluoro-11,16,17,21-tetrahydroxypregna-1,4-diene-3,20-dione
  AS name                         : pregna-1,4-diene-3,20-dione, 9α-fluoro-11,16,17,21-tetrahydroxy-,11β,16α-
 ynonyms                          : 9α-fluoro-16α-hydroxyprednisolone; 9α-fluoro-11β,16α,17α,21-tetrahydroxy-pregna-
                                    1,4-diene-3,20-dione; ∆1-9α-fluoro-16α-hydroxyhydrocortisone; ∆1-16α-hydroxy-9α-
                                    fluorohydrocortisone; 16α-hydroxy-9α-fluoroprednisolone
 olour and physical state         : fine, white or off-white, crystalline powder
molecular weight                  : 394.44
molecular formula                 : C21H27FO6
 tructural formula                :
melting point                     : 269-271 °C (mp also reported as 260-262.5 °C)
 ptical rotation                  : [α]25D = +75° (in acetone)
 apour pressure                   : 1x10-12 Pa (at 25 °C; estimated)
  og P(octanol-water)             : 1.16 (experimental)
                Triamcinolone and triamcinolone acetonide                                                          17
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<pre> olubility                         :  80 mg/L water (at 25 °C); 1 g soluble in 70 mL propylene glycol, and less than 20 mL
                                      dimethyl sulphoxide; soluble in dimethyl formamide; slightly soluble in alcohol and
                                      chloroform
 hemical name                      :  triamcinolone acetonide
  AS registry number               :  76-25-5
  C/EINECS number                  :  200-948-7
UPAC name (old)                    :  9-alpha-fluoro-11-beta,21-dihydroxy-16-alpha,17-alpha-isopropylidene-dioxypregna-
                                      1,4-diene-3,20-dione
  AS name                          :  pregna-1,4-diene-3,20-dione, 9-fluoro-11,21-dihydroxy-16,17-[(1-
                                      methylethylidene)bis(oxy)]-, (11β,16α)-
 ynonyms                           :  (11β,16α)-9-fluoro-11,21-dihydroxy-16,17-[(1-methylethylidene)bis(oxy)] pregna-1,4-
                                      diene-3,20-dione; 9α-fluoro-11β,16α,17,21-tetrahydroxypregna-1,4-diene-3,20-dione
                                      cyclic 16,17-acetal with acetone; 9α-fluoro-16α-hydroxyprednisolone acetonide;
                                      triamcinolone 16α,17-acetonide; 9α-fluoro-11β,21-dihydroxy-16α,17α-
                                      isopropylidenedioxy-1,4-pregnadiene-3,20-dione; 9α-fluoro-16α,17-
                                      isopropylidenedioxyprednisolone
 olour and physical state          :  white to cream coloured crystalline powder with slight odour
molecular weight                   :  434.50
molecular formula                  :  C24H31FO6
 tructural formula                 :
melting point                      :  292-294 °C
 ptical rotation                   :  [α]23D = +109° (c=0.75 in chloroform)
 apour pressure                    :  1.3x10-9 Pa (at 25 °C; estimated)
  og P(octanol-water)              :  2.53 (recommended: see http://logkow.cisti.nrc.ca/logkow/search.html)
 olubility                         :  practically insoluble in water; very soluble in dehydrated ethanol, chloroform, methanol;
                                      slightly soluble in ethanol; sparingly soluble in acetone and ethyl acetate
Data from5,21
                Triamcinolone and triamcinolone acetonide are glucocorticoid drugs applied for
                systemic and local anti-inflammatory activity. In the Netherlands, triamcinolone
                has been registered for oral use (tablets) in humans and triamcinolone acetonide
                for topical use in humans (ointment/cream; nasal spray; eye drops; suspensions
                for intramuscular, intra-articular, intrabursal injections) and cats and dogs
                (lotion; suspensions for intramuscular and subcutaneous injections).7
                Following intravenous injection of 3H-triamcionolone into dogs, the plasma half-
                life was about 116 min. The total radioactivity excreted within 72 hours in urine
                and faeces amounted to approximately 47 and 42%, respectively.11 Urine
                analyses revealed the presence of parent compound (20% of the dose injected),
  8             Triamcinolone/Tramcinolone acetonide
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<pre>6ß-hydroxytriamcinolone (25%), and a third compound (<5%), which had not
been identified but did not appear to be a glucuronide or sulphate conjugate.
Without presenting details, Florini et al. stated that a similar pattern of
metabolites was found in the urine of one human who received oral unlabeled
triamcinolone doses of 96 mg/day for three weeks.10 Following intravenous
injection into rats, the plasma half-life was about 52 min. Measured 40-60
minutes after injection, 3H-triamcinolone was primarily deposited in the muscle,
liver, intestine, skin and kidney. The total amount radioactivity excreted within
72 hours in urine and faeces amounted to approximately 26 and 56%,
respectively.11 Hochhaus et al. determined pharmacokinetic parameters of
triamcinolone following oral administration to human volunteers. Plasma half-
lives were approximately 165 min with maximum concentrations reached after
approximately 2 hours.16
When [14C-]-triamcinolone acetonide was orally administered to human
volunteers, peak plasma levels of triamcinolone acetonide and radioactivity were
found within 2 hours of administration. Within 24 hours, approximately 93% and
76% of the parent compound and total radioactivity were eliminated from the
plasma, respectively. Most of the radioactivity was excreted in the faeces and
urine within 72 and 24 hours, respectively, amounting to 51 and 37%,
respectively. Major metabolites identified in plasma, faeces and urine resulted
from oxidation at the C6 and C21 positions.2 In pharmacokinetic studies in
animals, generally similar excretion and biotransformation patterns were seen.
Hydrolysis of the acetonide moiety resulting in triamcinolone or triamcinolone
metabolites was not found to be a significant metabolic pathway.12,17 When 3[H]-
triamcinolone acetonide was injected intramuscularly into female A/J mice,
42%, 30%, and 2% of the administered dose was found 3 hours later at the
injection site, in bile and in urine, respectively. After 24 hours, some
radioactivity (1.3%) was present at the injection site, while bile/intestinal
contents/faeces and urine contained 66% and 15%, respectively. Given to
pregnant A/J, C3H, and CBA mice on gestational day 11.5, predominantly parent
compound was found in the placentas and embryos 0.5 hour after administration.
Concentrations of radioactivity in placentas and embryos of CBA mice were
about 40% lower than those in the other two strains. Thereafter, concentrations
fell markedly.37,38
Triamcinolone and triamcinolone acetonide                                         19
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<pre>2.2 Human studies
    Fertility studies
    Cunningham et al. (1975) investigated the possible ovulation-inhibiting activity
    of triamcinolone and triamcinolone acetonide in healthy women, aged 22-40,
    with a history of regular menstrual cycles. A group of six women received daily
    intramuscular injections of 12.5 mg of triamcinolone diacetate on days 1 and 2 or
    days 2 and 3 of the menstrual cycle. No menstrual irregularities were observed
    apart from an ovulation-inhibiting progesterone level (<1.0 ng/mL) in one
    subject. Another group of 11 women received 25 mg triamcinolone acetonide on
    day 1 or 2. Of these, seven had plasma progesterone levels <1.0 ng/mL, and six
    of these seven women had noted changes in the duration of the cycle and
    intermenstrual or post-menstrual spotting. Daily blood studies in three
    triamcinolone acetonide-treated subjects revealed that the normal midcycle surge
    of LH and FSH and the subsequent rise in progesterone were absent in each of
    these subjects. Using an incidence of 10.7% anovulatory cycles found in 430
    cycles of fertile women, aged 22-40, as a control, triamcinolone diacetate did not
    have an ovulation-inhibiting effect (p=0.8) while triamcinolone acetonide did
    (p=0.0001).8 Cunningham et al. (1978) confirmed this ovulation-inhibiting effect
    of triamcinolone acetonide in a mechanistic follow-up study.9
    Developmental toxicity studies
    Arduini and coworkers (1986) reported a double blind study in ten women at 35
    weeks of gestation. One group (n=5) received oral triamcinolone doses of 8 mg
    at 8:00, 16:00, and 24:00 hour for three consecutive days and the control group
    received a placebo. Blood cortisol, 17β-estradiol, unconjugated oestriol and
    ACTH (adrenocortiocotropin hormone) levels were measured every two hours
    and a 24-hour continuous recording of foetal heart rate beginning at 8:00 was
    performed on the third day of treatment and three weeks thereafter. At 35 weeks,
    the number of time periods during which foetuses were active as measured by
    foetal heart rate after treatment was increased in the treated group (p<0.001)
    compared to the placebo group, but not at 38 weeks. The placebo group showed
    similar incidence of activity at weeks 35 and 38. After treatment, a circadian
    heart rhythm was seen in week 38, but not in week 35, and in the placebo group
    in weeks 35 and 38. Simultaneously, maternal cortisol (p<0.001), oestriol
    (p<0.001) and ACTH (p<0.05) levels were reduced in the treated group
 0  Triamcinolone/Tramcinolone acetonide
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<pre>    compared to the placebo group in week 35, but not in week 38. 17β-Estradiol
    was not affected. Moreover, a loss of circadian variations of all hormones
    investigated was found in the treated group in week 35, but not in week 38 or in
    the placebo group. No differences were observed in infant weight and Apgar
    scores at birth.1
    Carmichael and coworkers (2007) reported a population-based case-control
    study on the possible association between corticosteroid use during pregnancy
    and orofacial clefts in offspring. The population consisted of deliveries occurring
    from October 1997 until December 2002 in eight US states. Exposures were
    assessed by telephone interviews for cases (1,141 with cleft lip ± cleft palate, 628
    with cleft palate) and controls (4,143). This yielded mothers of five infants with
    cleft lip ± cleft palate, mothers of one infant with cleft palate and nine control
    subjects, who reported triamcinolone use from four weeks before through 12
    weeks after conception. In this small study, no clear evidence was seen for an
    increased risk of cleft lip ± cleft palate (odds ratio 2.0; 95% CI 0.7-6.1) after
    triamcinolone use.6
        The Committee notes that it is not clearly indicated in the study whether
    triamcinolone use included use of triamcinolone or triamcinolone acetonide or
    both.
    Other epidemiological studies as cited in Carmichael et al.6 with therapeutic use
    of corticosteroids during pregnancy were available, but none included an
    adequate group of triamcinolone users and no specific conclusions for
    triamcinolone were drawn. It is also not clear whether triamcinolone or
    triamcinolone acetonide or other derivatives were used.
    Lactation
    There are no studies available regarding the effects of triamcinolone or its
    acetonide on human lactation. No reports on triamcinolone (acetonide)
    distribution into human breast milk were found. However, in general, systemic
    corticosteroids are distributed into breast milk.21
2.3 Animal studies
    Fertility and developmental toxicity studies in laboratory animals are
    summarized in Annex E. Generally, no data on effects in maternal animals due to
    Triamcinolone and triamcinolone acetonide                                            21
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<pre>  exposure to triamcinolone or triamcinolone acetonide were given in these
  studies.
  Fertility studies
  Triamcinolone
  Oral
  Selye et al. (1971) investigated the effect of several steroids on gestation in ARS/
  Sprague-Dawley rats (see below Developmental toxicity studies). Triamcinolone
  given by gavage at doses of 100 mg/kg bw twice daily on gestational days 2-6
  interrupted 8/11 pregnancies indicating preimplantation losses. No such effect
  was observed at doses of 10 mg/kg bw.28
  Subcutaneous
  Albino female rats (n=6) were given no drug or 0.1 mg/rat/day triamcinolone (ca.
  1 mg/kg bw/day) subcutaneously for 15 days. Twenty-four hours after the last
  injection rats were sacrificed and very limited investigations were made. Relative
  uterus and ovary weights were significantly decreased (p<0.01) in the
  triamcinolone-treated group. Ovarian alkaline phosphatase activity was
  significantly decreased (p<0.01). Histological investigation of the ovaries
  revealed no morphological changes.27
      The Committee notes that in this study, ‘triamcinolone’ was not further
  specified. In view of the route of administration and the dose, it could have been
  triamcinolone acetonide (see developmental toxicity studies below).
  Triamcinolone acetonide
  Intramuscular injection of daily doses of 4 mg of triamcinolone acetonide into
  baboons (n=5-8/group) during selected times of the menstrual cycle inhibited
  ovulation and shortened menstrual cycles.13
2 Triamcinolone/Tramcinolone acetonide
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<pre>Developmental toxicity studies
Triamcinolone
Oral
Bishop and coworkers (1985a) investigated the effect of administration of a diet
supplemented with soybean oil or soybean oil plus 70 mg triamcinolone to sows
(n=38-40) daily for on average the last ten days pre-partum. The 70-mg dose was
based on the level of triamcinolone per unit of metabolic weight (kg0.75) that had
been determined to result in a gluconeogenic response in growing rats and pigs.
The triamcinolone treatment had not affected sow weight gains and feed intake
during the 28-day lactation period. The colostrum fat content had increased by
21% compared to soybean-supplemented diet.3
In a subsequent study (Bishop, 1985b) in which sows (n=6-7) were given the
same diet and dose of triamcinolone for the last seven days of gestation, fat
percentage of colostrum was not affected. Triamcinolone did not affect the
number of stillbirths and the litter size up to 28 days of age, but did increase the
piglet weight at birth and at 14 and 28 days of age. After weaning till 165 days of
age, no significant effect on body weight of piglets was noted. At weaning (28
days), liver glycogen percentage and serum glucose were not affected, whereas
adrenal weight was decreased. In the subsequent study, litter size and birth
weight were not affected, nor were liver glycogen percentage and serum glucose
level (adrenal weight was not measured). Carcass protein and fat were increased,
which did not occur in the first study, although colostrum fat content had
increased in the first study.4
Gravid sows (n=5-7) were given a standard diet or a diet supplemented with 70
mg/kg bw/day of triamcinolone from gestational day 106 through parturition.
One or two pairs of littermate boars were selected from each litter and followed
till 30 weeks of age for effects on the gonadotropin-gonadal system and the onset
of puberty and post-puberal development. The body weight and testicular
volume of the boars were not affected. Although the plasma testosterone
concentration was slightly increased at week 16-28 in treated boars, the level at
the end of the study was comparable to that in the control group. Plasma cortisol
levels were not affected nor were the adrenal weights. Statistically significant
differences between treated and control boars with respect to onset and frequency
Triamcinolone and triamcinolone acetonide                                            23
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<pre>  of mounting and ejaculation indicated that triamcinolone induced acceleration of
  the development of sexual behaviour and earlier onset of puberty. At sacrifice,
  weights of testes, epididymides, seminal vesicles, bulbourethral glands and
  prostate gland were increased (p<0.10) in the triamcinolone group. The
  incidence of cytoplasmic droplets on spermatozoa recovered from the cauda
  epididymides was similar between treated and control groups, suggesting boars
  were at a similar level of sexual maturity physiologically at sacrifice.36
  Walker (1965) administered doses of 0.01 and 0.02 mg triamcinolone diacetate/
  day by gavage to A/J mice on gestational days 11-14 and one dose of 0.02 mg on
  gestational day 14. At gestational day 18, dams were killed. Foetuses were
  removed and their palate morphology investigated. No palate abnormalities were
  seen in foetuses of the low-dose (3 litters; 22 foetuses) and the single-dose group
  (3 litters; 26 foetuses). In the high-dose group (3 litters), 12 foetuses had normal
  palate morphology while cleft palate was seen in seven.33
  Selye et al. (1971) investigated the effect of several steroids on gestation in rats.
  Triamcinolone was given at a dose of 100 mg/kg bw twice daily on gestational
  days 4-8, 9-13, or 15-19. Cholesterol was given as a negative control at a similar
  dose and scheme. Eight days after insemination, successful fertilization was
  checked by a direct inspection of the uterus via a small laparotomy incision.
  Dams were allowed to give birth. If dams failed to give birth by the end of the
  23rd day, they were killed. For the group receiving cholesterol, no pregnancies
  were interrupted (i.e., total litter aborted or resorbed) when given in any stage of
  pregnancy. For triamcinolone, all pregnancies were interrupted. A lower dose of
  5 mg triamcinolone/kg bw given during gestational days 2-19 induced total
  abortion/resorption in 4/9 dams.28
  Subcutaneous
  Walker (1971) studied the induction of cleft palate by several anti-inflammatory
  drugs including triamcinolone in a limitedly described study. Rats were injected
  subcutaneously with 0.01 to 0.5 mg once daily on gestational days 12-15. No
  control group was included. Pregnant rats were killed at gestational day 19, and
  the uterus with foetuses was fixated, the lower jaw of the foetuses was removed
  and the condition of the palate recorded. At doses of 0.2 and 0.5 mg/day, two
  pregnant rats died before the end of gestation as did one rat at 0.1 mg/day. At
  doses of 0.01, 0.05 and 0.1 mg/day, two, eight and four litters could be examined,
  respectively. The total number of embryos was 27, 95 and 30 at 0.01, 0.05 and
4 Triamcinolone/Tramcinolone acetonide
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<pre>0.1 mg/day with no, three and six embryos resorbed, respectively. Cleft palate
was seen in 0, 45 and 80% of foetuses.35
Walker (1971) also reported that A/J mice given a single subcutaneous dose of
0.0175 mg/mouse/day on gestational day 11-14 and killed four days after the last
injection resulted in five resorptions in seven litters. Cleft palate was found in 44
out of 52 embryos, of which three had a combination of cleft lip-cleft palate. No
control group was included.35
Intramuscular
Rowland and Hendrickx (1983) compared the relative cleft palate inducing
potencies of triamcinolone, triamcinolone acetonide and cortisol in rats. On
gestational day 13, which was determined to be the most sensitive day for cleft
palate induction by triamcinolone acetonide, pregnant rats (n=10-11) were
intramuscularly injected with physiological saline or 10, 20 or 40 mg/kg bw
triamcinolone. Dams were killed on gestational day 20 and the number of live
foetuses and resorptions were counted. Live foetuses were weighed and
examined for external malformations. In the treated groups, there was no
statistically significant increase in either the percentage resorptions per litter or
the proportion of litters with at least one resorption. Triamcinolone treatment
resulted in statistically significantly, dose-relatedly decreased foetal weights at
20 and 40 mg/kg bw. At 10, 20 and 40 mg/kg bw, 45.5, 80 and 91%, respectively,
of the litters had cleft palates (controls: 0%) and 7.5, 20 and 34%, respectively of
the foetuses (controls: 0%). Foetuses with umbilical hernias were present in
triamcinolone-treated groups (not statistically significant), but not in the control
group. The ED50 (the dose causing cleft palate in 50% of the animals) value was
calculated to be 65 mg/kg bw. For triamcinolone acetonide, the ED50 was 1.1 mg/
kg bw, indicating that the relative cleft palate-inducing potency of triamcinolone
acetonide was about 59 times that of triamcinolone.25
Walker (1967) exposed New Zealand White rabbits daily to intramuscular doses
ranging from 0.01 to 5.0 mg/rabbit on gestational days 13-16 resulting in an
increased number of resorbed litters and of cleft palates at doses ≥1.0 and ≥0.10
mg, respectively. American Dutch rabbits given doses from 0.01 to 4.0 mg/rabbit
intramuscularly on gestation days 13-16 showed an increased number of
resorbed foetuses and cleft palates at doses ≥0.10 and ≥0.30 mg, respectively. All
foetuses with cleft palate had both palatine shelves lying in a transverse plane,
but separated throughout their length.34
Triamcinolone and triamcinolone acetonide                                             25
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<pre>  Shah (1976) investigated cleft palate induction in hamsters. Mated hamsters
  (n=3-4) were injected intramuscularly with triamcinolone doses of 0.25, 0.5, 1.0,
  2.5 and 5.0 mg in water on gestational day 11. A vehicle control group was
  included. Dams were killed on gestational day 15 and viable foetuses were
  weighed, fixated and examined for cleft palate development. Foetal weight was
  decreased at all doses. The number of live foetuses in the treated groups varied
  between 25 and 30 (vs. 31 in controls). At doses of 0.25, 0.5, 1.0, 2.5 and 5.0 mg,
  the percentages of resorptions were 3, 0, 17, 8 and 30, respectively (vs. 0% in
  controls) and percentages of foetuses with cleft palate 24, 42, 100, 100 and 100,
  respectively (vs. 0% in controls). The morphology of cleft palate varied with
  more partial cleft palates and less complete cleft palates at lower doses.31
  In subsequent studies, Shah (1979, 1980) reported on sequential morphological
  observations of triamcinolone-induced cleft palate in hamster foetuses. Pregnant
  hamsters (n=not specified) were given single intramuscular injections of 0 or 4
  mg triamcinolone on gestational day 11. Subsequently, dams were killed at two-
  to four-hour intervals until gestational day 13 and on gestational days 14 and 15
  and foetal heads were examined. Normal palatogenesis was completed between
  gestational days 12 and 13. It was shown that 32 hours after treatment
  triamcinolone caused basal cell necrosis and delayed differentiation of
  mesenchymal cells, thereby disrupting the timing of coordinated development of
  the palatal tissues. The delayed reorientation occurred before any general
  retardation of foetal growth as indicated by decreased crown-rump length and
  foetal weight after gestational day 13.29,30
  Based on the findings in their study that triamcinolone was less potent in
  inducing cleft palate than triamcinolone acetonide (see above), Rowland and
  Hendrickx (1983)25 assumed that the substance administered in the subcutaneous
  study of Walker (1971)35 and the intramuscular studies of Walker (1967)34 and
  Shah29-31 was triamcinolone acetonide and not triamcinolone.
  Triamcinolone acetonide
  Subcutaneous
  Walker (1965) injected daily doses of 0.006 mg of triamcinolone acetonide
  subcutaneously into A/J mice on gestational days 11-14. At gestational day 18,
  dams were killed. Foetuses were removed and their palate morphology
6 Triamcinolone/Tramcinolone acetonide
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<pre>investigated. There was no increase in the number of litters resorbed but there
was a high frequency of cleft palate in the foetuses examined (65%).33
Kusagani performed a series of experiments on the occurrence and dose-
response relationships of cleft palate, palatal slit and foetal mortality in mice
treated with triamcinolone acetonide.
     In the first experiment, C57BL/6 and SWV female mice were administered
subcutaneously single doses of 0, 1.0, 2.5, 4.0, 5.0 or 7.0 and 0, 1.0, 2.5 or 5.0
mg/kg bw, respectively, at gestational day 12. At gestational day 18, the dams
were killed and their uterine contents were examined immediately. In C57BL/6
mice, the number of resorptions/implantations did not significantly differ from
the control group. Treatment caused statistically significant dose-related
increases in the frequency of cleft palate development in live foetuses (0/209,
0%; 0/81, 0%; 16/119, 13%; 32/113, 28%; 27/82, 33%; 72/103, 70%,
respectively) and in palatal slit in live-cleft palate foetuses (12/209, 6%; 25/81,
31%; 36/103, 35%; 36/81, 44%; 34/55, 62%; 21/31, 68%, respectively). In SWV
mice, the number of resorptions/implantations (15/213, 7%; 14/143, 10%;
61/220, 28%; 67/170, 39%) and the frequency of cleft palate development in live
foetuses (0/198, 0%; 14/129, 11%; 79/159, 50%; 86/103, 83.5%, respectively)
were statistically significantly increased, whereas no changes were observed
concerning palatal slit development in cleft palate-live foetuses.19
In the second experiment, Kusagani transferred blastocysts recovered from the
uterus on gestational day 3 of untreated females to the right uterine horn of day 2
pseudopregnant females. Subsequently, these females were given a single
subcutaneous injection of triamcinolone acetonide at a dose of 2.5 mg/kg bw,
based on the gestational age (day 12) of recipient females. All animals (including
untreated females) were killed at gestational day 18. Kusagani concluded that ‘in
cleft palate induction by triamcinolone acetonide, the effects of uterine environment are
more important than those of fetal genotype, whereas in palatal slit occurrence the reverse
is true’. The SWV mice were less sensitive to exposure to triamcinolone
acetonide than the C57BL/6 mice.18
The third experiment was performed with C57BL/6 mice only, and focused on
the most sensitive developmental stages during pregnancy. The highest number
of resorbed litters ranged around treatment at gestation days 9 (lowest dose, 2.5
mg/kg bw) to 11 (highest dose, 5 mg/kg bw). The frequencies of cleft palate
development and palatal slits in cleft-palate live foetuses peaked at around
gestation day 12 (in both dose groups).20
Triamcinolone and triamcinolone acetonide                                                   27
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<pre>  Intramuscular
  Hendrickx et al. (1975) treated bonnet and rhesus monkeys, and baboons
  intramuscularly at various doses (range: 1-28 mg/kg bw) and at various
  gestational days (range: day 37-133), depending on the species. Foetuses were
  delivered by Caesarean section at gestational day 100, near term or naturally. Of
  each species, also ten untreated control foetuses were included. Effects observed
  in treated animals included: resorption (rhesus monkey only); intrauterine death
  (in all species used); malformations in the skeleton (all species), liver (one rhesus
  monkey), kidneys (one bonnet monkey), thymus (in particular in bonnet and
  rhesus monkeys) and lymphocytes (in surviving baboon offspring).15 The
  Committee noted that no statistical analyses have been performed.
  The same research group studied more specifically craniofacial and central
  nervous system malformations using the same animal species and a comparable
  study design. Treatment caused increases in prenatal death and stillbirths among
  bonnet and rhesus monkeys, but not among baboons. Furthermore, multiple
  cranial and central nervous system malformations were found in all species,
  although the type of malformations differed somewhat depending on type of
  species. No statistical analyses have been performed.14
  Further, this research group reported specifically on craniofacial malformations
  in rhesus monkeys (n=10/group) following intramuscular injections of
  triamcinolone acetonide of 10 mg/kg bw at gestational days 23, 25, 27, 29 and
  31. Ten untreated pregnant animals served as controls. Offspring were removed
  by hysterotomy on gestational days 35 and 42 (single mate), and on days 50, 60
  and 70 (multiple mate). Examination of rhesus embryos, which were obtained on
  gestational day 35, did not show gross abnormalities, but histological
  examination revealed a shortened anlage of the posterior cranial base. Embryos
  and foetuses obtained on the other gestational days showed craniofacial
  dysmorphia, encephalocele, malformations in the sphenoid bone, decreased
  ossification and remodelling on the facial bones, and abnormal position, due to
  the malformed sphenoid.23 In addition, on closer examination, Tarara et al.
  (1988) suggested that the encephalocele may have resulted from a combination
  of mesenchymal and neural tube malformations.32
  Walker (1965) injected daily doses of 0.0005-0.5 mg of triamcinolone acetonide
  intramuscularly into A/J mice on gestational days 11-14 and single doses of 0.05
  mg on gestational day 11 and of 0.0125 mg at gestational day 12, 13 or 14.
8 Triamcinolone/Tramcinolone acetonide
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<pre>At gestational day 18, dams were killed. Foetuses were removed and their palate
morphology investigated. Doses of 0.025-0.5 mg/day caused (almost) complete
resorption. Doses of 0.001-0.125 mg/day caused a dose-dependent increase in
frequency of cleft palate ranging from 18 to 100%. No effect was seen at the dose
of 0.0005 mg/day. Single doses also induced cleft palates in some foetuses.
Occasionally, cleft lip and cleft palate were seen.
     129/J, C3H/HeJ, C57BL/6J and DBA/IJ mice were treated similarly on
gestational days 11-14 with doses of 0.001-0.025 (129/J mice) or 0.0125 mg/day
(other strains). In 129/J mice, there was an increase in the number of resorbed
litters at doses ≥0.003 mg/day and in the frequency of cleft palate at doses
≥0.0125 mg/day. The dose of 0.0125 mg/day caused increases in the frequencies
of cleft palate in the C3H/HeJ, C57BL/6J and DBA/IJ, a small increase in the
number of resorbed foetuses in DBA/IJ mice and almost complete resorption in
C57BL/6J mice (no resorptions were seen in C3H/HeJ mice).33
Rowland and Hendrickx (1983) gave Sprague-Dawley rats intramuscular
injections of 0.125, 0,25 or 0,5 mg/kg bw, daily on gestational days 9-11, 12-14
or 15-17. A vehicle control group was included. Dams were killed on gestational
day 20, and foetuses were recovered and prepared for gross and histological
examination. No maternal lethality occurred in any of the treated animals. No
developmental effects were observed in the groups exposed on gestational days
9-11. In the groups treated on gestational days 12-14, there were dose-related
decreases in the percentages of viable foetuses/litter (89%, not statistically
significant; 77%, p≤0.05; 58%, p≤0.01, respectively; controls: 97%), and
increases in the percentages of litters with malformed foetuses (45%, not
statistically significant; 80%, p≤0.05; 100%, p≤0.05; controls: 9%), and of
malformed foetuses/litter (29%, not statistically significant; 61%, p≤0.05; 84%,
p≤0.05; controls: 2%). The incidences of specific malformations, expressed as
percentage of foetuses/litter were: for cleft palate: 23/45 (p≤0.05), 54/60
(p≤0.05) and 70/80 (p≤0.05), vs. 0/0 in controls; for umbilical hernias: 3/9, 20/50
(p≤0.05) and 58/80 (p≤0.05), vs. 0/0 in controls; and for undescendent testes:
0/0, 7/12.5 and 28/60 (p≤0.05), vs. 0/0 in controls. In the gestational days 15-17
groups, only the high-dose group was affected showing decreased percentages of
viable foetuses/litter (29% vs. 96% in controls; p≤0.05), and increased
percentages of litters with malformed foetuses (62.5% vs. 0% in controls;
p≤0.05) and of malformed foetuses/litter (32% vs. 0% in controls; p≤0.05).
Specific malformations observed were cleft palate in 19% of the foetuses
(p≤0.05) and 50% of the litters (not significant) and hypoplastic thymus in 22%
of the foetuses (p≤0.05) and 37.5% of the litters (not significant).26
Triamcinolone and triamcinolone acetonide                                           29
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<pre>  In another study, Rowland and Hendrickx (1983) compared the relative cleft
  palate inducing potencies of triamcinolone, triamcinolone acetonide and cortisol
  in rats. Rats (n=10-11) were intramuscularly injected with physiological saline or
  0.5, 2.5 or 5.0 mg/kg bw triamcinolone acetonide on gestational day 13, which
  was determined to be the most sensitive day for cleft palate induction by
  triamcinolone acetonide. Dams were killed on gestational day 20 and the number
  of live foetuses and resorptions were counted. Live foetuses were weighed and
  examined for external malformations. Treatment did not cause statistically
  significant increases in either the percentage resorptions per litter or the
  proportion of litters with at least one resorption. In the groups receiving 2.5 or
  5.0 mg/kg, there were increases in the proportion of litters with at least one foetal
  death (9/10, 90% and 7/9, 78%, respectively; controls: 0/10, 0%; p<0.05) and in
  the mean percentage of dead foetuses per litter (32 and 44%, respectively;
  controls; 0%; p<0.05). Mean foetal weights were statistically significantly
  decreased in all male dose groups and in the two higher female dose groups. At
  0.5, 2.5 and 5.0 mg/kg bw, 50, 100 and 100%, respectively, of the litters had cleft
  palates (controls: 0%; p<0.05 and p<0.005) and 21, 79 and 92%, respectively, of
  the foetuses (controls: 0%; p<0.005). In the two higher dose groups, umbilical
  hernias were observed in all litters and in 94.5 and 82%, respectively, of the
  foetuses. Triamcinolone acetonide was found to be a more potent cleft palate
  inducer than triamcinolone (see above).25
  Rotschild et al. (1997) studied the effects of triamcinolone acetonide in the
  airways and lungs of rat foetuses. Sprague-Dawley rats (n=3-5/group) received
  intramuscular injections of doses of 0.6 mg/kg bw/day on gestational day 12-14.
  Non-treated pregnant controls were included. Foetuses were removed on
  gestational days 15, 17, 18 and 21, and underwent gross and histological
  examination. On lung tissue, morphometric analysis was performed. Statistically
  significantly reduced maternal weight gain, foetal weight, placental weight and
  amniotic fluid weight were observed in the treated groups compared to controls.
  There was no significant difference in litter size between the groups. Cleft palate
  was found to be increased in the exposed foetuses pooled from gestational day 18
  and 20 (69/80 vs.1/100 in controls). Regarding pulmonary airways, the
  investigators found profound pulmonary hypoplasia in treated groups, which was
  accompanied by diminished number of intermediate airways, increased number
  of peripheral saccules and increased differentiation.24
0 Triamcinolone/Tramcinolone acetonide
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<pre>    Lactation
    No studies were found regarding the effects of triamcinolone or triamcinolone
    acetonide on or via lactation in laboratory animals.
2.4 Conclusion
    Triamcinolone
    Triamcinolone did not have an ovulation-inhibiting effect when given
    intramuscularly to six women during the first three days of the menstrual cycle.8
        In rats, oral administration on gestational days 2-6 caused preimplantation
    loss.28
        Overall, the Committee proposes not to classify triamcinolone for effects on
    fertility due to the absence of information on effects following relevant routes.
    Both human and animal data were available to evaluate the developmental
    toxicity of triamcinolone.
        In a small double blind study, oral treatment in week 35 of pregnancy
    resulted in transient effects on foetal activity and circadian heart rhythm but did
    not affect infant weight and Apgar scores at birth.1
        In a small population-based case-control study investigating use of
    triamcinolone and cleft lip ± cleft palate, no clear evidence was found for an
    increased risk.6 However, it was not clear whether triamcinolone use included
    use of triamcinolone or triamcinolone acetonide or both.
        Oral administration to sows for the last 10 days pre-partum, did not affect
    pregnancy outcome or piglets3,4, when given from gestational day 106 through
    parturition, triamcinolone induced an acceleration of development of sexual
    behaviour and an earlier onset of puberty in their male offspring.36 In laboratory
    animals, oral administration of triamcinolone caused interruption of pregnancies
    (postimplantation loss) in rats28 and an increased number of foetuses with cleft
    palate in a limited study in mice33. The latter finding was supported by the results
    of an intramuscular rat study. It was not reported whether effects were seen in the
    presence or absence of maternal toxicity.
        Overall, the Committee concludes that the human data are not sufficient for
    classification. The Committee is further of the opinion that the effects observed
    in laboratory animals occurred independent of any maternal toxicity. Therefore,
    based on the effects observed in laboratory animals, the Committee proposes to
    Triamcinolone and triamcinolone acetonide                                            31
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<pre>  classify triamcinolone for developmental effects in category 1B (presumed
  human reproductive toxicant).
  There were no human or animal data on effects on or via lactation of
  triamcinolone. Therefore, the Committee proposes not labelling triamcinolone
  for effects on or via lactation because of a lack of data.
  Proposed classification for fertility
  Lack of appropriate data precludes the assessment of triamcinolone for effects on
  fertility.
  Proposed classification for developmental toxicity
  Category 1B, H360D.
  Proposed labelling for effects on or via lactation
  Lack of appropriate data precludes the assessment of triamcinolone for effects on
  or via lactation.
  Triamcinolone acetonide
  Triamcinolone acetonide had an ovulation-inhibiting effect in 7/11 women when
  given intramuscularly during one of the first two days of the menstrual cycle.8
      Intramuscular injection into baboons during selected times of the menstrual
  cycle inhibited ovulation and shortened menstrual cycles.13
      Overall, the Committee proposes not to classify triamcinolone acetonide for
  effects on fertility due to a lack of appropriate human and animal data.
  In a small population-based case-control study investigating use of triamcinolone
  and cleft lip ± cleft palate, no clear evidence was found for an increased risk.6
  However, it was not clear whether triamcinolone use included use of
  triamcinolone or triamcinolone acetonide or both.
      In laboratory animals, viz, monkeys14,15,23,32, rats24-26 and mice18-20,33,
  triamcinolone acetonide induced high rates of cleft palate. It was generally not
  reported whether this effect was seen in the presence or absence of maternal
  toxicity, but the Committee is of the opinion that this occurred independent of
  maternal toxicity. All the studies used routes (subcutaneous and intramuscular
2 Triamcinolone/Tramcinolone acetonide
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<pre>injection) less relevant to occupational exposure. Kinetic studies showed that
triamcinolone acetonide is systemically absorbed following oral administration
to human volunteers.2 In addition, triamcinolone caused developmental effects
following oral administration (see afore). Based on these findings, the
Committee assumes that occupational exposure to triamcinolone acetonide could
lead to internal exposures.
    Overall, based on the effects observed in laboratory animals, the Committee
proposes to classify triamcinolone acetonide for developmental effects in
category 1B (presumed human reproductive toxicant).
There were no human or animal data on effects on or via lactation of
triamcinolone acetonide.
    Therefore, the Committee proposes not labelling triamcinolone acetonide for
effects on or via lactation because of a lack of data.
Proposed classification for fertility
Lack of appropriate data precludes the assessment of triamcinolone acetonide for
effects on fertility.
Proposed classification for developmental toxicity
Category 1B, H360D.
Proposed labelling for effects on or via lactation
Lack of appropriate data precludes the assessment of triamcinolone acetonide for
effects on or via lactation.
Triamcinolone and triamcinolone acetonide                                        33
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<pre>4 Triamcinolone/Tramcinolone acetonide</pre>

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<pre>References
Arduini D, Rizzo G, Parlati E, Giorlandino C, Valensise H, Dell'Acqua S, et al. Modifications of
ultradian and circadian rhythms of fetal heart rate after fetal-maternal adrenal gland suppression:
a double blind study. Prenat Diagn 1986; 6: 409-417.
Argenti D, Jensen BK, Hensel R, Bordeaux K, Schleimer R, Bickel C, et al. A mass balance study to
evaluate the biotransformation and excretion of [14C]-triamcinolone acetonide following oral
administration. J Clin Pharmacol 2010; 40: 770-780.
Bishop TC, Stahly TS, Cromwell GL. Effects of dietary additions of fat and triamcinolone for sows
during late gestation on subsequent pig performance. J Anim Sci 1985; 61: 1467-1475.
Bishop TC, Stahly TS, Cromwell GL. Effects of dietary fat and triamcinolone additions during late
gestation on the body energy reserves of neonatal pigs. J Anim Sci 1985; 61: 1476-1484.
Budavari S, O'Neil M, Smith A, Heckelman P, Obenchain J, editors. Triamcinolone. In: The Merck
Index; an encyclopedia of chemicals, drugs, and biologicals. Whitehouse Station NJ, USA: Merck &
Co, Inc.; 1996.
Carmichael SL, Shaw GM, Ma C, Werler MM, Rasmussen SA, Lammer EJ. Maternal corticosteroid
use and orofacial clefts. Am J Obstet Gynecol 2007; 197: 585.e1-585.e7.
College ter Beoordeling van Geneesmiddelen (Medicines Evaluation Board) (CBG-MEB). 2012.
Internet: http://www.cbg-meb.nl/CBG/nl/humane-geneesmiddelen/geneesmiddeleninformatiebank/
default.htm [cited May 2011].
Cunningham GR, Caperton EM Jr, Goldzieher JW. Antiovulatory activity of synthetic corticoids.
J Clin Endocrinol Metab 1975; 40: 265-267.
Cunningham GR, Goldzieher JW, de la Pena A, Oliver M. The mechanism of ovulation inhibition by
triamcinolone acetonide. J Clin Endocrinol Metab 1978; 46: 8-14.
References                                                                                          35
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<pre>0 Florini JR, Peets EA, Buyske DA. Plasma half-life, tissue distribution, and excretion of
  triamcinolone-H3. J Pharmacol Exp Ther 1961; 131: 287-293.
1 Florini JR, Smith LL, Buyske DA. Metabolic fate of a synthetic corticosteroid (triamcinolone) in the
  dog. J Biol Chem 1961; 236: 1038-1042.
2 Gordon S, Morrison J. The metabolic fate of triamcinolone acetonide in laboratory animals. Steroids
  1978; 32: 25-35.
3 Hagino N. The effect of synthetic corticosteroids on ovarian function in the baboon. J Clin
  Endocrinol Metab 1972; 35: 716-721.
4 Hendrickx AG, Pellegrini M, Tarara R, Parker R, Silverman S, Steffek AJ. Craniofacial and central
  nervous system malformations induced by triamcinolone acetonide in nonhuman primates: I. General
  teratogenicity. Teratology 1980; 22: 103-114.
5 Hendrickx AG, Sawyer RH, Terrell TG, Osburn BI, Henrickson RV, Steffek AJ. Teratogenic effects of
  triamcinolone on the skeletal and lymphoid systems in nonhuman primates. Fed Proc 1975; 34:
  1661-1667.
6 Hochhaus G, Pörtner M, Barth J, Möllmann H, Rohdewald P. Oral bioavailability of triamcinolone
  tablets and a triamcinolone diacetate suspension. Pharm Res 1990; 7: 558-560.
7 Kripalani KJ, Cohen AI, Weliki I, Schreiber EC. Metabolism of triamcinolone acetonide-21-
  phosphate in dogs, monkeys, and rats. J Pharm Sci 1975; 64: 1351-1359.
8 Kusanagi T. Dose-response relations of palatal slit, cleft palate, and fetal mortality in mice treated
  with a glucocorticoid. Teratology 1983; 28: 165-168.
9 Kusanagi T. Occurrence of cleft palate, palatal slit, and fetal death in mice treated with a
  glucocorticoid: an embryo transfer experiment. Teratology 1983; 27: 395-400.
0 Kusanagi T. Sensitive stages and dose-response analyses of palatal slit and cleft palate in C57BL/6
  mice treated with a glucocorticoid. Teratology 1984; 29: 281-286.
1 National Library of Medicine (NLM), editor. Triamcinolone. In: Hazardous Substances Data Bank
  (HSDB) [cited January 2011] .
2 Niesink RJM, de Vries J, Hoolinger MA, editors. Toxicology, principles and applications. Boca
  Raton FL, USA: CRC Press; 1995.
3 Parker RM, Hendrickx AG. Craniofacial and central nervous system malformations induced by
  triamcinolone acetonide in nonhuman primates: II. Craniofacial pathogenesis. Teratology 1983; 28:
  35-44.
4 Rotschild A, Solimano A, Sekhon HS, Massoud EA, Thurlbeck WM. Effect of triamcinolone
  acetonide on the development of the pulmonary airways in the fetal rat. Pediatr Pulmonol 1997; 23:
  76-86.
5 Rowland JM, Hendrickx AG. Comparative teratogenicity of triamcinolone acetonide, triamcinolone,
  and cortisol in the rat. Teratog Carcinog Mutagen 1983; 3: 313-319.
6 Rowland JM, Hendrickx AG. Teratogenicity of triamcinolone acetonide in rats. Teratology 1983; 27:
  13-18.
6 Triamcinolone/Tramcinolone acetonide
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<pre>7 Sarkar SL. Effects of natural and semisynthetic adrenal cortical hormones on the gonads of adult
  female albino rats. Ind J Physiol Pharmacol 1967; 11: 153-157.
8 Selye H, Taché Y, Szabo S. Interruption of pregnancy by various steroids. Fertil Steril 1971; 22:
  735-740.
9 Shah RM. Cleft palate development in hamster embryos following triamcinolone treatment. J Anat
  1979; 129: 531-539.
0 Shah RM. Ultrastructural observations on the development of triamcinolone-induced cleft palate in
  hamsters. Invest Cell Pathol 1980; 3: 281-294.
1 Shah RM, Kilistoff A. Cleft palate induction in hamster fetuses by glucocorticoid hormones and their
  synthetic analogues. J Embryol Exp Morphol 1976; 36: 101-108.
2 Tarara RP, Hendrickx AG. Central nervous system malformations induced by triamcinolone
  acetonide in nonhuman primates: pathogenesis. Teratology 1988; 38: 259-270.
3 Walker BE. Cleft palate produced in mice by human-equivalent dosage with triamcinolone. Science
  1965; 149: 862-863.
4 Walker BE. Induction of cleft palate in rabbits by several glucocorticoids. Proc Soc Exp Biol Med
  1967; 125: 1281-1284.
5 Walker BE. Induction of cleft palate in rats with antiinflammatory drugs. Teratology 1971; 4: 39-42.
6 Zavos PM, Stahly TS. Sexual development and performance in boars exposed prenatally to
  triamcinolone. Theriogenology 1988; 30: 137-148.
7 Zimmerman EF, Bowen D. Distribution and metabolism of triamcinolone acetonide in inbred mice
  with different cleft palate sensitivities. Teratology 1972; 5: 335-344.
8 Zimmerman EF, Bowen D. Distribution and metabolism of triamcinolone acetonide in mice sensitive
  to its teratogenic effects. Teratology 1972; 5: 57-70.
  Literature consulted but not cited
  Goulding EH, Watanabe T, Pratt RM. Normal and abnormal development in whole embryo culture.
  Environ Health Perspect 1987; 75: 137-138.
  Gur C, Diav-Citrin O, Shechtman S, Arnon J, Ornoy A. Pregnancy outcome after first trimester
  exposure to corticosteroids: a prospective controlled study. Reprod Toxicol 2004;18: 93-101.
  Hahn T, Barth S, Graf R, Engelmann M, Beslagic D, Reul JMHM, et al. Placental glucose transporter
  expression is regulated by glucocorticoids. J Clin Endocrinol Metab 1999; 84: 1445-1452.
  Kavlock RJ, Short RD Jr, Chernoff N. Further evaluation of an in vivo teratology screen. Teratog
  Carcinog Mutagen 1987; 71: 7-16.
  Kenny FM, Preeyasombat C, Spaulding JS, Migeon C J. Cortisol production rate. IV. Infants born of
  steroid-treated mothers and of diabetic mothers. Infants with trisomy syndrome and with
  anencephaly. Pediatrics 1966; 37: 960-966.
  Kulin HE, Metzl K, Peterson R. Urinary tetrahydrocortisone and tetrahydrocortisol in infants born of
  mothers treated with corticosteroids during pregnancy. J Pediatr 1966; 69: 648-651.
  References                                                                                           37
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<pre>  Llorca G, Garrel D. Effects of corticosteroids on skeletal growth in mice. Sem Hop 1988; 64: 513-
  525.
  Shah RM. Morphological, cellular, and biochemical aspects of differentiation of normal and
  teratogen-treated palate in hamster and chick embryos. Curr Top Dev Biol 1984; 19: 103-35.
  Zaki FG. Effects of steroids on fetal rat liver. Proc Electron Microsc Soc Amer 1969; 27: 350-351.
8 Triamcinolone/Tramcinolone acetonide
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<pre>A The Committee
B The submission letter (in English)
C Regulation (EC) 1272/2008 of the European Community
D Additional considerations to Regulation (EC) 1272/2008
E Comments on the public draft
F Fertility and developmental toxicity studies
  Annexes
                                                         39
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<pre>0 Triamcinolone/Tramcinolone acetonide</pre>

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<pre>nnex A
     The Committee
     •  A.H. Piersma, chairman
        Professor of Reproductive and Developmental Toxicology, National Institute
        of Public Health and the Environment, Bilthoven
     •  D. Lindhout
        Professor of Medical Genetics, Paediatrician (not practising), Clinical
        Geneticist, University Medical Centre, Utrecht
     •  N. Roeleveld
        Reproductive Epidemiologist, Radboud University Nijmegen Medical
        Centre, Nijmegen
     •  J.G. van Vliet
        Reproductive Toxicologist, TNO Triskelion BV, Zeist
     •  D.H. Waalkens-Berendsen
        Reproductive Toxicologist, Zeist
     •  P.J.J.M. Weterings
        Toxicologist, Weterings Consultancy BV, Rosmalen
     •  A.S.A.M. van der Burght, scientific secretary
        Health Council of the Netherlands, Den Haag
     •  J.T.J. Stouten, scientific secretary
        Health Council of the Netherlands, Den Haag
     The Committee                                                                 41
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<pre>  The first draft of this report was prepared by Dr. H. Barendse from the
  Regulatory Affairs Department of Wil Research Europe BV (Den Bosch, the
  Netherlands), by contract with the Ministry of Social Affairs and Employment.
  The Health Council and interests
  Members of Health Council Committees are appointed in a personal capacity
  because of their special expertise in the matters to be addressed. Nonetheless, it
  is precisely because of this expertise that they may also have interests. This in
  itself does not necessarily present an obstacle for membership of a Health
  Council Committee. Transparency regarding possible conflicts of interest is
  nonetheless important, both for the chairperson and members of a Committee
  and for the President of the Health Council. On being invited to join a
  Committee, members are asked to submit a form detailing the functions they
  hold and any other material and immaterial interests which could be relevant for
  the Committee’s work. It is the responsibility of the President of the Health
  Council to assess whether the interests indicated constitute grounds for non-
  appointment. An advisorship will then sometimes make it possible to exploit the
  expertise of the specialist involved. During the inaugural meeting the
  declarations issued are discussed, so that all members of the Committee are
  aware of each other’s possible interests.
2 Triamcinolone/Tramcinolone acetonide
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<pre>nnex B
     The submission letter (in English)
     Subject          : Submission of the advisory report Triamcinolone and
                         triamcinolone acetonide
     Your reference : DGV/MBO/U-932342
     Our reference : U-7651/HS/fs/543-N13
     Enclosed         : 1
     Date             : April 5, 2013
     Dear Minister,
     I hereby submit the advisory report on the effects of triamcinolone and
     triamcinolone acetonide on fertility and on the development of the progeny; it
     also concerns effects on lactation and on the progeny via lactation. This advisory
     report is part of an extensive series in which reproductive toxic substances are
     classified in accordance with European guidelines. This involves substances to
     which people can be exposed while pursuing their occupation.
     The advisory report was prepared by the a permanent committee of the Health
     Council of the Netherlands, the Subcommittee on the Classification of
     Reproduction Toxic Compounds. The advisory report was subsequently
     reviewed by the Health Council’s Standing Committee on Health and the
     Environment.
     The submission letter (in English)                                                 43
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<pre>  Today, I sent copies of this advisory report to the State Secretary of Infrastructure
  and the Environment and to the Minister of Health, Welfare and Sport, for their
  information.
  Yours sincerely,
  (signed)
  Prof. dr. W.A. van Gool,
  President
4 Triamcinolone/Tramcinolone acetonide
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<pre>nnex C
     Regulation (EC) 1272/2008 of the
     European Community
     3.7. Reproductive toxicity
     3.7.1. Definitions and general considerations
     3.7.1.1. Reproductive toxicity includes adverse effects on sexual function and fertility in adult males
     and females, as well as developmental toxicity in the offspring. The definitions presented below are
     adapted from those agreed as working definitions in IPCS/EHC Document No 225, Principles for
     Evaluating Health Risks to Reproduction Associated with Exposure to Chemicals. For classification
     purposes, the known induction of genetically based heritable effects in the offspring is addressed in
     Germ Cell Mutagenicity (section 3.5), since in the present classification system it is considered more
     appropriate to address such effects under the separate hazard class of germ cell mutagenicity.
     In this classification system, reproductive toxicity is subdivided under two main headings:
     (a) adverse effects on sexual function and fertility;
     (b) adverse effects on development of the offspring.
     Some reproductive toxic effects cannot be clearly assigned to either impairment of sexual function
     and fertility or to developmental toxicity. Nonetheless, substances with these effects, or mixtures
     containing them, shall be classified as reproductive toxicants.
     Regulation (EC) 1272/2008 of the European Community                                                     45
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<pre>  3.7.1.2. For the purpose of classification the hazard class Reproductive Toxicity is differentiated into:
  •     adverse effects
        •    on sexual function and fertility, or
        •    on development;
  •     effects on or via lactation.
  3.7.1.3. Adverse effects on sexual function and fertility
  Any effect of substances that has the potential to interfere with sexual function and fertility. This
  includes, but is not limited to, alterations to the female and male reproductive system, adverse effects
  on onset of puberty, gamete production and transport, reproductive cycle normality, sexual behaviour,
  fertility, parturition, pregnancy outcomes, premature reproductive senescence, or modifications in
  other functions that are dependent on the integrity of the reproductive systems.
  3.7.1.4. Adverse effects on development of the offspring
  Developmental toxicity includes, in its widest sense, any effect which interferes with normal
  development of the conceptus, either before or after birth, and resulting from exposure of either
  parent prior to conception, or exposure of the developing offspring during prenatal development, or
  postnatally, to the time of sexual maturation. However, it is considered that classification under the
  heading of developmental toxicity is primarily intended to provide a hazard warning for pregnant
  women, and for men and women of reproductive capacity. Therefore, for pragmatic purposes of
  classification, developmental toxicity essentially means adverse effects induced during pregnancy, or
  as a result of parental exposure. These effects can be manifested at any point in the life span of the
  organism. The major manifestations of developmental toxicity include (1) death of the developing
  organism, (2) structural abnormality, (3) altered growth, and (4) functional deficiency.
  3.7.1.5. Adverse effects on or via lactation are also included in reproductive toxicity, but for
  classification purposes, such effects are treated separately (see Table 3.7.1 (b)). This is because it is
  desirable to be able to classify substances specifically for an adverse effect on lactation so that a
  specific hazard warning about this effect can be provided for lactating mothers.
  3.7.2. Classification criteria for substances
  3.7.2.1. Hazard categories
  3.7.2.1.1. For the purpose of classification for reproductive toxicity, substances are allocated to one of
  two categories. Within each category, effects on sexual function and fertility, and on development, are
  considered separately. In addition, effects on lactation are allocated to a separate hazard category.
6 Triamcinolone/Tramcinolone acetonide
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<pre>                                       Table 3.7.1(a)
                     Hazard categories for reproductive toxicants
Categories               Criteria
CATEGORY 1               Known or presumed human reproductive toxicant
                         Substances are classified in Category 1 for reproductive toxicity when
                         they are known to have produced an adverse effect on sexual function
                         and fertility, or on development in humans or when there is evidence
                         from animal studies, possibly supplemented with other information, to
                         provide a strong presumption that the substance has the capacity to
                         interfere with reproduction in humans. The classification of a
                         substance is further distinguished on the basis of whether the evidence
                         for classification is primarily from human data (Category 1A) or from
                         animal data (Category 1B).
             Category 1A Known human reproductive toxicant
                         The classification of a substance in Category 1A is largely based on
                         evidence from humans.
             Category 1B Presumed human reproductive toxicant
                         The classification of a substance in Category 1B is largely based on
                         data from animal studies. Such data shall provide clear evidence of an
                         adverse effect on sexual function and fertility or on development in
                         the absence of other toxic effects, or if occurring together with other
                         toxic effects the adverse effect on reproduction is considered not to be
                         a secondary non-specific consequence of other toxic effects. However,
                         when there is mechanistic information that raises doubt about the
                         relevance of the effect for humans, classification in Category 2 may be
                         more appropriate.
CATEGORY 2               Suspected human reproductive toxicant
                         Substances are classified in Category 2 for reproductive toxicity when
                         there is some evidence from humans or experimental animals,
                         possibly supplemented with other information, of an adverse effect on
                         sexual function and fertility, or on development, and where the
                         evidence is not sufficiently convincing to place the substance in
                         Category 1. If deficiencies in the study make the quality of evidence
                         less convincing, Category 2 could be the more appropriate
                         classification.
                         Such effects shall have been observed in the absence of other toxic
                         effects, or if occurring together with other toxic effects the adverse
                         effect on reproduction is considered not to be a secondary non-specific
                         consequence of the other toxic effects.
Regulation (EC) 1272/2008 of the European Community                                               47
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<pre>                                                Table 3.7.1(b)
                                   Hazard category for lactation effects.
                                   EFFECTS ON OR VIA LACTATION
  Effects on or via lactation are allocated to a separate single category. It is recognised that for many
  substances there is no information on the potential to cause adverse effects on the offspring via
  lactation. However, substances which are absorbed by women and have been shown to interfere
  with lactation, or which may be present (including metabolites) in breast milk in amounts sufficient
  to cause concern for the health of a breastfed child, shall be classified and labelled to indicate this
  property hazardous to breastfed babies. This classification can be assigned on the:
  (a) human evidence indicating a hazard to babies during the lactation period; and/or
  (b) results of one or two generation studies in animals which provide clear evidence of adverse
  effect in the offspring due to transfer in the milk or adverse effect on the quality of the milk; and/or
  (c) absorption, metabolism, distribution and excretion studies that indicate the likelihood that the
  substance is present in potentially toxic levels in breast milk.
  3.7.2.2. Basis of classification
  3.7.2.2.1. Classification is made on the basis of the appropriate criteria, outlined above, and an
  assessment of the total weight of evidence (see 1.1.1). Classification as a reproductive toxicant is
  intended to be used for substances which have an intrinsic, specific property to produce an adverse
  effect on reproduction and substances shall not be so classified if such an effect is produced solely as
  a non-specific secondary consequence of other toxic effects.
  The classification of a substance is derived from the hazard categories in the following order of
  precedence: Category 1A, Category 1B, Category 2 and the additional Category for effects on or via
  lactation. If a substance meets the criteria for classification into both of the main categories (for
  example Category 1B for effects on sexual function and fertility and also Category 2 for
  development) then both hazard differentiations shall be communicated by the respective hazard
  statements. Classification in the additional category for effects on or via lactation will be considered
  irrespective of a classification into Category 1A, Category 1B or Category 2.
  3.7.2.2.2. In the evaluation of toxic effects on the developing offspring, it is important to consider the
  possible influence of maternal toxicity (see section 3.7.2.4).
  3.7.2.2.3. For human evidence to provide the primary basis for a Category 1A classification there
  must be reliable evidence of an adverse effect on reproduction in humans. Evidence used for
  classification shall ideally be from well conducted epidemiological studies which include the use of
  appropriate controls, balanced assessment, and due consideration of bias or confounding factors. Less
  rigorous data from studies in humans shall be supplemented with adequate data from studies in
  experimental animals and classification in Category 1B shall be considered.
8 Triamcinolone/Tramcinolone acetonide
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<pre>3.7.2.3. Weight of evidence
3.7.2.3.1. Classification as a reproductive toxicant is made on the basis of an assessment of the total
weight of evidence, see section 1.1.1. This means that all available information that bears on the
determination of reproductive toxicity is considered together, such as epidemiological studies and
case reports in humans and specific reproduction studies along with sub-chronic, chronic and special
study results in animals that provide relevant information regarding toxicity to reproductive and
related endocrine organs. Evaluation of substances chemically related to the substance under study
may also be included, particularly when information on the substance is scarce. The weight given to
the available evidence will be influenced by factors such as the quality of the studies, consistency of
results, nature and severity of effects, the presence of maternal toxicity in experimental animal
studies, level of statistical significance for inter-group differences, number of endpoints affected,
relevance of route of administration to humans and freedom from bias. Both positive and negative
results are assembled together into a weight of evidence determination. A single, positive study
performed according to good scientific principles and with statistically or biologically significant
positive results may justify classification (see also 3.7.2.2.3).
3.7.2.3.2. Toxicokinetic studies in animals and humans, site of action and mechanism or mode of
action study results may provide relevant information which reduces or increases concerns about the
hazard to human health. If it is conclusively demonstrated that the clearly identified mechanism or
mode of action has no relevance for humans or when the toxicokinetic differences are so marked that
it is certain that the hazardous property will not be expressed in humans then a substance which
produces an adverse effect on reproduction in experimental animals should not be classified.
3.7.2.3.3. If, in some reproductive toxicity studies in experimental animals the only effects recorded
are considered to be of low or minimal toxicological significance, classification may not necessarily
be the outcome. These effects include small changes in semen parameters or in the incidence of
spontaneous defects in the foetus, small changes in the proportions of common foetal variants such as
are observed in skeletal examinations, or in foetal weights, or small differences in postnatal
developmental assessments.
3.7.2.3.4. Data from animal studies ideally shall provide clear evidence of specific reproductive
toxicity in the absence of other systemic toxic effects. However, if developmental toxicity occurs
together with other toxic effects in the dam, the potential influence of the generalised adverse effects
shall be assessed to the extent possible. The preferred approach is to consider adverse effects in the
embryo/foetus first, and then evaluate maternal toxicity, along with any other factors which are likely
to have influenced these effects, as part of the weight of evidence. In general, developmental effects
that are observed at maternally toxic doses shall not be automatically discounted. Discounting
Regulation (EC) 1272/2008 of the European Community                                                      49
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<pre>  developmental effects that are observed at maternally toxic doses can only be done on a case-by-case
  basis when a causal relationship is established or refuted.
  3.7.2.3.5. If appropriate information is available it is important to try to determine whether
  developmental toxicity is due to a specific maternally mediated mechanism or to a non-specific
  secondary mechanism, like maternal stress and the disruption of homeostasis. Generally, the presence
  of maternal toxicity shall not be used to negate findings of embryo/foetal effects, unless it can be
  clearly demonstrated that the effects are secondary non-specific effects. This is especially the case
  when the effects in the offspring are significant, e.g. irreversible effects such as structural
  malformations. In some situations it can be assumed that reproductive toxicity is due to a secondary
  consequence of maternal toxicity and discount the effects, if the substance is so toxic that dams fail to
  thrive and there is severe inanition, they are incapable of nursing pups; or they are prostrate or dying.
  3.7.2.4. Maternal toxicity
  3.7.2.4.1. Development of the offspring throughout gestation and during the early postnatal stages
  can be influenced by toxic effects in the mother either through non-specific mechanisms related to
  stress and the disruption of maternal homeostasis, or by specific maternally-mediated mechanisms. In
  the interpretation of the developmental outcome to decide classification for developmental effects it
  is important to consider the possible influence of maternal toxicity. This is a complex issue because
  of uncertainties surrounding the relationship between maternal toxicity and developmental outcome.
  Expert judgement and a weight of evidence approach, using all available studies, shall be used to
  determine the degree of influence that shall be attributed to maternal toxicity when interpreting the
  criteria for classification for developmental effects. The adverse effects in the embryo/foetus shall be
  first considered, and then maternal toxicity, along with any other factors which are likely to have
  influenced these effects, as weight of evidence, to help reach a conclusion about classification.
  3.7.2.4.2. Based on pragmatic observation, maternal toxicity may, depending on severity, influence
  development via non-specific secondary mechanisms, producing effects such as depressed foetal
  weight, retarded ossification, and possibly resorptions and certain malformations in some strains of
  certain species. However, the limited number of studies which have investigated the relationship
  between developmental effects and general maternal toxicity have failed to demonstrate a consistent,
  reproducible relationship across species. Developmental effects which occur even in the presence of
  maternal toxicity are considered to be evidence of developmental toxicity, unless it can be
  unequivocally demonstrated on a case-by-case basis that the developmental effects are secondary to
  maternal toxicity. Moreover, classification shall be considered where there is a significant toxic effect
  in the offspring, e.g. irreversible effects such as structural malformations, embryo/foetal lethality,
  significant post-natal functional deficiencies.
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<pre>3.7.2.4.3. Classification shall not automatically be discounted for substances that produce
developmental toxicity only in association with maternal toxicity, even if a specific maternally-
mediated mechanism has been demonstrated. In such a case, classification in Category 2 may be
considered more appropriate than Category 1. However, when a substance is so toxic that maternal
death or severe inanition results, or the dams are prostrate and incapable of nursing the pups, it is
reasonable to assume that developmental toxicity is produced solely as a secondary consequence of
maternal toxicity and discount the developmental effects. Classification is not necessarily the
outcome in the case of minor developmental changes, when there is only a small reduction in foetal/
pup body weight or retardation of ossification when seen in association with maternal toxicity.
3.7.2.4.4. Some of the end points used to assess maternal effects are provided below. Data on these
end points, if available, need to be evaluated in light of their statistical or biological significance and
dose response relationship.
Maternal mortality:
an increased incidence of mortality among the treated dams over the controls shall be considered
evidence of maternal toxicity if the increase occurs in a dose-related manner and can be attributed to
the systemic toxicity of the test material. Maternal mortality greater than 10 % is considered
excessive and the data for that dose level shall not normally be considered for further evaluation.
Mating index
(no. animals with seminal plugs or sperm/no. mated × 100) (*)
Fertility index
(no. animals with implants/no. of matings × 100)
Gestation length
(if allowed to deliver)
Body weight and body weight change:
Consideration of the maternal body weight change and/or adjusted (corrected) maternal body weight
shall be included in the evaluation of maternal toxicity whenever such data are available. The
() It is recognised that the Mating index and the Fertility index can also be affected by the male.
Regulation (EC) 1272/2008 of the European Community                                                         51
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<pre>  calculation of an adjusted (corrected) mean maternal body weight change, which is the difference
  between the initial and terminal body weight minus the gravid uterine weight (or alternatively, the
  sum of the weights of the foetuses), may indicate whether the effect is maternal or intrauterine. In
  rabbits, the body weight gain may not be useful indicators of maternal toxicity because of normal
  fluctuations in body weight during pregnancy.
  Food and water consumption (if relevant):
  The observation of a significant decrease in the average food or water consumption in treated dams
  compared to the control group is useful in evaluating maternal toxicity, particularly when the test
  material is administered in the diet or drinking water. Changes in food or water consumption need to
  be evaluated in conjunction with maternal body weights when determining if the effects noted are
  reflective of maternal toxicity or more simply, unpalatability of the test material in feed or water.
  Clinical evaluations (including clinical signs, markers, haematology and clinical chemistry studies):
  The observation of increased incidence of significant clinical signs of toxicity in treated dams relative
  to the control group is useful in evaluating maternal toxicity. If this is to be used as the basis for the
  assessment of maternal toxicity, the types, incidence, degree and duration of clinical signs shall be
  reported in the study. Clinical signs of maternal intoxication include: coma, prostration, hyperactivity,
  loss of righting reflex, ataxia, or laboured breathing.
  Post-mortem data:
  Increased incidence and/or severity of post-mortem findings may be indicative of maternal toxicity.
  This can include gross or microscopic pathological findings or organ weight data, including absolute
  organ weight, organ-to-body weight ratio, or organ-to-brain weight ratio. When supported by
  findings of adverse histopathological effects in the affected organ(s), the observation of a significant
  change in the average weight of suspected target organ(s) of treated dams, compared to those in the
  control group, may be considered evidence of maternal toxicity.
  3.7.2.5. Animal and experimental data
  3.7.2.5.1. A number of internationally accepted test methods are available; these include methods for
  developmental toxicity testing (e.g. OECD Test Guideline 414), and methods for one or two-
  generation toxicity testing (e.g. OECD Test Guidelines 415, 416).
  3.7.2.5.2. Results obtained from Screening Tests (e.g. OECD Guidelines 421 — Reproduction/
  Developmental Toxicity Screening Test, and 422 — Combined Repeated Dose Toxicity Study with
  Reproduction/Development Toxicity Screening Test) can also be used to justify classification,
2 Triamcinolone/Tramcinolone acetonide
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<pre>although it is recognised that the quality of this evidence is less reliable than that obtained through
full studies.
3.7.2.5.3. Adverse effects or changes, seen in short- or long-term repeated dose toxicity studies,
which are judged likely to impair reproductive function and which occur in the absence of significant
generalised toxicity, may be used as a basis for classification, e.g. histopathological changes in the
gonads.
3.7.2.5.4. Evidence from in vitro assays, or non-mammalian tests, and from analogous substances
using structure-activity relationship (SAR), can contribute to the procedure for classification. In all
cases of this nature, expert judgement must be used to assess the adequacy of the data. Inadequate
data shall not be used as a primary support for classification.
3.7.2.5.5. It is preferable that animal studies are conducted using appropriate routes of administration
which relate to the potential route of human exposure. However, in practice, reproductive toxicity
studies are commonly conducted using the oral route, and such studies will normally be suitable for
evaluating the hazardous properties of the substance with respect to reproductive toxicity. However,
if it can be conclusively demonstrated that the clearly identified mechanism or mode of action has no
relevance for humans or when the toxicokinetic differences are so marked that it is certain that the
hazardous property will not be expressed in humans then a substance which produces an adverse
effect on reproduction in experimental animals shall not be classified.
3.7.2.5.6. Studies involving routes of administration such as intravenous or intraperitoneal injection,
which result in exposure of the reproductive organs to unrealistically high levels of the test substance,
or elicit local damage to the reproductive organs, including irritation, must be interpreted with
extreme caution and on their own are not normally the basis for classification.
3.7.2.5.7. There is general agreement about the concept of a limit dose, above which the production
of an adverse effect is considered to be outside the criteria which lead to classification, but not
regarding the inclusion within the criteria of a specific dose as a limit dose. However, some
guidelines for test methods, specify a limit dose, others qualify the limit dose with a statement that
higher doses may be necessary if anticipated human exposure is sufficiently high that an adequate
margin of exposure is not achieved. Also, due to species differences in toxicokinetics, establishing a
specific limit dose may not be adequate for situations where humans are more sensitive than the
animal model.
3.7.2.5.8. In principle, adverse effects on reproduction seen only at very high dose levels in animal
studies (for example doses that induce prostration, severe inappetence, excessive mortality) would
not normally lead to classification, unless other information is available, e.g. toxicokinetics
Regulation (EC) 1272/2008 of the European Community                                                       53
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<pre>              information indicating that humans may be more susceptible than animals, to suggest that
              classification is appropriate. Please also refer to the section on maternal toxicity (3.7.2.4) for further
              guidance in this area.
              3.7.2.5.9. However, specification of the actual ‘limit dose’ will depend upon the test method that has
              been employed to provide the test results, e.g. in the OECD Test Guideline for repeated dose toxicity
              studies by the oral route, an upper dose of 1 000 mg/kg has been recommended as a limit dose, unless
              expected human response indicates the need for a higher dose level.
              3.7.3. Classification criteria for mixtures
              3.7.3.1. Classification of mixtures when data are available for all ingredients or only for some
              ingredients of the mixture
              3.7.3.1.1. The mixture shall be classified as a reproductive toxicant when at least one ingredient has
              been classified as a Category 1A, Category 1B or Category 2 reproductive toxicant and is present at
              or above the appropriate generic concentration limit as shown in Table 3.7.2 for Category 1A,
              Category 1B and Category 2 respectively.
              3.7.3.1.2. The mixture shall be classified for effects on or via lactation when at least one ingredient
              has been classified for effects on or via lactation and is present at or above the appropriate generic
              concentration limit as shown in Table 3.7.2 for the additional category for effects on or via lactation.
                                                              Table 3.7.2
   Generic concentration limits of ingredients of a mixture classified as reproduction toxicants or for effects on or via
                                        lactation that trigger classification of the mixture
ngredient classified as:            Generic concentration limits triggering classification of a mixture as:
                                    Category 1A              Category 1B               Category 2              Additional category
                                    reproductive toxicant reproductive toxicant reproductive toxicant for effects on or via
                                                                                                               lactation
  ategory 1A r                      ≥ 0,3 %
 productive toxicant                [Note 1]
  ategory 1B                                                 ≥ 0,3 %
eproductive toxicant                                         [Note 1]
  ategory 2                                                                            ≥ 3,0 %
eproductive toxicant                                                                   [Note 1]
Additional category for                                                                                        ≥ 0,3 %
 ffects on or via lactation                                                                                    [Note 1]
Note:     The concentration limits in the table above apply to solids and liquids (w/w units) as well as gases (v/v units).
Note 1: If a Category 1 or Category 2 reproductive toxicant or a substance classified for effects on or via lactation is
          present in the mixture as an ingredient at a concentration above 0,1 %, a SDS shall be available for the mixture
          upon request.
  4           Triamcinolone/Tramcinolone acetonide
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<pre>              3.7.3.2. Classification of mixtures when data are available for the complete mixture
              3.7.3.2.1. Classification of mixtures will be based on the available test data for the individual
              ingredients of the mixture using concentration limits for the ingredients of the mixture. On a case-by-
              case basis, test data on mixtures may be used for classification when demonstrating effects that have
              not been established from the evaluation based on the individual components. In such cases, the test
              results for the mixture as a whole must be shown to be conclusive taking into account dose and other
              factors such as duration, observations, sensitivity and statistical analysis of reproduction test systems.
              Adequate documentation supporting the classification shall be retained and made available for review
              upon request.
              3.7.3.3. Classification of mixtures when data are not available for the complete mixture: bridging
              principles
              3.7.3.3.1. Subject to paragraph 3.7.3.2.1, where the mixture itself has not been tested to determine its
              reproductive toxicity, but there are sufficient data on the individual ingredients and similar tested
              mixtures to adequately characterise the hazards of the mixture, these data shall be used in accordance
              with the applicable bridging rules set out in section 1.1.3.
              3.7.4. Hazard Communication
              3.7.4.1. Label elements shall be used for substances or mixtures meeting the criteria for classification
              in this hazard class in accordance with Table 3.7.3
                                                               Table 3.7.3
                                             Label elements for reproductive toxicity
Classification                  Category 1A or Category 1B             Category 2                           Additional category for
                                                                                                            effects on or via lactation
GHS Pictograms                                                                                              No pictogram
 ignal Word                     Danger                                 Warning                              No signal word
Hazard Statement                H360: May damage fertility or the H361: Suspected of damaging               H362: May cause harm to
                                unborn child (state specific effect if fertility or the unborn child (state breast-fed children.
                                known)(state route of exposure if it specific effect if known) (state
                                is conclusively proven that no other route of exposure if it is
                                routes of exposure cause the           conclusively proven that no other
                                hazard)                                routes of exposure cause the
                                                                       hazard)
 recautionary Statement         P201                                   P201                                 P201
 revention                      P202                                   P202                                 P260
                                P281                                   P281                                 P263
                                                                                                            P264
                                                                                                            P270
              Regulation (EC) 1272/2008 of the European Community                                                                     55
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<pre> recautionary Statement P308 + P313               P308 + P313 P308 + P313
 esponse
 recautionary Statement P405                      P405
 torage
 recautionary Statement P501                      P501
Disposal
 6           Triamcinolone/Tramcinolone acetonide
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<pre>nnex D
     Additional considerations to
     Regulation (EC) 1272/2008
     The classification and labelling of substances is performed according to the
     guidelines of the European Union (Regulation (EC)1272/2008) presented in
     Annex B. 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 B,
         3.7.2.2.1.)
     • adverse effects in a reproductive study, reported without information on the
         parental or maternal toxicity, may lead to a classification other than category
         1B, when the effects occur at dose levels which cause severe toxicity in
         general toxicity studies
     • clear adverse reproductive effects will not be disregarded on the basis of
         reversibility per se
     Additional considerations to Regulation (EC) 1272/2008                              57
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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.
8 Triamcinolone/Tramcinolone acetonide
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<pre>nnex        E
            Fertility and developmental toxicity
            studies in animals
able 1 Fertility studies in laboratory animals with triamcinolone.
uthors            species           experimental period/design      dose/route       general toxicity effects on reproductive
                                                                                                        organs/ effects on
                                                                                                        reproduction
arkar, 1967       female rats       15 d; sacrifice 24 h after last 0, 0.1 mg/rat/d; not reported       no histological change of
                  albino            injection; histological         sc                                  ovary; decreased uterine
                  (n=6/group)       investigation of ovaries;                                           weight, ovary weight
                                    determination of uterine and                                        and ovarian tissue
                                    ovary weight, ovarian tissue                                        alkaline phosphatase
                                    alkaline phosphatase activity                                       activity (p<0.01)
=day(s); h=hour(s); n=number; sc=subcutaneous
able 2.1 Developmental toxicity studies in animals with triamcinolone: oral.
uthors         species         experimental period/      dose/route     general      developmental toxicity
                               design                                   toxicity
elye, 1971     Sprague-        gd 2-6, 4-8, 9-13, 15-19 100 mg/kg       not reported number of interrupted pregnancies 8/11,
               Dawley rats                               bw (controls:               10/10, 11/11, 9/9 at gd 2-6, 4-8, 9-13 or 15-
               (n=9-11/                                  cholesterol:                19, resp., vs. none in controls
               group)                                    100 mg/kg
                                                         bw); twice
                                                         daily; gavage
            Fertility and developmental toxicity studies in animals                                                            59
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<pre>elye, 1971   Sprague-      gd 2-19                     5 mg/kg bw    not reported number of interrupted pregnancies 4/9 vs.
             Dawley rats                               (controls:                 none in controls
             (n=9)                                     cholesterol:
                                                       100 mg/kg
                                                       bw);twice
                                                       daily; gavage
elye, 1971   Sprague-      gd 2-6                      10 mg/kg bw   not reported no interrupted
             Dawley rats                               (controls:
             (n=5)                                     cholesterol:
                                                       100 mg/kg
                                                       bw); twice
                                                       daily
ishop, 1985a Yorkshire x   last 10 d pre-partum        0, 70 mg/d;   sow weight   no effect on number of stillbirths, litter size
             Hampshire     examintions: bw, food soybean-            gain, feed   up to 28 d of age; increase of piglet weight
             pigs (n=38-   intake sows (26/group); supplemented      intake not   at birth, 14, 28 d of age; after weaning till
             40/group)     protein (13/group), fat diet              affected     165 d of age no effect on bw of piglets;
                           (26/group) content                        during 28-d  decreased adrenal weight; increased serum
                           colostrum; growing of                     lactation;   glucose; % liver glycogen, and carcass fat
                           piglets followed till 165                 colostrum    and protein not affected
                           d old; % liver glycogen,                  fat content
                           serum glucose, adrenal                    increased by
                           weight, carcass fat and                   21%
                           protein at 28 d (1 male/
                           litter)
ishop, 1985b Yorkshire x   last 7 d pre-partum         0, 70 mg/d;   colostrum    litter size, birth weight not affected; % liver
             Hampshire     examinations: fat           soybean-      fat content glycogen, serum glucose level not affected;
             pigs (n=6-7/  content colostrum (5/       supplemented  not affected increased carcass protein and fat
             group)        group); carbohydrate, diet
                           fat. protein metabolism
                           in piglets at birth, 6, 12,
                           24, 48 h of age (1/litter/
                           time point)
avos, 1988   Yorkshire x   from gd 106 through         0, 70 mg/kg   not reported bw, testicular volume not affected; slightly
             Hampshire     parturition; one or two bw; standard                   increased plasma testosterone
             pigs (n=5-7/  pairs of littermate boars diet                         concentrations at wk 16-28, terminal levels
             group)        (closest to the mean pig                               not affected; plasma cortisol levels, adrenal
                           weight of the litter)                                  weights not affected ; increased percentage
                           from each litter                                       of boars with ejaculate containing
                           followed till 30 wk of                                 spermatozoa (p<0.05) at an earlier point in
                           age; examinations: bw,                                 time (p<0.01); earlier and higher mounting
                           plasma testosterone,                                   activity (p<0.10), more ejaculates
                           cortisol; sexual                                       (p<0.05), a greater number of ejaculates
                           performance parameters                                 (p<0.001) and ejaculation at an earlier age;
                                                                                  comparable semen volumes, increased
                                                                                  sperm concentrations at each time point
                                                                                  (p<0.10); increased testes, epididymides,
                                                                                  seminal vesicles, bulbourethral glands,
                                                                                  prostate gland (p<0.10) weights; no effect
                                                                                  on incidence of cytoplasmic droplets on
                                                                                  spermatozoa recovered from the cauda
                                                                                  epididymides
w=body weight; d=day(s); gd=gestational day(s); n=number; wk=week(s)
0          Triamcinolone/Tramcinolone acetonide
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<pre> able 2.2 Developmental toxicity studies in laboratory animals with triamcinolone: subcutaneous.
 uthors     species      experimental        dose/route                    general toxicity        developmental toxicity
                         period/design
Walker,     Holtzman gd 12-15;               0.01, 0.05, 0.1, 0.2, 0.5     mortality in dams:      number of resorptions 0, 3, 6 and
 971        rats (n=2- sacrifice gd 19       mg/rat/da                     0, 0, 1, 2, 2 at 0.01,  percentage of embryos with cleft
            4/group)                                                       0.05, 0.1, 0.2, 0.5     palate 0, 45, 80% at 0.01, 0.05 and
                                                                           mg, resp; no dams       0.1 mg, resp
                                                                           left at 0.2 and 0.5
                                                                           mg
Walker,     A/J mice     gd 11-14;           0.0175 mg/rat/da              not reported            5 embryos resorbed; 44/52 embryos
 971        (n=7)        sacrifice gd 18                                                           with cleft palate (85%); of these 3
                                                                                                   had cleft lip-cleft palate
 According to Rowland and Hendrikx (1983) not triamcinolone, but triamcinolone acetonide was used here.
 w=body weight; d=day(s); gd=gestational day(s); n=number
 able 2.3 Developmental toxicity studies in laboratory animals with triamcinolone: intramuscular
 uthors          species          experimental      dose/route         general            developmental toxicity
                                  period/design                        toxicity
Walker, 1967     New Zealand gd 13-16;               0.01, 0.1,        not reported       number of resorbed litters: 0/8, 0/3, 0/4, 0/1,
                 white rabbits sacrifice gd 21 0.25, 0.3, 0.5,                            0/3, 0/2, 2/7, 3/3, 1/1 at 0.01, 0.1, 0.25, 0.3,
                 (n=1-8/group)                      0.75, 1.0, 2.0,                       0.5, 0.75, 1.0, 2.0, 5.0 mg, resp; number of
                                                    5.0 mg/                               resorbed foetuses: 1, 0, 0, 0, 3, 2, 6 at 0.01,
                                                    rabbit/da                             0.1, 0.25, 0.3, 0.5, 0.75, 1.0 mg, resp; number
                                                                                          of cleft palate in live foetuses: 0/55, 4/23, 4/
                                                                                          28, 0/4, 2/11, 4/14, 17/32 at 0.01, 0.1, 0.25,
                                                                                          0.3, 0.5, 0.75, 1.0 mg, resp
Walker, 1967     American         gd 13-16;         0.01, 0.1, 0.2,    not reported       no resorbed litters; number of resorbed
                 Dutch rabbits sacrifice gd 21 0.3, 0.6, 1.0,                             foetuses: 1, 5, 8, 4, 5, 12, 5, 32 at 0.01, 0.1,
                 (n=2-7/group)                      2.0, 4.0 mg/                          0.2, 0.3, 0.6, 1.0, 2.0, 4.0 mg, resp; number of
                                                    rabbit/da                             cleft palate in live foetuses: 0/16, 0/32, 1/27,
                                                                                          11/24, 5/9, 4/4, 5/5, 0/0 at 0.01, 0.1, 0.2, 0.3,
                                                                                          0.6, 1.0, 2.0, 4.0 mg, resp
 hah, 1976       Golden Syrian gd 11;               0, 0.25, 0.5,      not reported       at all doses: decreased foetal weight,
                 hamsters         sacrifice gd 15; 1.0, 2.5, 5.0                          increased % cleft palate; at 5.0 mg:
                 (n=3-4/group) foetuses             mg/hamster                            reduced number of live foetuses; at ≥1.0 mg:
                                  weighed,                                                increased % resorptions; dose-related
                                  investigated                                            increased number of complete cleft palates;
                                  for cleft palate                                        the number of partial cleft palates increased
                                                                                          at the 3 lower doses and then decreased at the
                                                                                          2 highest doses
             Fertility and developmental toxicity studies in animals                                                                     61
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<pre> hah, 1979,      Golden Syrian      gd 11; sacrifice 0, 4 mg/         not reported  32 h after treatment: basal cell necrosis and
 980             hamsters           in 2-4 h         hamster                        delayed differentiation of mesenchymal cells,
                 (n=3-4/group)      intervals until                                 thereby disrupting the timing of coordinated
                                    gd 13 and on                                    development of the palatal tissues; delayed
                                    gd 14 +15;                                      reorientation before any general retardation
                                    foetuses                                        of foetal growth as indicated by crown-rump
                                    weighed,                                        length and foetal weight (p<0.001 after gd
                                    measured,                                       13)
                                    investigated
                                    for cleft palate
                                    (n=17-38/time
                                    point)
 owland/         Sprague-          gd 13; sacrifice 0, 10, 20, 40    not reported  no increase in % of resorptions per litter or
Hendrickx,       Dawley rats       gd 20;            mg/kg bw                      proportion of litters with at least one
 983             (n=10-11)         examinations:                                   resorption; increased % litters/foetuses with
                                   number of live,                                 cleft palate (dose-related; all partial clefts) and
                                   dead foetuses,                                  umbilical hernias (not statistically significant)
                                   resorptions;                                    at all doses; decreased foetal weight at 20 and
                                   foetal weight;                                  40 mg/kg bw
                                   sex; external
                                   malformations
 According to Rowland and Hendrikx (1983) not triamcinolone, but triamcinolone acetonide was used here.
 w=body weight; d=day(s); gd=gestational day(s); h=hour(s); n=number
 able 3 Fertility studies in laboratory animals with triamcinolone acetonide.
 uthors            species            experimental period/design      dose/route        general toxicity effects on reproductive
                                                                                                          organs/ effects on
                                                                                                          reproduction
Hagino, 1972       baboons            during 2 d preceding the        0, 4 mg/          not reported      inhibition of ovulation
                   (n=5-8/ group)     expected time of ovulation      baboon/d; im                        shortening of menstrual
                                      (cycle d 12-14); or for 2 d                                         cycles
                                      during the early cycle of
                                      follicle development; or on d
                                      1 and 3 of menstruation; or on
                                      d 1 of menstruation; or on d 1
                                      and 3 of menstruation, for 2-7
                                      consecutive cycles
 =day(s); h=hour(s); im=intramuscular; n=number
 2            Triamcinolone/Tramcinolone acetonide
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<pre> able 4.1 Developmental toxicity studies in laboratory animals with triamcinolone acetonide: subcutaneous.
 uthors    species       experimental          dose           general   developmental toxicity
                         period/design                        toxicity
Kusanagi, C57BL/6        gd 12; sacrifice gd   C57BL/6: 0, not          C57BL/6 mice (in order of increasing dose):
 983a      mice (n=10- 18                      1.0, 2.5, 4.0, reported  number of resorbed litters/implants: 41/250 (16.4%,
           16/group;                           5.0, 7.0 mg/             control), 10/91 (11.1%), 12/131 (9.2%), 13/126
           controls:                           kg bw                    (10.3%), 14/96 (14.6%), 21/124 (16.9%); cleft palate in
           n=29);                              SWV: 0, 1.0,             live foetuses: 0/209 (0%, control), 0/81 (0%), 16/119
           female SWV                          2.5, 5.0 mg/             (13.4%), 32/113 (28.3%), 27/82 (32.9%), 72/103
           mice (n=11-                         kg bw                    (69.9%); palatal slit in live foetuses with cleft palate:
           16/group;                                                    12/209 (5.7%), 25/81 (30.9%), 36/103 (35.0%), 36/81
           controls                                                     (44.4%), 34/55 (61.8%), 21/31 (67.7%).
           n=15)                                                        SWV mice (in order of increasing dose):
                                                                        number of resorbed litters/implants: 15/213 (7.0%,
                                                                        control), 14/143 (9.8%), 61/220 (27.7%), 67/170
                                                                        (39.4%); cleft palate in live foetuses: 0/198 (0%,
                                                                        control), 14/129 (10.9%), 79/159 (49.7%), 86/103
                                                                        (83.5%); palatal slit in live foetuses with cleft palate: 0/
                                                                        198 (0%, control), 0/115 (0%), 0/80 (0%), 0/17 (0%).
                                                                        SWV mice differed in response of palatal slit
                                                                        development in live foetuses with cleft palate.
Kusanagi, C57BL/6        at gd 3 blastocysts 0, 2.5 mg/kg not           C57BL/6  C57BL/6 transfer:
 983b      mice (n=14 were recovered           bw             reported number of resorbed litters/implants: 8/60 (13.3%) vs. 3/
           or 16; female from the uterus, and                           31 in controls (9.7%); cleft palate in live foetuses: 3/52
           SWV mice      transferred                                    (5.8%) vs. 0/28 (0%); palatal slit in live foetuses with
           (n=15 or 16) surgically to the                               cleft palate: 21/49 (42.9%) vs. 6/28 (21.4%)
                         uterus of day 2                                C57BL/6  SWV transfer:
                         pseudopregnant                                 number of resorbed litters/implants: 25/70 (35.7%) vs.
                         females (from the                              16/48 (33.3%); cleft palate in live foetuses: 7/45
                         same or other                                  (15.6%) vs. 0/32 (0%); palatal slit in live foetuses with
                         species); these                                cleft palate: 6/38 (15.8%) vs. 0/32 (0%)
                         females were treated                           SWV  SWV transfer:
                         on gd 12 based on                              number of resorbed litters/implants: 30/74 (40.5%) vs.
                         the gestational age                            22/56 (39.3%); cleft palate in live foetuses: 17/44
                         of recipient females;                          (38.6%) vs. 0/34 (0%); palatal slit in live foetuses with
                         sacrifice gd 18                                cleft palate: 0/27 (0%) vs. 0/34 (0%
                                                                        SWV  C57BL/6 transfer:
                                                                        number of resorbed litters/implants: 6/54 (11/1%) vs. 4/
                                                                        53 (7.5%); cleft palate in live foetuses: 2/48 (4.2%) vs.
                                                                        0/49 (0%; palatal slit in live foetuses with cleft palate:
                                                                        0/46 (0%) vs. 0/49 (0%)
             Fertility and developmental toxicity studies in animals                                                            63
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<pre>Kusanagi, C57BL/6         on single days       gd 9: 0, 2.5, not        gd 9 (in order of increasing dose):
 984       mice (n=14- during gd 6-15;         5.0, 10.0,    reported   number of resorbed litters/implants: 41/250 (16.4%),
           16 (controls: sacrifice gd 18       15.0 mg/kg               19/128 (14.8%), 12/123 (9.8%), 41/126 (32.5%), 69/
           n=29)                               bw;                      140 (49.3%); cleft palate in live foetuses: 0/209 (0%),
                                               gd 6-15: 0,              1/109 (0.9%), 6/111 (5.4%), 11/85 (12.9%), 10.71
                                               2.5, 5.0 mg/             (14.1%); palatal slit in live foetuses with cleft palate:
                                               kg bw.                   12/209 (5.7%), 22/108 (20.4%), 41/105 (39.0%), 34/74
                                                                        (46.0%), 27/61 (44.3%).
                                                                        Kusanagi showed that the number of resorptions/
                                                                        implants was highest when treatment took place at gd
                                                                        8-11, and that the frequency of cleft palates and palatal
                                                                        slits was highest at gd 12-13.
 w=body weight; d=day(s); gd=gestational day(s); n=number
 able 4.2 Developmental toxicity studies in laboratory animals with triamcinolone acetonide: subcutaneous.
 uthors   species          experimental period/ dose         general       developmental toxicity
                           design                            toxicity
Hen-      bonnet monkeys   1 or 4 consecutive d    bonnet: not reported    effects observed included: resorption (rhesus
 rickx,   (Macaca          on:                     15-20                   monkey only), intrauterine death (all species), and
 975      radiate) (n=5)   bonnet: gd 41–44        mg/kg                   malformations (all species);
          rhesus monkeys   (bonnet m.); rhesus     bw                      type of malformations: cleft palate in 1 bonnet
          (Macaca          gd 37-48                rhesus:                 monkey; choanal atresia and mandibular overbite in
          mulatta) (n=10)  baboon: gd 50-133       3-28, or                a baboon; hyperextension of the knee, medial
          baboons (Papio   delivery at gd 100      3-19 mg/                rotation of the hind limbs in 2 bonnet monkeys;
          cynocephalus)    (near term, or          kg bw                   depression of the sternum toward spine in 1 baboon;
          (n=6)            naturally)              baboon:                 syndactyly, hypoplasia and cutaneous webbing in
          controls: n=10/                          1-14 mg/                digits in 1 rhesus monkey; alterations in facial
          species                                  kg bw                   development in 3 bonnet monkeys and 8 rhesus
                                                                           monkeys; malformations in the liver in 1 rhesus
                                                                           monkey; renal malformations in 1 bonnet monkey;
                                                                           growth retardation in all 3 species; pronounced
                                                                           malformation in the thymus in all bonnet monkeys,
                                                                           most rhesus monkeys (13/17), and 2 baboons (2/6);
                                                                           deficiency in both total and subpopulations of
                                                                           lymphocytes in surviving baboons offspring
                                                                           (animals demonstrated persistent lymphopenia);
                                                                           no statistical analyses performed.
 4           Triamcinolone/Tramcinolone acetonide
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<pre>Hen-    bonnet monkeys  single or multiple-day 5-20 mg/ not reported major malformations:
 rickx, (Macaca         treatment between gd kg bw                   bonnet monkeys (single vs. multiple-day treatment):
 980    radiata) (n=15) 21-43; foetuses of                           craniofacial dysmorphia, 60 vs. 100%; aplasia cutis
        rhesus monkeys  bonnet, rhesus                               congenital, 60 vs. 20%; cranium bifidum occultum,
        (Macaca         monkeys delivered by                         80 vs. 30%; cranium bifidum, 20 vs. 70%; arched
        mulatta) (n=18) Caesarean section or                         palate, 0 vs. 50%; cleft palate, 0 vs. 30%;
        baboons (Papio  naturally; sacrifice                         meningocele, 20 vs. 70%; encephalocele, 0 vs. 0%;
        cynocephalus)   remaining offspring:                         occipital lobe hypoplasia, 40 vs. 20%; cerebellar
        (n=6)           18-30 mo; foetuses of                        hypoplasia, 20 vs. 40%; hydrocephalus, 0 vs. 30%;
        controls: n=10  baboons delivered by                         midbrain beaking, 40 vs. 20%; growth retardation, 0
        (bonnet) or 14  Caesarean section at                         vs. 40%;
        (rhesus and     gd 100±2;                                    rhesus monkeys (single vs. multiple-day treatment):
        baboon)         gross and                                    craniofacial dysmorphia, 100 vs. 100%; aplasia cutis
                        histopathology                               congenital, 25 vs. 7%; cranium bifidum occultum, 50
                        examination                                  vs. 14%; cranium bifidum, 50 vs. 86%; arched
                        restricted to                                palate, 75 vs. 64%; cleft palate, 0 vs. 14%;
                        craniofacial and cns                         meningocele, 50 vs. 36%; encephalocele, 0 vs. 50%;
                        malformations                                occipital lobe hypoplasia, 100 vs. 29%; cerebellar
                                                                     hypoplasia, 50 vs. 71%; hydrocephalus, 50 vs. 43%;
                                                                     midbrain beaking, 50 vs. 57%; growth retardation, 0
                                                                     vs. 43%;
                                                                     baboons (multiple-day treatments, 5 or 10 mg/kg bw,
                                                                     respectively): craniofacial dysmorphia, 100 vs.
                                                                     100%; aplasia cutis congenita, 33 vs. 0%; cranium
                                                                     bidifum occultum, 33 vs.0%; cranium bificum, 0 vs.
                                                                     100%; arched palate, 33 vs. 50%; cleft palate, 0 vs.
                                                                     0%; meningocele, 0 vs. 50%; encephalocele, 0 vs.
                                                                     50%; occipital lobe hypoplasia, 100 vs. 50%;
                                                                     cerebellar hypoplasia, 100 vs. 100%; hydrocephalus,
                                                                     0 vs. 50%; midbrian beaking, 0 vs. 0%; growth
                                                                     retardation, 100%;
                                                                     prenatal death and stillbirths tripled in bonnet
                                                                     monkeys, doubled in rhesus monkeys, not changed
                                                                     in baboons.
 arker, rhesus monkeys gd 23, 25, 27, 29, 31; 0, 10 mg/ not reported gross observations:
 983    (Macaca         offspring recovered kg bw                    gd 35 (n=2): no exposure related malformations
        mulatta) (n=10; by hysterotomy at gd                         observed;
        controls: n=10) 35 and 42 (single                            gd 42/43 (n=2): craniofacial dysmorphia; occipital
                        mate), and 50, 60, and                       encephalocele; subcutaneous oedema; low-set ears
                        70 (multiple mate);                          (1 animal); appendicular malformations (1 animal);
                        embryos and                                  gd 50 (n=2): craniofacial dysmorphia; occipital
                        foetuses: gross and                          encephalocele; subcutaneous oedema; low-set ears;
                        histological                                 exophtalmia; arched or cleft palate (1 animal);
                        examination                                  gd 60(n=2): craniofacial dysmorphia; occipital
                        restricted to                                encephalocele; subcutaneous oedema; low-set ears;
                        craniofacial and cns                         appendicular malformations (1 animal);
                        malformations                                gd 70 (n=2): craniofacial dysmorphia; occipital
                                                                     encephalocele; low-set ears; exophtalmia; arched or
                                                                     cleft palate
           Fertility and developmental toxicity studies in animals                                                     65
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<pre>                                                                     major histological major findings:
                                                                     gd 35: shortened parachordal mesenchymal
                                                                     condensation; increased cephalic flexure in the brain;
                                                                     gd 42/43, 50, 60, 70: abnormal parachordal cartilage
                                                                     morphology; thin, underdeveloped sphenoid;
                                                                     shortening of the posterior cranial base, decreased
                                                                     cranial base angle; decreased ossification and
                                                                     remodelling in the facial bones, and abnormal
                                                                     position due to the malformed sphenoid
  ow-   Sprague-Dawley gd 9-11, gd 12-14, or 0, 0.125, no maternal effects on prenatal development (in order of
and,    rats (n=9-11/  gd 15-17; sacrifice gd 0.25, 0.5 lethality    increasing exposure level):
Hen-    group)         20                     mg/kg     observed     gd 9-11: viable foetuses/litters: 96, 97, 89, 83%;
 rickx                                        bw                     litters with malformed foetuses: 0, 0, 0, 14%;
 983                                                                 malformed foetuses/litter: 0, 0, 0, 2%;
                                                                     gd 12-14: viable foetuses/litters: 97, 89, 77, 58%;
                                                                     litters with malformed foetuses: 9, 45, 80 (p<0.05),
                                                                     100% (p<0.05); malformed foetuses/litter: 2, 29, 61
                                                                     (p<0.05), 84% (p<0.05);
                                                                     gd 15-17: viable foetuses/litters: 98, 96, 100,
                                                                     92%(p<0.05); litters with malformed foetuses: 0, 0,
                                                                     0, 63% (p<0.05); malformed foetuses/litter: 0, 0, 0,
                                                                     32%(p<0.05);
                                                                     incidence of specific malformations (percentage of
                                                                     foetuses/litter with):
                                                                     gd 9-11: no malformations observed;
                                                                     gd 12-14 (in order of increasing dose): cleft palate: 0/
                                                                     0, 23/45 (p<0.05), 54/60 (p<0.05), 70/80 (p<0.05);
                                                                     umbilical hernias: 0/0, 3/9, 20/50 (p<0.05), 58/80
                                                                     (p<0.05); undescended testes: 0/0, 0/0, 7/13, 28/60
                                                                     (p<0.05); hypoplastic thymus: 0/0, 0/0, 0/0, 0/0;
                                                                     gd 15-17 (0.5 mg/kg bw): cleft palate: 19/50
                                                                     (p<0.05); umbilical hernias: 0/0; undescended testes:
                                                                     0/0; hypoplastic thymus: 22/38 (p<0.05);
                                                                     no malformations observed in groups given the other
                                                                     doses.
  ot-   Sprague-Dawley gd 12-14; sacrifice on 0, 0.6    reduced      general findings:
 child, rats (n=3-5/   gd 15, 17, 18, 21;     mg/kg     maternal     significantly increased number of foetuses with cleft
 997    group          lung tissue of         bw        weight gain, palates (69/80 in treated pooled gd 18 and 21 vs. 1/
                       foetuses examined by             placental    100 in controls; no effect on litter size
                       morphometry                      weight,      morphometry findings (data of GD 21; control vs.
                                                        amniotic     treatment):
                                                        fluid weight mean linear intercept (µm): 58.8±1.0 vs. 50.3±2.0
                                                        (p<0.05)     (p=0.04); mean chord length of saccules (µm):
                                                                     9.9±0.4 vs. 12.6±0.7 (p=0.009); volume density of
                                                                     saccular air(proportions): 17.7±0.4 vs. 25.1±1.7
                                                                     (p=0.007); volume density of saccular wall: 66.8±1.2
                                                                     vs. 57.1±1.73 (p = 0.002); volume density of
                                                                     bronchial air: 2.0±0.2 vs. 4.0±1.0 (p=0.1); volume
                                                                     density of bronchial wall: 4.1±0.5 vs. 6.0±1.0
                                                                     (p=0.11); volume density of non-parenchyma tissue:
                                                                     9.4±0.7 vs. 7.7±1.0 (p=0.18);
  6         Triamcinolone/Tramcinolone acetonide
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<pre>                                                                      peripheral airway count higher in treated animals
                                                                      compared to controls (p<0.001); significantly
                                                                      reduced pole to pole length (p<0.05);
                                                                      histological lung tissue examination: profound
                                                                      pulmonary hypoplasia, accompanied by diminished
                                                                      intermediate airways numbers, increased peripheral
                                                                      saccules numbers, increased cell differentiation.
w=body weight; cns=central nervous system; d=day(s); gd=gestational day(s); mo=month(s); n=number
         Fertility and developmental toxicity studies in animals                                                        67
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<pre>8 Triamcinolone/Tramcinolone acetonide</pre>

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<pre>Health Council of the Netherlands
Advisory Reports
The Health Council’s task is to       In addition, the Health Council
advise ministers and parliament on    issues unsolicited advice that
issues in the field of public health. has an ‘alerting’ function. In some
Most of the advisory opinions that    cases, such an alerting report
the Council produces every year       leads to a minister requesting
are prepared at the request of one    further advice on the subject.
of the ministers.
Areas of activity
Optimum healthcare                    Prevention                          Healthy nutrition
What is the optimum                   Which forms of                      Which foods promote
result of cure and care               prevention can help                 good health and
in view of the risks and              realise significant                 which carry certain
opportunities?                        health benefits?                    health risks?
Environmental health                  Healthy working                     Innovation and
Which environmental                   conditions                          the knowledge
influences could have                 How can employees                   infrastructure
a positive or negative                be protected against                Before we can harvest
effect on health?                     working conditions                  knowledge in the
                                      that could harm their               field of healthcare,
                                      health?                             we first need to
                                                                          ensure that the right
                                                                          seeds are sown.
www.healthcouncil.nl
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<br><br>