<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>Enflurane
Evaluation of the effects on reproduction, recommendation for classification
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<pre>Gezondheidsraad                              Voorzitter
Health Council of the Netherlands
Aan de Staatssecretaris Sociale Zaken en Werkgelegenheid
Onderwerp           : Aanbieding advies ‘Enflurane’
Uw kenmerk          : DGV/MBO/U-932542
Ons kenmerk         : U-1038/AvdB/RA/543-A6
Bijlagen            :2
Datum               : 6 september 2002
Mijnheer de staatssecretaris,
Bij brief van 3 december 1993, nr DGV/MBO/U-932542, verzocht de Staatssecretaris van
Welzijn, Volksgezondheid en Cultuur namens de Minister van Sociale Zaken en Werkgelegenheid
om naast het afleiden van gezondheidskundige advieswaarden ook te adviseren over andere
onderwerpen ten behoeve van de bescherming van beroepsmatig aan stoffen blootgestelde
personen. In 1995 heeft de Staatssecretaris van Sociale Zaken en Werkgelegenheid besloten tot het
opstellen van een zogenaamde niet-limitatieve lijst van voor de voortplanting vergiftige stoffen.
Op deze lijst komen stoffen die volgens de richtlijnen van de Europese Unie ingedeeld moeten
worden in categorie 1, 2 en 3 wat betreft effecten op de voortplanting en stoffen die schadelijk
kunnen zijn voor het nageslacht via de borstvoeding. De Gezondheidsraad is verzocht om voor
stoffen een classificatie volgens de EU-criteria voor te stellen.
      In dit kader bied ik u hierbij een advies aan over Enfluraan. Dit advies is opgesteld door de
Commissie Reprotoxische stoffen van de Gezondheidsraad en beoordeeld door de Beraadsgroep
Gezondheid en Omgeving. Ik heb deze publicatie heden ter kennisname aan de Minister van
Volksgezondheid, Welzijn en Sport en aan de Minister van de Volkshuisvesting, Ruimtelijke
Ordening en Milieu gestuurd.
Hoogachtend,
prof. dr JA Knottnerus
Bezoekadres                                                               Postadres
Parnassusplein 5                                                          Postbus 16052
2511 VX Den Haag                                                          2500 BB Den Haag
Telefoon (070) 3407520                                                    Telefax (070) 340 75 23
E-mail: A.vd.burght@gr.nl                                                 www.gr.nl
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<pre>Enflurane
Evaluation of the effects on reproduction, recommendation for classification
Committee for Compounds toxic to reproduction,
a Committee of the Health Council of the Netherlands
to
the Minister and State Secretary of Social Affairs and Employment
No. 2002/12OSH, The Hague, 6 september 2002
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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...” (Section 21, Health
Act).
     The Health Council receives most requests for advice from the Ministers of Health,
Welfare & Sport, Housing, Spatial Planning & the Environment, Social Affairs &
Employment, and Agriculture, Nature Preservation & Fisheries. 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.
Preferred citation:
Health Council of the Netherlands: Committee for Compounds toxic to reproduction.
Enflurane; Evaluation of the effects on reproduction, recommendation for
classification. The Hague: Health Council of the Netherlands, 2002; publication no.
2002/12OSH.
all rights reserved
ISBN: 90-5549-441-0
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<pre>    Contents
    Samenvatting 7
    Executive summary 8
1   Scope 9
1.1 Background 9
1.2 Committee and procedure 9
1.3 Additional considerations 10
1.4 Labeling for lactation 11
1.5 Data 12
1.6 Presentation of conclusions 12
1.7 Final remark 12
2   Enflurane 13
2.1 Introduction 13
2.2 Human studies 13
2.3 Animal studies 16
2.4 Conclusion 18
    References 21
    Contents                       5
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<pre>  Annexes 26
A The committee 27
B Comments on the public draft 29
C Directive (93/21/EEC) of the European Community 30
D Fertility and developmental toxicity studies 36
E Abbreviations 47
  Contents                                           6
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<pre>Samenvatting
Op verzoek van de Minister van Sociale Zaken en Werkgelegenheid beoordeelt de
Gezondsheidsraad de effecten op de reproductie van stoffen waaraan mensen tijdens de
beroepsuitoefening kunnen worden blootgesteld. De Commissie Reproductietoxische
stoffen, een commissie van de Raad, adviseert een classificatie van reproductietoxische
stoffen volgens Richtlijn 93/21/EEC van de Europese Unie. In het voorliggende rapport
heeft de commissie enfluraan onder de loep genomen.
De aanbevelingen van de commissie zijn:
    Voor effecten op de fertiliteit meent de commissie dat er onvoldoende geschikte
    gegevens beschikbaar zijn. Zij adviseert daarom om enfluraan niet te classificeren.
    Voor effecten op de ontwikkeling is de commissie van mening dat er onvoldoende
    geschikte humane gegevens zijn en dat voldoende diergegevens laten zien dat
    enfluraan de ontwikkeling van het nageslacht niet schaadt. Zij adviseert daarom
    enfluraan niet te classificeren.
    Voor effecten tijdens lactatie, adviseert de commissie om enfluraan niet te
    kenmerken wegens onvoldoende geschikte gegevens.
Samenvatting                                                                            7
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<pre>Executive summary
On request of the Minister of Social Affairs and Employment, the Health Council of
the Netherlands evaluates the effects on the reproduction of substances at the
workplace. The Health Council’s Committee for Compounds Toxic to Reproduction
recommends to classify compounds toxic to reproduction according to the Directive
93/21/EEC of the European Union. In the present report the committee has reviewed
enflurane.
The committee’s recommendations are
    For effects on fertility, the committee recommends not to classify enflurane due to
    a lack of appropriate human and animal data.
    For developmental toxicity, the committee is of the opinion that a lack of
    appropriate human data precludes the assessment of enflurane and that sufficient
    animal data show that no classification is indicated
    For effects during lactation, the committee is of the opinion that a lack of
    appropriate data precludes the labeling of enflurane.
Executive summary                                                                       8
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<pre>Chapter 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. The classification is performed by the Health Council’s Committee for
        Compounds Toxic to Reproduction according to the guidelines of the European Union
        (Directive 93/21/EEC). The committee’s advice on the classification will be applied by
        the Ministry of Social Affairs and Employment to extend the existing list of
        compounds classified as toxic to reproduction (class 1, 2 or 3) or labelled as ‘may
        cause harm to breastfed babies’ (R64).
1.2     Committee and procedure
        The present document contains the classification of enflurane by the Health Council’s
        Committee for Compounds Toxic to Reproduction. The members of the committee are
        listed in Annex A. The first draft of this report was prepared by dr ir MEM Kuilman
        and ir DH Waalkens-Berendsen at the Department of Target Organ Toxicology of TNO
        Nutrition and Food Research, Zeist, The Netherlands, by contract with the Ministry of
        Social Affairs and Employment. The classification is based on the evaluation of
        published human and animal studies concerning adverse effects with respect to fertility
        and development and lactation of the above mentioned compound.
        Scope                                                                                   9
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<pre>    Classification and labeling was performed according to the guidelines of the European
    Union listed in Annex C.
     Classification for fertility and development:
     Category 1             Substances known to impair fertility in humans (R60)
                            Substances known to cause developmental toxicity in humans (R61)
     Category 2             Substances which should be regarded as if they impair fertility in humans (R60)
                            Substances which should be regarded as if they cause developmental toxicity in
                            humans (R61)
     Category 3             Substances which cause concern for human fertility (R62)
                            Substances which cause concern for humans owing to possible developmental
                            toxic effects (R63)
     No classification for effects on fertility or development
     Labelling for lactation:
                            May cause harm to breastfed babies (R64)
                            No labelling for lactation
    In 2002, the President of the Health Council released a draft of the report for public
    review. The individuals and organizations that commented on the draft report are listed
    in Annex B. The committee has taken these comments into account in deciding on the
    final version of the report.
1.3 Additional considerations
    The classification of compounds toxic to reproduction on the basis of the Directive
    93/21/EEC is ultimately dependent on an integrated assessment of the nature of all
    parental and developmental effects observed, their specificity and adversity, and the
    dosages at which the various effects occur. The directive necessarily leaves room for
    interpretation, dependent on the specific data set under consideration. In the process of
    using the directive, the committee has agreed upon a number of additional
    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 progeny, the compound will be classified in category 1, irrespective
         the general toxic effects (see Annex C, 4.2.3.1 category 1).
    Scope                                                                                                   10
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<pre>         Adverse effects in a reproductive or developmental study, in the absence of data on
         parental toxicity, occurring at dose levels which cause severe toxicity in other
         studies, need not necessarily lead to a category 2 classification.
         If, after prenatal exposure, small reversible changes in foetal growth and in skeletal
         development (e.g. wavy ribs, short rib XIII, incomplete ossification) in offspring
         occur in a higher incidence than in the control group in the absence of maternal
         effects, the substance will be classified in category 3 for developmental toxicity. If
         these effects occur in the presence of maternal toxicity, they will be considered as a
         consequence of this and therefore the substance will not be classified for
         developmental toxicity (see Annex C, 4.2.3.3 developmental toxicity final
         paragraph).
         Clear adverse reproductive effects will not be disregarded on the basis of
         reversibility per se.
         Effects on sex organs in a general toxicity study (e.g. in a subchronic or chronic
         toxicity study) may warrant classification for fertility.
         The committee not only uses guideline studies (studies performed according to
         OECD standard protocols*) for the classification of compounds, but non-guideline
         studies are taken into consideration as well.
1.4 Labeling for lactation
    The recommendation for labeling substances for effects during lactation is also based
    on Directive 93/21/EEC. The Directive defines that substances which are absorbed by
    women and may interfere with lactation or which may be present (including
    metabolites) in breastmilk in amounts sufficient to cause concern for the health of a
    breastfed child, should be labeled with R64. Unlike the classification of substances for
    fertility and developmental effects, which is based on a hazard identification only
    (largely independent of the dosage), the labeling for effects during lactation is based on
    a risk characterization and therefore also includes consideration of the level of
    exposure of the breastfed child.
         Consequently, a substance should be labeled for effects during lactation when it is
    likely that the substance would be present in breast milk in potentially toxic levels. The
    committee considers a concentration of a compound as potentially toxic to the breastfed
    child when this concentration is above an exposure limit for the general population, eg
    the acceptable daily intake (ADI).
*   Organisation for Economic Cooperation and Development
    Scope                                                                                       11
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<pre>1.5 Data
    Literature searches were conducted in the on-line databases Toxline and Medline,
    starting from 1966 up to 2000. Literature was selected primarily on the basis of the text
    of the abstracts. Publications cited in the selected articles, but not selected during the
    primary search, were reviewed if considered appropriate. In addition, handbooks and a
    collection of most recent reviews were consulted as well as several websites regarding
    (publications on) toxicology and health. References are divided in literature cited and
    literature consulted but not cited.
         The committee chose to describe human studies in the text, starting with review
    articles and, in addition, the studies are summarized in Annex D. Of each study the
    quality of the study design (performed according to internationally acknowledged
    guidelines) and the quality of documentation are considered.
         Animal data are described in the text and summarized in Annex D.
1.6 Presentation of conclusions
    The classification is given with key effects, species and references specified. In case a
    substance is not classified as toxic to reproduction, one of two reasons is given:
         Lack of appropriate data preclude assessment of the compound for reproductive
         toxicity.
         Sufficient data show that no classification for toxic to reproduction is indicated.
1.7 Final remark
    The classification of compounds is based on hazard evaluation* only, which is one of a
    series of elements guiding the risk evaluation process. The committee 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.
*   for definitions see Tox95
    Scope                                                                                      12
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<pre>Chapter 2
        Enflurane
2.1     Introduction
         Name                :    Enflurane
         CAS-no              :    13838-16-9
         Synonyms            :    2-chloro-1,1,2-trifluoroethyl difluoromethyl ether
         Use                 :    anaesthetic gas (since 1974)
         Mol weight          :    184.49
         Chem formula        :    C3H2ClF5O
         Conversion factor   :    1 ppm = 7.55 mg/m3 (101 kPa, 25ºC)
                                  1 mg/m3 = 0.13 ppm
                                  1% = 10000 ppm = 75500 mg/m3
2.2     Human studies
        Human studies are described in more detail in Tables 1 and 2 (annex D).
        Fertility
        Wyrobek et al. (1981) collected semen samples from 46 anaesthesiologists and 26
        beginning residents in anaesthesiology and detected no differences in sperm
        concentration and number of abnormal sperm cells (Wyr81).
        Enflurane                                                                       13
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<pre>     In a recent study, Peelen et al. (Pee99) reported that the time to pregnancy was not
affected in operation chamber assistants (OR 0.9, 95% CI 0.6-1.4).
     In both studies, however, the composition of the anaesthetic gas mixtures, and the
level and duration of exposure were not reported. Therefore, the committee is of the
opinion that these studies are not sufficient for classification.
     Samples of nasal ciliated epithelium were obtained from 18 non-smoking healthy
patients, of which 8 were males. The samples were exposed for 3 hours to either 5%
enflurane, 3.6% isoflurane or 2.25% halothane. Over a 4 hour observation period the
cilia beat frequency reduced significantly compared with controls exposed to air alone.
The effects of the three compounds was similar (Rap96a). After 1 hour exposure period
the beat frequency returned to baseline values after 60 minutes of washout of enflurane
and isoflurane (Rap96b). Studies on the effect on spermatozoa motility were not
available.
Development
Occupational exposure
Several epidemiological studies were performed in which females occupationally
exposed to anaesthetics and wives of males occupationally exposed to anaesthetics
were inquired about the course and outcome of their pregnancies, with specific
attention for miscarriages and congenital anomalies (Ame74, Cor74, Pha77, Ros78,
Eri79, Lau81, Hem85, Joh87, Gui90, Mat93). In all studies, except Eri79, Lau81, Hem
85 and Joh87, some effects on these parameters were suggested. However, most studies
were criticized by several authors (Fer78, Ves78, Dud81, Tan85) for the following
reasons: studies were retrospective and often loaded questionnaires were used. Age
differences occurred between the exposed and control group and no consideration was
given to social factors, medication, illnesses and possible stress. Furthermore, the
composition of the anaesthetic gas mixtures, in which enflurane was one component,
the duration and level of exposure and its timing in pregnancy and other exposure were
often not reported. Most of these objections were also true for the more recent studies
(Hem85, Joh87, Gui90, Mat93).
     In a recent study, Peelen et al. (Pee99) found no increased risk for spontaneous
abortion, preterm birth and congenital abnormalities among operation personal after
correction for alcohol use, work circumstances and other occupational exposure.
Women present at the beginning of operations had higher risks for preterm birth and
women present at tonsil operations for spontaneous abortions. In this study operation
personnel was exposed to a mixture of anaesthetic gasses and duration of exposure was
Enflurane                                                                                 14
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<pre>    not specified. For that reasons it was not clear if enflurane caused the slight increases in
    reproductive effects.
         The committee concluded that none of the studies available could be used for the
    classification of enflurane for the aforementioned reasons.
    Exposure of pregnant woman during surgery or delivery
    Several studies have been performed regarding anaesthetics during pregnancy or at
    delivery and pregnancy outcome. Stefani et al. (Ste82) found no differences in
    neurobehaviour within 24 h after birth between infants born of mothers anaesthetized
    with enflurane alone (0.3-0.8% [22650-60400 mg/m3]) during parturition and born of
    mothers not anaesthetized during parturition.
         In a cohort study in Canada among women who underwent surgery with
    anaesthesia and women who underwent no surgery during pregnancy, no association
    was found between the incidence of anomalies and anaesthesia nor between the rate of
    abortion and anaesthesia during pregnancy (Dun86). However, taking the type of
    anaesthesia into account (general, local, spinal/block), a significant increase in abortion
    rate was found in women who underwent general anaesthesia during pregnancy (RR
    1.58, 95% CI 1.19-2.09). In this study, no correction was made for socio-economic and
    life-style factors. Furthermore, the relative effect of the anaesthesia versus other
    variables (eg site of operation, indication for the procedure, co-medication) is unclear.
         A case-control study with 694 infants with major central nervous system defects,
    showed no association between the total of these effects or between single effects and
    anaesthesia undergone by their mothers during pregnancy (Syl94). However,
    hydrocephalus with any other effect (OR 2.9, 95% CI 1.2, 6.8) and especially with eye
    defects (OR 39.6, 95% CI 7.5, 209.2) was found to be associated with anaesthesia
    during pregnancy.
         In both studies the anaesthetic gas used was not specified. Therefore, it is not clear
    if enflurane caused the increases in developmental effects.
    Lactation
    No publications were available concerning the excretion of enflurane in human breast
    milk.
2.3 Animal studies
    Fertility and developmental toxicity studies with enflurane in experimental animals are
    summarized in tables 3 and 4 (Annex D), respectively.
    Enflurane                                                                                    15
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<pre>Fertility studies
Male (C57B1/C3H)F1 mice were exposed by inhalation to air, 0.12 and 1.2% [9060
and 90600 mg/m3] enflurane for 4 h/day for 5 days (Lan81). After 28 days epididymal
spermatozoa were evaluated for morphological changes. The percentage abnormal
spermatozoa of the animals exposed to the highest concentration of enflurane was
slightly increased compared to the control (2.04% ± 0.13 vs. 1.42% ± 0.08). For the
lowest concentration group no difference in abnormal spermatozoa was observed.
Twenty percent of the animals in the high-dose group died; other toxic effects were not
described in this study. The committee doubts the relevance of these findings for the
(human) fertility.
    Wharton et al. (Wha81) exposed 4 week old male Swiss/ICR mice during 11 weeks
prior to mating with non-exposed females inhalatory to 0, 0.01, 0.1 and 1% [755, 7550
and 75500 mg/m3] enflurane for 4 h/day 5 days/week. The males showed reduced
weight gain after 5.5 weeks of exposure. Therefore the highest concentration was
reduced to 0.5% [37750 mg/m3]. No difference in pregnancy rate, number of
implantations, live foetuses or reproduction loss was observed.
    Similar parameters (on number of implantations, live foetuses or reproduction loss)
were also unaffected after inhalatory exposure of male Sprague Dawley rats to 20 and
200 ppm [151 and 1510 mg/m3] enflurane during 63 days prior to mating with
non-exposed females for 8h/day 5 days/week (Hal81, Gre82). Paternal toxic effects
were not observed.
    Cameron et al. (Cam83) did not find any influence on serum testosterone,
luteinizing hormone and follicle stimulating hormone in male Sprague-Dawley rats
after inhalatory exposure to 50, 500 and 1000 ppm [377.5, 3775 and 7550 mg/m3]
enflurane 6h/day for 11, 9 and 3 days, respectively. General toxic effects were not
presented.
Developmental toxicity
Saito et al. (Sai74) exposed pregnant ddY mice from gestation day (GD) 7-12 during 1
h/day inhalatory to 0, 0.05 and 0.75% [3775 and 56625 mg/m3] enflurane and pregnant
Wistar rats from GD 9-14 during 1 h/day inhalatory to 0, 0.05 and 1.25% [3775 and
94375 mg/m3] enflurane. Fifteen rats and mice underwent Caesarean section whereas 5
animals were allowed to deliver. No treatment related differences on a range of
developmental features, including external, visceral, skeletal and behavioural
development were found in any of the species. Treatment related differences in
maternal body weight were not observed.
Enflurane                                                                               16
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<pre>     Strout et al. (Str77) treated pregnant Sprague Dawley rats from GD 1-18 inhalatory
with 0, 10.7 and 63.7 ppm [80.8 and 480.9 mg/m3] enflurane for 8 h/day. Litter size
was not affected, but birth weights of exposed offspring were higher than in controls.
Cross-fostering studies showed no effects on body weight after exposure to the
low-dose. In the high-dose groups, offspring delivered by untreated and cross-fostered
by treated dams or vice versa showed decreased body weight at PN 7, but not at PN 14
or 21. Offspring delivered and fostered by treated dams showed an increased body
weight at PN 21. No maternal toxicity was observed. The committee is of the opinion
that the effects on body weight were minor effects and might be due to the modest
anaesthetic effect of enflurane.
     Pope and Persaud (Pop78) observed lower foetal weights after inhalatory exposure
of Sprague Dawley rats on GD 0-20 to 3200 ppm [24160 mg/m3] enflurane for 8h/day
in the absence of maternal toxicity.
     Wharton et al. (Wha81) treated in a first experiment female Swiss/ICR mice
inhalatory with 0, 0.01, 0.1 and 1% [755, 7550 and 75500 mg/m3] enflurane 4h/day, 7
days/week. The exposure started 3 weeks prior to mating with untreated males and was
continued until GD 18. The highest dose was decreased to 0.5% [37750 mg/m3] at the
beginning of the mating period as females showed reduced weight gain during the
premating period. No difference in gestational weight was observed. A dose related
increase was seen in lumbar rib formation reaching statistical significance in the
highest treatment group. Also, a higher incidence of increased renal pelvic cavitation
was observed in this group. No effect was found on the number of live foetuses and
implantations, percentage of resorptions or foetal death and foetal weight. In a
following experiment, exposure of female mice to aforementioned concentrations
levels during GD 6-15 resulted in a decrease in foetal weight, length and ossification
and an increased incidence of major malformations (cleft palate), minor skeletal
anomalies and variants, visceral variants (increased renal pelvic cavitation) and minor
anomalies (enlarged brain ventricle) at the highest concentration. At this concentration
(1%) a reduced gestational weight was observed. Treatment at the same concentrations
levels of males 11 weeks prior to mating with untreated females showed no difference
in foetal weight and length.
     Chalon et al. (Cha81) studied the maze performance of albino mice 6-7 weeks of
age exposed during pregnancy by inhalation to 2 and 4% [151000 and 302000 mg/m3]
enflurane on GD 6 and 11 or 14 and 17 during 30 minutes. Treated mice were slower
on day 3, 5, 7 and 10 of the training period (10 days) compared to controls, but not on
the first day. Maternal toxicity was not presented.
     Exposure of male Sprague Dawley rats to 20 and 200 ppm [151 and 1510 mg/m3]
enflurane 8h/day for 5 days/week during 63 days prior to mating with non-treated
females did not result in any treatment related differences in foetal and placental
Enflurane                                                                                17
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<pre>    features compared to controls (Hal81, Gre82). Similarly, no effects were found in the
    offspring of females exposed to the same concentrations of enflurane 28 days prior to
    mating with non-treated males and during gestation. No effects on fertility and
    reproduction parameters were detected among the progeny of offspring of males
    exposed inhalatory to 20 ppm enflurane during 63 days prior to mating with
    non-treated females (Hal81). At 200 ppm these effects were not studied (Gre82).
    General toxic effects were not observed.
        Fischer 344 rats exposed in utero to 1500 ppm [11325 mg/m3] enflurane on GD
    0-20 during 6h/day did not show any treatment related differences in a battery of
    behavioural tests at several ages (Pet82). Differences found were a shortened
    pentobarbital sleep time at puberty indicative of a changed metabolism and an
    increased percentage of litters with 6 or less pups (35% versus 5% in controls).
    Detailed litter data were not given. Mean pup weight and postnatal growth were
    unaffected. Effects on maternal weight gain and behaviour were not observed.
        Mazze et al. (Maz86) exposed pregnant Sprague Dawley rats by inhalation to
    1.65% [124575 mg/m3] enflurane for 5 h/day on GD 14-16 (period I), for 6h/day on
    GD 11-13 (period II), or 6 h/day on GD 8-10 (period III). A decreased foetal weight
    was observed in the period I and period III treated groups. When exposed from GD
    11-13 (period II) an increased incidence of rudimentary lumbar rib was observed. All
    dams suffered from light general anaesthesia, whereas the dams exposed GD 14-16
    (period I) showed lower weight gain. No effects were found on number of
    implantations/dam, live foetuses/dam and resorptions/dam.
    Lactation
    No publications were available.
2.4 Conclusion
    Only two studies concerning the effects of anaesthetic gasses on human fertility were
    available (Wyr81, Pee99). In these studies no effects on sperm quality (Wyr81) and
    time to pregnancy (Pee99) were observed. However, no conclusions can be drawn
    about the effects of enflurane on human fertility, as the anaesthetic gasses used were
    not specified. For this reason, the committee is of the opinion that a lack of appropriate
    human data preclude the assessment of enflurane for effects on fertility.
        In male mice and rats exposed inhalatory to 337.5-37750 mg/m3 enflurane no
    changes in pregnancy rate, number of implantations, live foetuses, reproduction loss
    and hormone levels were observed (Wha81, Hal81, Gre82, Cam83). The increase in
    abnormal sperm morphology in mice found by Land et al. in the high dose group was
    Enflurane                                                                                  18
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<pre>only slight and in addition mortality was observed (Lan81). No studies concerning
female fertility were available.
     In view of these animal data, a lack of appropriate data precludes the assessment
for fertility.
Epidemiological studies considering occupational exposure (Ame74, Cor74, Pha77,
Ros78, Eri79, Lau81, Hem85, Joh87, Gui90, Mat93, Pee99) gave rise to concern about
the effects of anaesthetic gas mixtures on abortion, foetal development, preterm birth
and congenital anomalies. In addition, a cohort study regarding anaesthesia during
pregnancy and pregnancy outcome showed general anaesthesia to be associated with an
increase in abortion rate (Dun86). In a case control study, hydrocephalus with any
other congenital effect, and especially with eye defects, was associated with
anaesthesia during pregnancy (Syl94). However, as the anaesthetic gasses used were
not specified in any of these studies, the committee is of the opinion that it is not clear
whether the effects described were caused by enflurane. A study comparing infants
born of mothers under 0.3-0.8% [22650-60400 mg/m3] (pure) enflurane anaesthesia
alone and infants of mothers born without anaesthesia showed no differences in
neurobehaviour 2 to 24h after parturition (Ste82). Considering the above described
studies, the committee is of the opinion that a lack of appropriate human data preclude
the assessment of enflurane for effects on development.
     In several studies in rats and mice, effects of enflurane on development were
observed. Pope and Persaud (Pop78) and Mazze et al. (Maz86) found a decreased
foetal weight after exposure of female Sprague Dawley rats to 3200 ppm [24160
mg/m3] and 1.65% enflurane [124575 mg/m3], respectively. In addition, an increased
incidence of rudimentary lumbar rib was found in the latter study. However, the
committee considers these findings as secondary to growth retardation. In addition, the
effects were found in the presence maternal toxicity (light anaesthesia) (Maz86) or
maternal toxicity could be expected based on the concentration used (Pop78). Wharton
et al (Wha81) found an increase in lumbar rib formation as well as a higher incidence
of increased renal pelvic cavitation in foetuses of Swiss/ICR mice treated 3 weeks prior
to mating with untreated males with 1% [75500 mg/m3] and during gestation with 0.5%
[37750 mg/m3]. The high concentration during premating resulted in lower body
weight gain, whereas during gestation no maternal toxicity was observed. Exposure of
pregnant mice to 1% [75500 mg/m3] during gestation resulted in a decrease in foetal
weight, length and ossification and a variety of skeletal and visceral anomalies,
malformations and variants. However, a reduced gestational weight was observed at
this concentration. Chalon et al. (Cha81) found 6 to 7 week old mice exposed in utero
to 2 or 4% [151000 or 302000 mg/m3] enflurane to perform slower in the maze than
control mice. In this study, maternal toxicity was not described. The committee
Enflurane                                                                                   19
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<pre>considers that the doses used in Wharton et al (Wha81) and Chalon et al (Cha81) are
likely to have caused maternal effects.
    In view of the animal studies with respect to the effects on development, the
committee concludes that only effects on foetal body weight were found in the
presence of maternal toxicity (light anaesthesia). Therefore, the committee is of the
opinion that sufficient animal data show that no classification of enflurane is indicated.
As no studies on enflurane in breast milk were available, the committee recommends
not to label enflurane for effects during lactation because of a lack of appropriate data.
Proposed classification for fertility
A lack of appropriate human and animal data precludes the assessment of enflurane for
effects on fertility.
Proposed classification for developmental toxicity
A lack of appropriate human data precludes the assessment of enflurane for effects on
development and sufficient animal data show that no classification is indicated.
Proposed labeling for effect during lactation
Lack of appropriate data precludes the assessment of enflurane for labeling for effects
during lactation.
Enflurane                                                                                  20
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<pre>      References
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Cha81 Chalon J, Tang C-K, Ramanathan S, Eisner M, Katz R, Turndorf H. Exposure to halothane and enflurane
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Eri79 Ericson A, Källèn B. Survey of infants born in 1973 or 1975 to Swedish women working in operating
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Gui90 Guirguis SS, Pelmear PL, Roy ML, Wong L. Health effects associated with exposure to anaesthetic gases
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<pre>Hal81  Halsey MJ, Green CJ, Monk SJ, Doré C, Knight JF, Luff NP. Maternal and paternal chronic exposure to
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Hem85  Hemminki K, Kyronen P, Lindbohm ML. Spontaneous abortions and malformations in the offspring of
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Joh87  Johnson JA, Buchan RM, Reif JS. Effect of waste anesthetic gas and vapor exposure on reproductive
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Lan81  Land PC, Owen El, Linde HW. Morphologic changes in mouse spermatozoa after exposure to inhalational
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Lau81  Lauwerys R, Siddons M, Misson CB, Borlee I, Bouckaert A, Lechat MF, DeTemmerman P. Anaesthetic
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Pee99  Peelen S, Roeleveld N, Heederik D, Kromhout H, de Kort W. Reproductie-toxische effecten bij
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Pet82  Peters MA, Hudson PM. Postnatal development and behavior in offspring of enflurane exposed pregnant
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Pha77  Pharoah POD, Alberman E, Doyle P. Outcome of pregnancy among women in anestetic practice. Lancet
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Pop78  Pope WDB, Persaud TVN. Foetal growth retardation in the rat following chronic exposure to the
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Rap96a Raphael JA, Selwyn DA, Mottram SD et al. Effects of 3 MAC of halothane, enflurane and isoflurane on
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Rap96b Raphael JA, Strupisch J, Selwyn DA et al. Recovery of respiratory ciliary function after depression by
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Ros78  Rosenberg PH, Väntinnen H. Occupational hazards to reproduction and health in anaesthetists and
       paediatricians. Acta Anaesthesiol. Scand. 1978; 22:202-207.
Sai74  Saito N, Urakawa M, Ito R. Influence of enflurane on fetus and growth after birth in mice and rats. Oyo
       Yakuri. 1974; 8: 1269-1276 (Japanese).
Ste82  Stefani SJ, Hughes SC, Shnider SM, Levinson G, Abboud TK, Henriksen EH, Williams V, Johnson J.
       Neonatal neurobehavioral effects of inhalation analgesia for vaginal delivery. Anesthesiology. 1982; 56:
       351-355.
Str77  Strout CD, Nahrwold ML, Taylor MD, Zagon IS. Effects of subanesthetic concentrations of enflurane on
       rat pregnancy and early development. Env. Health Persp. 1977; 21: 211-214.
Syl94  Sylvester GC, Khourt MJ, Lu X, Erickson JD. First-trimester anesthesia exposure and the risk of central
       nervous system defects: a population-based case-control study. Am. J. Publ. Health 1994; 84: 1757-1760.
       References                                                                                                22
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<pre>Tan85  Tannenbaum TN, Goldberg RJ. Exposure to anesthetic gases and reproductive outcome. J. Occup. Med.
       1985; 27: 659-668.
Tox95  Niesink RJM, de Vries J, Hollinger MA, eds, Toxicology, Principles and Applications, Boca Raton: CRC
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Ves78  Vessey MP. Epidemiological studies of the occupational hazards of anaesthesia- a review.Anaesth. 1978;
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Wha81  Wharton RS, Mazze RI, Wilson AI. Reproduction and fetal development in mice chronically exposed to
       enflurane. Anesthesiology 1981; 54: 505-510.
Wyr81  Wyrobek AJ, Brodsky J, Gordon L, Moore DH, Watchmaker G, Cohen EN. Sperm studied in
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       Literature consulted but not cited
.Abb81 Abboud TK, Shnider SM, Wright RG, Rolbin SH, Craft JB, Henriksen EH, Johnson J, Jones MJ, Hughes
       SC, Levinson G. Enflurane analgesia in obstetrics. Anesth. Analg. 1981; 60: 133-137.
Ask70  Askrog V, Harvald B. Teratogen effekt inhalationsanaestetika. Nord. Medicin 1970; 16:498-500.
Bad80  Baden JM, Rice SA, Wharton RS, Laughlin NK. Metabolic and toxicologic studies with enflurane in
       Swiss/ICR mice. J. Environ. Pathol. Toxicol. 1980; 4: 293-303.
Bai94  Baillot A, Brünner M, Diepenbrock F, Sander J. Belastung der Operationssaalluft mit Narkosegases in
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Bur85  Buring JE, Hennekens CH, Mayrent SL, Rosner B, Greenberg ER, Colton T. Health experiences of
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Bus76  Bussard DA. Congenital anomalies and inhalation anesthetics. JADA 1976; 93: 606-609.
Coh71  Cohen EN, Bellville JW, Brown BW. Anesthesia, pregnancy and miscarriage: a study of operating nurses
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Coh75  Cohen EN, Brown BW, Bruce DL et al. A survey of anesthetic Health hazards among dentists. J. Am.
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Coh80  Cohen EN, Brown BW, Wu ML et al. Occupational disease in dentistry and chronic exposure to trace
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Cor74b Corbett TH. Inhalation anesthesia: an occupational hazard. Hospital Practice 1974; 9: 81-88.
Ebi94  Ebi KL, Rice SA. Reproductive and developmental toxicity of anesthetics in humans. Anesth. Toxicity
       1994; 175-198.
Fis76  Fiserova-Bergerova V. Fluoride in bone of rats anesthetized during gestation with enflurane or
       methoxyflurane. Anestesiology 1976; 45: 483-486.
Fri88  Friedman JM. Teratogen update: anesthetic agents. Teratology 1988; 37: 69-77.
Fri96  Friedler G. Paternal exposures: impact on reproductive and developmental outcome. An overview.
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Har81  Hardin BD, Bond GP, Sikov MR, Andrew FD, Beliles RP, Niemeier RW. Testing of selected workplace
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       References                                                                                             23
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<pre>Hea98 Health Council of the Netherlands: Dutch Expert Committee on Occupational Standards (DECOS).
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Hem85 Hemminki K, Vineis P. Extrapolation of the evidence on teratogenicity of chemicals between humans and
      experimental animals: chemicals other than drugs. Teratogenesis, Carcinog. Mutagen. 1985; 5:251-358.
Her77 Herrera J, Mantilla M. Teratogenic effects of halogens on mice. Excerpta Med. Int. Congr. Ser. 1977; 399:
      15-21.
Hin85 Hinkley RE, Wright BD. Comparative effects of halothane, enflurane, and methoxyflurane on the
      incidence of abnormal development using sea urchin gametes as an in vitro model system. Anesth. Analg.
      1985; 64: 1005-1009.
Inf85 Infante PF, Tsongas TA. Anesthetic gases and pregnancy: a review of evidence for an occupational
      hazard. Occ. Haz. Reprod. 1985: 287-294.
Jon78 Jones DJ, Hodgson BJ, Stehling LC, Zauder HL. Enflurane and uterine contractibility in rabbits. Anesth.
      Analg. 1978; 57: 160-165.
Kal90 Källén B, Mazze RI. Neural tube defects and first trimester operations. Teratology 1990; 41:
      717-720.Kni72Knill-Jones RP, Rodrigues LV, Moir DD, Spence AA. Anaesthetic practice and pregnancy:
      controlled survey of women anaesthetists in the United Kingdom. Lancet 1972; 1:1326-1328.
Kni75 Knill-Jones RP, Newman BJ, Spence AA. Anaesthetic practice and pregnancy: controlled survey of male
      anaesthetists in the United Kingdom. Lancet 1975; 2:807-809.
Lan79 Land PC, Owen EL, Linde HW. Mouse sperm morphology following exposure to anesthetics during early
      spermatogenesis. Anesthesiology 1979; 51: S259.
Mar97 Marx T. Belastung des Arbeitsplatzes mit volatilen Anasthetika und Lachgas. Anasthesiol. Intensivmed
      Notfallmed Schmerzther 1997; 32: 532-540.
Maz89 Mazze RI, Källén B. Reproductive outcome after anesthesia and operation during pregnancy: a registry
      study of 5405 cases. Am. J. Obstet. Gynecol. 1989; 161: 1178-1185.
Mon82 Monk SJ, Doré C, Green CJ, Halsey MJ, Knight JK, Luff NP. Is chronic exposure to enflurane teratogenic
      or toxic at 200 ppm? A study in rats. Br. J. Anesth. 1982; 54: 1139-1140.
Nat90 Natsume N, Miura S, Sugimoto S, Nakamura T, Horiuchi R, Kondo S, Furukawa H, InagakiS, Kawai T,
      Yamada M, Arai T, Hosoda R. Teratogenicity caused by halothane, enflurane and sevoflurane, and
      changes depending on O2 concentration. Teratology 1990; 42: 30A (abstract).
Plu86 Plummer JL, Hall PdelaM, Jenner MA, Ilsley AH, Cousins MJ. Effects of chronic inhalation of halothane,
      enflurane or isoflurane in rats. Br. J. Anaesth. 1986; 58: 517-523.
Raj89 Rajhans GS, Brown DA, Whaley D, Wong L, Guirguis SS. Hygiene aspects of occupational exposure to
      waste anaesthetic gases in Ontario hospitals. Ann. Occup. Hyg. 1989; 33: 27-45.
Rey98 Reynolds F. Effects of labour analgesia on the baby. Fetal and Maternal Med. Rev. 1998; 10: 45-59.
Ric93 Rice SA. Anaesthesia in pregnancy and the fetus: toxicological aspects. In: Reynolds F. Effects on the
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      References                                                                                                24
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<pre>Rod83 Rodier PM. Differential structural effects of three behavioral teratogens. In: Developments in the Science
      and Practice of Toxicology. 1983: 53-60. (Eds: Hayes AW, Schnell RC, Miya TS. Elsevier Science
      Publishers).
Rod86 Rodier PM, Aschner M, Lewis LS, Koëter HBWM. Cell proliferation in developing brain after brief
      exposure to nitrous oxide or halothane. Anesthesiology 1986; 64: 680-687.
Ros73 Rosenberg P, Kirves A. Miscarriages among operating theatre staff. Acta Anaeast. Scand. 1973; 53: 37-42.
Shn65 Shnider SM, Webster GM. Maternal and fetal hazards of surgery during pregnancy. Am. J. Obst. Gynecol.
      1965; 92: 891-900.
Smi63 Smith BE. Fetal prognosis after anesthesia during gestation. Anesth. Analg. 1963; 42: 521-526.
Tom79 Tomlin PJ. Health problems of anaesthetists and their families in the West Midlands. Br. Med. J. 1979:
      779-784.
Wal75 Walts LF, Forsythe AB, Moore JG. Critique: Occupational disease among operating room personnel.
      Anesthesiology 1975; 42:608-611.
      References                                                                                                 25
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<pre>A The committee
B Comments on the public draft
C Directive (93/21/EEG) of the European Community
D Fertility and developmental toxicity studies
E Abbreviations
  Annexes
                                                  26
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<pre>Annex A
      The committee
         BJ Blaauboer, chairman
         Toxicologist; Research Institute of Toxicology, Utrecht
         JN van den Anker
         Professor of pediatrics and pharmacology; The George Washington University
         Medical Center, USA
         AM Bongers, advisor
         Ministry of Social Affairs and Employment, The Hague
         HFP Joosten
         Toxicologist; NV Organon, Department of Toxicology and Drug Disposition, Oss
         D Lindhout
         Professor of medical genetics, paediatrician; UMC, Utrecht
         JHJ Copius Peereboom-Stegeman
         Toxicologist; Catholic University Nijmegen, Nijmegen
         AH Piersma
         Reproductive toxicologist; National Institute of Public Health and the
         Environment, Bilthoven
         N Roeleveld
         Epidemiologist; Catholic University Nijmegen, Nijmegen.
         DH Waalkens-Berendsen
         Reproductive toxicologist; TNO Nutrition and Food Research, Zeist
         PJJM Weterings
         Toxicologist; Weterings Consultancy BV, Rosmalen
      The committee                                                                   27
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<pre>    ASAM van der Burght, scientific secretary
    Health Council of the Netherlands, Den Haag
The first draft of the present document was prepared by MEM Kuilman and DH
Waalkens-Berendsen, from the TNO Nutrition and Food Research in Zeist, by contract
with the Ministry of Social Affairs and Employment.
Secretarial assistance: T van der Klugt.
Lay-out: J van Kan.
The committee                                                                      28
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<pre>Annex B
      Comments on the public draft
      A draft of the present report was released in 2002. The following persons and
      organizations have commented on the draft review:
          RD Zumwalde
          National Institute for Occupational Safety and Health, USA
      Comments on the public draft                                                  29
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<pre>Annex C
      Directive (93/21/EEC) of the European
      Community
      4.2.3         Substances toxic to reproduction
      4.2.3.1       For the purposes of classification and labelling and having regard to the present
                    state of knowledge, such substances are divided into 3 categories:
      Category 1:
      Substances known to impair fertility in humans
      There is sufficient evidence to establish a causal relationship between human exposure to the substance
      and impaired fertility.
      Substances known to cause developmental toxicity in humans
      There is sufficient evidence to establish a causal relationship between human exposure to the substance
      and subsequent developmental toxic effects in the progeny.
      Category 2:
      Substances which should be regarded as if they impair fertility in humans:
      Directive (93/21/EEC) of the European Community                                                         30
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<pre>There is sufficient evidence to provide a strong presumption that human exposure to the substance may
result in impaired fertility on the basis of:
     Clear evidence in animal studies of impaired fertility in the absence of toxic effects, or, evidence of
     impaired fertility occurring at around the same dose levels as other toxic effects but which is not a
     secondary non-specific consequence of the other toxic effects.
     Other relevant information.
Substances which should be regarded as if they cause developmental toxicity to humans:
There is sufficient evidence to provide a strong presumption that human exposure to the substance may
result in developmental toxicity, generally on the basis of:
     Clear results in appropriate animal studies where effects have been observed in the absence of signs
     of marked maternal toxicity, or at around the same dose levels as other toxic effects but which are not
     a secondary non-specific consequence of the other toxic effects.
     Other relevant information.
Category 3:
Substances which cause concern for human fertility:
Generally on the basis of:
     Results in appropriate animal studies which provide sufficient evidence to cause a strong suspicion of
     impaired fertility in the absence of toxic effects, or evidence of impaired fertility occurring at around
     the same dose levels as other toxic effects, but which is not a secondary non-specific consequence of
     the other toxic effects, but where the evidence is insufficient to place the substance in Category 2.
     Other relevant information.
Substances which cause concern for humans owing to possible developmental toxic effects:
Generally on the basis of:
     Results in appropriate animal studies which provide sufficient evidence to cause a strong suspicion of
     developmental toxicity in the absence of signs of marked maternal toxicity, or at around the same
     dose levels as other toxic effects but which are not a secondary non-specific consequence of the other
     toxic effects, but where the evidence is insufficient to place the substance in Category 2.
     Other relevant information.
Directive (93/21/EEC) of the European Community                                                                31
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<pre>4.2.3.2       The following symbols and specific risk phrases apply:
Category 1:
For substances that impair fertility in humans:
T; R60: May impair fertility
For substances that cause developmental toxicity:
T; R61: May cause harm to the unborn child
Category 2:
For substances that should be regarded as if they impair fertility in humans:
T; R60: May impair fertility
For substances that should be regarded as if they cause developmental toxicity in humans:
T; R61: May cause harm to the unborn child.
Category 3:
For substances which cause concern for human fertility:
Xn; R62: Possible risk of impaired fertility
For substances which cause concern for humans owing to possible developmental toxic effects:
Xn; R63: Possible risk of harm to the unborn child.
4.2.3.3       Comments regarding the categorisation of substances toxic to reproduction
Reproductive toxicity includes impairment of male and female reproductive functions or capacity and the
induction of non-inheritable harmful effects on the progeny. This may be classified under two main
headings of 1) Effects on male or female fertility, 2) Developmental toxicity.
1)   Effects on male or female fertility, includes adverse effects on libido, sexual behaviour, any aspect of
     spermatogenesis or oogenesis, or on hormonal activity or physiological response which would
Directive (93/21/EEC) of the European Community                                                               32
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<pre>      interfere with the capacity to fertilise, fertilisation itself or the development of the fertilised ovum up
      to and including implantation.
2)    Developmental toxicity, is taken in its widest sense to include any effect interfering with normal
      development, both before and after birth. It includes effects induced or manifested prenatally as well
      as those manifested postnatally. This includes embrytoxic/fetotoxic effects such as reduced body
      weight, growth and developmental retardation, organ toxicity, death, abortion, structural defects
      (teratogenic effects), functional defects, peripostnatal defects, and impaired postnatalmental or
      physical development up to and including normal pubertal development.
Classification of chemicals as toxic to reproduction is intended to be used for chemicals which have an
intrinsic or specific property to produce such toxic effects. Chemicals should not be classified as toxic to
reproduction where such effects are solely produced as a non-specific secondary consequence of other
toxic effects. Chemicals of most concern are those which are toxic to reproduction at exposure levels
which do not produce other signs of toxicity.
The placing of a compound in Category 1 for effects on Fertility and/or Developmental Toxicity is done
on the basis of epidemiological data. Placing into Categories 2 or 3 is done primarily on the basis of
animal data. Data from in vitro studies, or studies on avian eggs, are regarded as ‘supportive evidence’ and
would only exceptionally lead to classification in the absence of in vivo data.
In common with most other types of toxic effect, substances demonstrating reproductive toxicity will be
expected to have a threshold below which adverse effects would not be demonstrated. Even when clear
effects have been demonstrated in animal studies the relevance for humans may be doubtful because of the
doses administrated, for example, where effects have been demonstrated only at high doses, or where
marked toxicokinetic differences exist, or the route of administration is inappropriate. For these or similar
reasons it may be that classification in Category 3, or even no classification, will be warranted.
Annex V of the Directive specifies a limit test in the case of substances of low toxicity. If a dose level of
at least 1000 mg/kg orally produces no evidence of effects toxic to reproduction, studies at other dose
levels may not be considered necessary. If data are available from studies carried out with doses higher
than the above limit dose, this data must be evaluated together with other relevant data. Under normal
circumstances it is considered that effects seen only at doses in excess of the limit dose would not
necessarily lead to classification as Toxic to Reproduction.
Effects on fertility
For the classification of a substance into Category 2 for impaired fertility, there should normally be clear
evidence in one animal species, with supporting evidence on mechanism of action or site of action, or
chemical relationship to other known antifertility agents or other information from humans which would
Directive (93/21/EEC) of the European Community                                                                   33
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<pre>lead to the conclusion that effects would be likely to be seen in humans. Where there are studies in only
one species without other relevant supporting evidence then classification in Category 3 may be
appropriate.
Since impaired fertility may occur as a non-specific accompaniment to severe generalised toxicity or
where there is severe inanition, classification into Category 2 should only be made where there is evidence
that there is some degree of specificity of toxicity for the reproductive system. If it was demonstrated that
impaired fertility in animal studies was due to failure to mate, then for classification into Category 2, it
would normally be necessary to have evidence on the mechanism of action in order to interpret whether
any adverse effect such as alteration in pattern of hormonal release would be likely to occur in humans.
Developmental toxicity
For classification into Category 2 there should be clear evidence of adverse effects in well conducted
studies in one or more species. Since adverse effects in pregnancy or postnatally may result as a secondary
consequence of maternal toxicity, reduced food or water intake, maternal stress, lack of maternal care,
specific dietary deficiencies, poor animal husbandry, intercurrent infections, and so on, it is important that
the effects observed should occur in well conducted studies and at dose levels which are not associated
with marked maternal toxicity. The route of exposue is also important. In particular, the injection of
irritant material intraperitoneally may result in local damage to the uterus and its contents, and the results
of such studies must be interpreted with caution and on their own would not normally lead to
classification.
Classification into Category 3 is based on similar criteria as for Category 2 but may be used where the
experimental design has deficiencies which make the conclusions less convincing, or where the possibility
that the effects may have been due to non-specific influences such as generalised toxicity cannot be
excluded.
In general, classification in category 3 or no category would be assigned on an ad hoc basis where the only
effects recorded are small changes in the incidences of spontaneous defects, small changes in the
proportions of common variants such as are observed in skeletal examinations, or small differences in
postnatal developmental assessments.
Effects during Lactation
Substances which are classified as toxic to reproduction and which also cause concern due to their effects
on lactation should in addition be labelled with R64 (see criteria in section 3.2.8).
Directive (93/21/EEC) of the European Community                                                                34
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<pre>For the purpose of classification, toxic effects on offspring resulting only from exposure via the breast
milk, or toxic effects resulting from direct exposure of children will not be regarded as ‘Toxic to
Reproduction’, unless such effects result in impaired development of the offspring.
Substances which are not classified as toxic to reproduction but which cause concern due to toxicity when
transferred to the baby during the period of lactation should be labelled with R64 (see criteria in section
3.2.8). This R-phrase may also be appropriate for substances which affect the quantity or quality of the
milk.
R64 would normally be assigned on the basis of:
a)   toxicokinetic studies that would indicate the likelihood that the substance would be present in
     potentially toxic levels in breast milk, and/or
b)   on the basis of results of one or two generation studies in animals which in- dicate the presence of
     adverse effects on the offspring due to transfer in the milk, and/or
c)   on the basis of evidence in humans indicating a risk to babies during the lactational period.
     Substances which are known to accumulate in the body and which subsequently may be released into
     milk during lactation may be labelled with R33 and R64.
Directive (93/21/EEC) of the European Community                                                             35
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<pre>Annex D
      Fertility and developmental toxicity
      studies
      See next pages.
      Fertility and developmental toxicity studies 36
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<pre>Table 1.1 Fertility studies in man.
authors exposure                study type/data      study/comparation population         investigated effects remarks
                                collection                                                and results
Wyr81     Mixture: waste        Cohort study/ semen  46 anaesthesiologist 26 beginning    No effect on sperm   Mixed exposure
          anaesthetics          sampling             residents in anaesthesiology         concentration and    Controlled for
          Exposure for at                                                                 sperm abnormalities  smoking,
          least one year                                                                                       medical history,
                                                                                                               sauna use
Pee99     Mixture: waste        Retrospective survey 427 pregnant females (age 22-37      No effect on time to Mixed exposure
          anaesthetics          The Netherlands      years) employed in anaesthesia/      pregnancy
          Employment in         1990-1997/postal     1,010 pregnant females (age 22-37
          anaesthesia           questionnaire        years) nurses employed in department
                                                     of orthopaedics, gynaecology or
                                                     surgery
              Fertility and developmental toxicity studies                                                                   37
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<pre>Tabel 2.1 Developmental toxicity studies in man.
authors   exposure                       study type/data     study/comparation population      investigated effects and remarks
                                         collection                                            results
Ame74     Mixture: waste anaesthetics    Retrospective       18,568 pregnancies in 29,810      Increase of              Mixed exposure Rates
          Females: exposure during 1st survey USA            exposed OT personnel from 4       spontaneous abortions    were standardised by
          trimester of pregnancy and     1972-1974/postal    societies                         in exposed females       the direct method
          work in OT during previous     questionnaire       5,620 pregnancies in 10,420       Increase of congenital   adjusted for maternal
          calendar year.                                     unexposed physicians, nurses and  abnormalities in         age and smoking
          Males, work in OT during                           their wives from 2 societies plus exposed females and
          year prior ro pregnancy                            unexposed individuals and their   wives of exposed males
                                                             wives from study population
Cor74     Mixture: waste anaesthetics    Retrospective       434 births to 268 nurses who      Increase in congenital   Mixed exposure Age
          OT employment during           survey USA / postal practised anaesthesia during      abnormalities            was not a factor in the
          pregnancy                      questionnaire and   pregnancy                                                  observed differences
                                         telephone interview 261 births to nurses who did not                           between exposed and
                                                             practice anaesthesia during                                non-exposed groups
                                                             pregnancy and published incidence
                                                             rates
Pha77     Mixture: waste anaesthetics    Retrospective       670 pregnancies while employed as Risk on spontaneous      Mixed exposure
          Appointment as                 survey UK/ postal   anaesthesiologist                 abortion, low birth      Effects were
          anaesthesiologist at time of   questionnaire       1,977 pregnancies while women     weight, stillbirths and  standardised for
          conception                                         had no medical appointments       congenital               maternal age,
                                                                                               abnormalities            smoking habits and
                                                                                               (cardiovascular)         parity
                                                                                               increased
Ros78     Mixture: waste anaesthetics    Retrospective       248 pregnancies in                No difference in         Mixed exposure
          Member Finnish Society of      survey Finland      anaesthesiologists families       spontaneous abortions    Results were
          Anaesthesiologists             1961-1976/postal    266 pregnancies in pediatricians  Low birth weight and     corrected for smoking
                                         questionnaire       families (no OT exposure)         congenital               habits
                                                                                               abnormalities
                                                                                               (musculoskeletal)
                                                                                               increased
              Fertility and developmental toxicity studies                                                                                   38
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<pre>Table 2.2 Developmental toxicity studies in man.
authors  exposure              study type/data   study/comparation population        investigated effects and remarks
                               collection                                            results
Eri79    Mixture: waste        Cohort Sweden     494 women who worked                No difference in birth   Mixed exposure
         anaestheticswomen     1973 and          throughout pregnancy, 37 women      weight, perinatal death  Corrections were
         working in OT         1975/Registry     who worked more than half of their  rate, congenital         made for maternal
         during pregnancy      data              pregnancies and 10 women who        abnormalities            age and parity
         who gave birth in                       worked less than half of their      Pregnancy duration in
         1973 and 1975                           pregnancies                         weeks decreased
                                                 19,127 women employed in
                                                 medical work who delivered in
                                                 1973 or 1975
Lau81    Mixture: waste        Retrospective     Pregnancies in 149                  No difference in         Mixed exposure
         anaesthetics          survey Belgium/   anaesthesiologists and their wives  spontaneous abortions,   No differences in
         Exposure anaesthetic  postal            and 240 OT nurses and their         sum of all abnormal      maternal smoking
         gasses by one or both questionnaire     wives/pregnancies in 531            pregnancies, premature   habits between
         parents during or in                    occupational physicians,            birth, stillbirth and    different groups
         the year before                         dermatologists, intensive care, and congenital
         pregnancy                               other nurses and their wives        abnormalities Increased
                                                                                     number of males born
Ste85    No inhalation agent Experimental        Analgesia during vaginal delivery   No significant           *Neurologic and
         (n=21),               design            of baby, infants underwent          differences in neuro     Adaptive Capacity
         0.3-0.8%[22650 and                      neurobehavioural testing*           behavioural status       Score at 15 min, 2
         60400 mg/m3]                                                                occurred                 and 24 h and Early
         enflurane and oxygen                                                                                 Neonatal
         (n=22)                                                                                               Neurobehavioural
                                                                                                              Scale at 2 and 24h
Hem85 Mixture: waste           Case-control      1.169 employed nurses who had       No significant increase  1 and 2. Mixed
         anaesthetics exposure Finland           spontaneous abortion/ 469           in risk of spontaneous   exposureMatched
         during 1st trimester 1973-1979/         employed nurses who gave birth to   abortion or congenital   on maternal age
                               registry data for a healthy infant 2. 38 employed     abnormalities            and other potential
                               outcomes postal   nurses who gave birth to an infant                           exposures
                               questionnaire     with congenital abnormalities/ 99
                                                 employed nurses who gave birth to
                                                 a healthy infant 1 and 2: cases
                                                 excluded from controls
             Fertility and developmental toxicity studies                                                                      39
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<pre>Table 2.3 Developmental toxicity studies in man.
authors   exposure        study type/data     study/comparation population       investigated effects and results            remarks
                          collection
Dun86     Mixture:        Cohort Canada       Women who underwent surgery        No association was found between the        Anaesthetic gas used
          anaesthesia     1971-1978 health    with anaesthesia during            incidence of anomalies or between the       was not specified
          during          insurance data and pregnancy and women who did         rate of abortion and anaesthesia during     Socio-economic and
          pregnancy       provincial          not (n=2565) women were            surgery by subdividing in type of           lifestyle factors were
                          congenital-anomali matched on geographic area and      anaesthesia (general, local, spinal/block)  not taken into account
                          es registry         age groups were compared for       a significant increase in abortion rate was
                                              abortion rate and frequency of     found in those women who underwent
                                              anomalies                          general anaesthesia (RR 1.58, 95% CI
                                                                                 1.19-2.09) when compared with their
                                                                                 matched controls
Joh87    Mixture: waste Case-control          278 spontaneous abortions and      No statistically significant increase in    Mixed
          anaesthetics    USA/postal          stillbirths and 98 live birth with spontaneous abortions                       exposureResults
                          questionnaire       congenital abnormalities that                                                  adjusted for x-ray
                          (additional         occurred to female veterinarians                                               exposure
                          questionnaire sent  and veterinarian assistants and
                          to senior female    wives of male veterinarians
                          veterinary          642 normal pregnancies chosen
                          assistants)         on a stratified random basis
Gui90    Mixture: waste Retrospective         Exposed (n=6336) and               Significant increase in spontaneous         Mixed exposureOR’s
          anaesthetics    study Ontario       non-exposed (n=2202) hospital      abortion and congenital abnormality         were standardised for
                          1981-1985/          staff and their or their wives     among exposed females (OR 1.98, 95%         age, smoking, alcohol
                          questionnaire       pregnancies/children               CI 1.53-2.56; OR 2.24, 95% CI               consumption,
                                                                                 1.69-2.97) and spouses of exposed males     previous abortion and
                                                                                 (OR 2.3, 95% CI 1.68-3.13; OR 1.46,         occupation
                                                                                 95% CI 1.04-2.05)
               Fertility and developmental toxicity studies                                                                                       40
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<pre>Table 2.4 Developmental toxicity studies in man.
authors exposure         study type/data        study/comparation       investigated effects and results  remarks
                         collection             population
Mat93     Mixture:       Case-control USA       4915 cases (live and    Potential maternal exposure to    Mixed exposure RR for
          waste          1968-1980/             still-born infants with anaesthetic gasses was            maternal exposure based
          anaesthetics telephone                serious malformations)  associated with spina bifida (RR  on only three cases No
                         questionnaire,         and 3027 control babies = 6.27; 95% CI 1.54-25.48)        adjustment was made for
                         cases were                                     offspring of fathers exposed to   confounding factors,
                         registered with the                            anaesthetic gasses had a          however, when adjustment
                         Metropolitan                                   significantly decreased risk of   was applied for maternal
                         Atlanta Congenital                             birth defects (RR = 0.45; 95% CI  education, age and alcohol
                         Defects Program                                0.21-0.98)                        consumption, results were
                                                                                                          the same
Syl94     Mixture:       Atlanta birth          694 infants with major  No relation with anaesthesia was  Anaesthetic gas used was
          anaesthesia    defects                CNS defects,            observed taking all CNS defects   not specified Age, median
          during         case-control study     Metropolitan Atlanta    into account. No significant      parity, smoking and
          surgery in     1968-1980/             Congenital Defects      associations were found between   drinking, mean weight
          first          telephone              Program 2984 controls,  isolated effects and anaesthesia. gain and mean education
          trimester of   interviews             1% random sample        Hydrocephalus with any other      were equal for both groups
          pregnancy                             Atlanta metropolitan    effect (OR 2.9, 95% CI 1.2, 6.8)  Odds ratios were adjusted
                                                                        and especially with eye defects   for race, hospital of birth
                                                                        (OR 39.6, 95% CI 7.5, 209.2)      and period of birth
                                                                        was found to be associated with
                                                                        general anaesthesia
Pee99     Mixture:       Retrospective          427 pregnant females    Increased risk for abortion (OR   Mixed exposure
          waste          survey                 (age 22-37 years)       1.3, 95% CI 0.8-2.1), preterm     *Controlled for age,
          anaesthetics   The Netherlands        employed in             birth (OR* 1.4, 95% CI 0.7-2.8)   education, menstrual cycle,
          Employment     1990-1997/postal       anaesthesia/1,010       and congenital abnormalities      life style and
          in             questionnaire          pregnant females (age   (OR* 1.8, 95% CI 1.0-4.1)         circumstances during
          anaesthesia                           22-37 years) nurses                                       work.
                                                employed in department
                                                of orthopaedics,
                                                gynaecology or surgery
               Fertility and developmental toxicity studies                                                                           41
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<pre>Table 3.1 Fertility studies in animals with enflurane.
authors    species           experimental               dose and route      general toxicity       effects on reproductive organs    remarks
                             period/design                                                         and reproduction
Lan81      Male              4h/day during 5            0, 0.12 and 1.2%    At high concentration At high concentration
           (C57B1/C3H consecutive weekdays              [9060 and 90600     2 animals died.        percentage of abnormal
           )F1 mice          sacrifice 28 days after    mg/m3] enflurane    paternal toxicity not  spermatozoa increased
           (low n=5,         start of exposure sperm    inhalation          described
           high n=10)        morphology of both
                             cauda epididymides
Wha81      Male              11 weeks premating         0, 0.01, 0.1 and 1% Reduced weight gain No difference in pregnancy rate, *highest dose
           Swiss/ICR         4h/day, 5 days/week        [755, 7550 and      of males exposed at    number of implantations, live     was reduced to
           mice (n=10)       mating with untreated      75500 mg/m3]        highest                foetuses and reproductive loss    0.5% after 5.5
                             females                    enflurane           concentration*                                           weeks of
                                                        inhalatory          No difference in                                         treatment as
                                                                            gestational weight                                       males were
                                                                            gain                                                     failing to gain
                                                                                                                                     weight
Hal81      Male              8h/day, 5 consecutive      0 and 20 ppm [151   No effect on body      No differences in pregnancy
           Sprague           days/week for 99 days      mg/m3] enflurane    weight gain, liver and rates, number of live foetuses or
           Dawley rats       after 63 days males were inhalatory            kidney weight or       implantations and percentage
           (n=20)            mated with untreated                           histology              resorptions or dead in utero
                             females
Gre82      Male              8h/day, 5 consecutive      0 and 200 ppm       No effect on body      No differences in pregnancy
           Sprague           days/week for 100 days     [1510 mg/m3]        weight gain, liver and rates, number of live foetuses or
           Dawley rats       after 63 days males were enflurane             kidney weight or       implantations and percentage
           (n=20)            mated with untreated       inhalatory          histology              resorptions, deciduomata or
                             females                                                               dead in utero
Cam83      Male              6h/day for 3, 9 or 11 days 0, 50, 500 and 1000 No effects presented   No influence on testosterone,
           Sprague           at high, mid and low       ppm [377.5, 3775                           LH and FSH levels observed
           Dawley rats       concentration              and 37550 mg/m3]
           (n=5)                                        enflurane
                                                        inhalatory
              Fertility and developmental toxicity studies                                                                                           42
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<pre>Table 4.1 Developmental toxicity studies in animals with enflurane.
authors   species          experimental            dose and route   maternal toxicity developmental toxicity                            remarks
                           period/design
Sai74     Pregnant ddY     Exposure from GD 7 0, 0.05% and          No differences in No differences in number of implantations,
          mice (n=20)      until GD 12 during 1 0.75% [3775         maternal body     number of dead foetuses, foetal body weight,
                           h/day aesarean          and 56625        weight            sex ratio, external, internal and bone anomalies
                           section at day GD 18 mg/m3]                                no treatment related differences in percentage
                           (n=15) or allowed to inhalatory                            live births and survival at 3 and 6 weeks of age,
                           deliver naturally                                          pup body weights, external, auditory and
                           (n=5)                                                      behavioural features at 3 weeks and anatomical,
                                                                                      sex and bone features at 6 weeks of age
Sai74     Pregnant Wistar  Exposure from GD 9 0, 0.05% and          No differences in No differences in number of implantations,
          rats (n=20)      until GD 14 during 1 1.25% [3775         maternal body     number of dead foetuses, foetal body weight,
                           h/day aesarean          and 94375        weight            sex ratio, external, internal and bone anomalies
                           section at day GD 18 mg/m3]                                no treatment related differences in percentage
                           (n=15) or allowed to inhalatory                            live births and survival at 3 and 6 weeks of age,
                           deliver naturally                                          pup body weights, external, auditory and
                           (n=5)                                                      behavioural features at 3 weeks and anatomical,
                                                                                      sex and bone features at 6 weeks of age
Str77     Pregnant Sprague Exposure from GD 0 0, 10.7 and 63.7 No differences in      No significant difference in litter size birth
          Dawley rats      to GD18 for 8 h/day ppm [80.8 and        weight or weight  weight of both treated groups significantly
          (n=6-13)         after delivery          480.9 mg/m3]     gain, feeding     increased no weight differences during lactation
                           cross-fostering study inhalatory         habits, behaviour among offspring of the low-dose group in the
                                                                    or appearance     high-dose group offspring delivered by control
                                                                                      mothers and cross-fostered by treated mothers
                                                                                      and offspring of treated mothers fostered by
                                                                                      untreated mothers had a lower weight at PN 7,
                                                                                      but not at PN 14 or PN 21, offspring of treated
                                                                                      mothers fostered by treated mothers had higher
                                                                                      birth weights at PN 21
Pop78     Pregnant Sprague Exposure from GD 0 0 and 3200 ppm No maternal              Significant decrease in mean body weight of
          Dawley rats      to GD 20 for 8 h/day [24800 mg/m3] deaths no               foetuses of exposed mothers compared to
          (n=5-8)                                  inhalatory       significant       controls, no increase in the incidence of foetal
                                                                    changes in weight resorptions all foetuses at term were alive and
                                                                    gain no           showed no external defects or major skeletal
                                                                    pathological      effects no pathological changes
                                                                    changes
               Fertility and developmental toxicity studies                                                                                  43
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<pre>Table 4.2 Developmenal toxicity studies in animals with enflurane.
authors   species        experimental          dose and route      maternal toxicity  developmental toxicity                     remarks
                         period/design
Wha81     Female         3 weeks prior to      0, 0.01, 0.1 and    Highest            No differences in pregnancy rates, number *highest dose
          Swiss/ICR      mating                1% [755, 7550       concentration      of implantations and live foetuses,        was reduced to
          mice (n=39-48) continuously until    and 75500           induced ataxia     percentage of resorptions or foetuses dead 0.5% at the
                         GD 18, 4h/day, 7      mg/m3] enflurane followed by light     in utero and mean foetal weight            beginning of
                         days/week mating      inhalatory          sleep and reduced  dose-related increase in lumbar rib        the mating
                         with untreated                            weight gain* no    formation, significant at highest          period as
                         males                                     difference in      concentration increased incidence of       females were
                                                                   gestational weight IRPC at highest concentration              failing to gain
                                                                   gain                                                          weight
Wha81     Pregnant       GD 6-15, 4h/day, 7 0, 0.01, 0.1 and       Reduced            No differences in pregnancy rates, number
          female         days/week             1% [755, 7550       gestational weight of implantations and live foetuses,
          Swiss/ICR                            and 75500           gain at highest    percentage of resorptions or foetuses dead
          mice (n=26-34)                       mg/m3] enflurane concentration         in utero at highest concentration mean
                                               inhalatory                             foetal weight and length and ossification
                                                                                      decreased and increased incidence of
                                                                                      major malformations (mostly cleft palate),
                                                                                      minor skeletal anomalies (bent and fused
                                                                                      ribs, fused vertebrae), skeletal variants
                                                                                      (mostly lumbar ribs), visceral variants
                                                                                      (mostly IRPC) and minor visceral
                                                                                      anomalies
Wha81     male           11 weeks premating 0, 0.01, 0.1 and       Reduced weight     No difference in foetal weight and foetal  *highest dose
          Swiss/ICR      4h/day, 5             1% [755, 7550       gain of males      length                                     was reduced to
          mice (n=10)    days/week mating      and 75500           exposed at highest                                            0.5% after 5.5
                         with untreated        mg/m3] enflurane concentration*no                                                 weeks of
                         females               inhalatory          difference in                                                 premating
                                                                   gestational weight                                            treatment as
                                                                   gain                                                          males were
                                                                                                                                 failing to gain
                                                                                                                                 weight
              Fertility and developmental toxicity studies                                                                                     44
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<pre>Table 4.3 Developmental toxicity studies in animals with enflurance.
authors   species        experimental period/design         dose and    maternal toxicity   developmental toxicity                       remarks
                                                            route
Cha81     Albino mice    mothers of mice were exposed on 0, 2 and 4%    Not presented       All mice born from exposed mothers
          (n=6), aged    GD6 and 11 or GD 14 and 17 for [151000 and                         were slower in maze performance from
          6-7 weeks      30 minutes mice were trained 5     302000                          day 3-10 of training than control mice
                         times on maze performance (day mg/m3]
                         1, 3, 5, 7 and 10)                 enflurane
                                                            inhalatory
Hal81     Male Sprague 8h/day, 5 consecutive days/week 0 and 20 ppm No effect on body       No difference in placental weight, crown
          Dawley rats    for 99 days after 63 days males    [151 mg/m3] weight gain, liver  rump length or sex ratio foetal weight
          (n=20)         were mated with untreated          enflurane   and kidney weight   slightly decreased, probably as litter size
                         females progeny was mated          inhalatory  or histology        was larger no difference in skeletal
                                                                                            abnormalities no fertility or reproduction
                                                                                            effects in first generation
Hal81     Female         8h/day, 5 consecutive days/week 0 and 20 ppm No effect on body     No differences in pregnancy rates,
          Sprague        for 28 days prior to mating and    [151 mg/m3] weight gain and     number of live foetuses or implantations
          Dawley rats    during gestation after 28 days     enflurane   liver and kidney    and percentage total foetal loss no
          (n=20)         females were mated with            inhalatory  weight or histology difference in placental weight, crown
                         untreated males                                                    rump length or sex ratio foetal weight
                                                                                            slightly decreased due to larger litter size
                                                                                            no difference in skeletal abnormalities
Gre82     Male Sprague 8h/day, 5 consecutive days/week 0 and 200        No effect on body   No difference in foetal and placental
          Dawley rats    for 100 days after 63 days males   ppm [1510   weight gain, liver  weight, crown rump length or sex ratio
          (n=20)         were mated with untreated          mg/m3]      and kidney weight   significant less skeletal abnormalities
                         females                            enflurane   or histology        after treatment with enflurane*
                                                            inhalatory
              Fertility and developmental toxicity studies                                                                                    45
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<pre>Table 4.4 Developmental toxicity studies in animals with enflurane.
authors   species       experimental         dose and     maternal       developmental toxicity               remarks
                        period/design        route        toxicity
Gre82     Female        8h/day, 5            0 and 200    No effect      No differences in pregnancy rates,   *Controls values were
          Sprague       consecutive          ppm [1510    on body        number of live foetuses or           low compared to other
          Dawley rats   days/week for 28     mg/m3]       weight gain    implantations and percentage         control values, all
          (n=20)        days prior to        enflurane    and liver      resorptions, deciduomata or dead in  values within normal
                        mating and during    inhalatory   weight or      utero no difference in foetal and    range therefore no
                        gestation after 28                liver and      placental weight, crown rump         treatment related
                        days females were                 kidney         length or sex ratio increase in      increase
                        mated with                        histology      supplementary ribs after treatment
                        untreated males                   kidneys        with enflurane*
                                                          slightly
                                                          enlarged
Pet82     Pregnant      6h/day during GD     0 and 1500   No effect      Exposed females had 35% small        *brain, pituitary,
          Fischer 344   0-20 mothers were    ppm          on maternal    litters (6 pups) whereas controls    thyroid, thymus,
          rats (n=30)   allowed to litter    [11325       weight gain    5% no difference in pup weight,      lungs, heart, kidney,
                        and raise their      mg/m3]       or gross       weight gain and postnatal survival   adrenal, liver, spleen,
                        young until PN 28    enflurane    behaviour      through 75 weeks no difference in    prostate, testis,
                                             inhalatory                  righting reflex, temperature         epididymis, seminal
                                                                         regulation and eye opening or        vesicles, ovary and
                                                                         organ*/body weights at any age no    uterus
                                                                         differences in clinical chemical or  **righting reflex,
                                                                         haematological profile behaviour     inclined screen,
                                                                         tests** performed at several ages    open-field activity,
                                                                         did not show differences at puberty  food maze behaviour,
                                                                         pentobarbital sleep time was         activity wheel,
                                                                         significantly shortened after        swimming stress test,
                                                                         exposure in males but not at adult   shock avoidance
                                                                         and geriatric age and not in females learning
Maz86     Pregant       6h/day on            0 and        I, II and III: II: increased number of
          Sprague       I. GD 14-16          1.65%        light          developmental variants
          Dawley rats   II. GD 11-13         [124575      anaesthesiaI (rudimentary lumbar rib)
          (n=39-50      III. GD 8-10         mg/m3]       : decreased
          control,      screening for        enflurane    weight gain
          20-23         skeletal and soft    inhalation
          enflurane)    tissue anomalies
                        after Caesarean
                        section
             Fertility and developmental toxicity studies                                                                           46
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<pre>Annex E
      Abbreviations
      Abbreviations used:
      bw          =      body weight
      CI          =      confidence interval
      CNS         =      central nervous system
      d           =      day
      F           =      female(s)
      GD          =      gestation day
      i.p.        =      intraperitoneal
      IRPC        =      increased renal pelvic cavitation
      i.v.        =      intravenous
      M           =      male(s)
      n           =      number
      NOAEL       =      no adverse effect level
      OECD        =      Organisation for Economic Cooperation and Development
      OR          =      Odds ratio
      OT          =      Operating theatre
      PN          =      postnatal
      RR          =      relative risk
      Abbreviations                                                            47
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<br><br>