<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>Ethanol
Evaluation of the effects on reproduction, recommendation for classification
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<pre>Aan de Staatssecretaris van Sociale Zaken en Werkgelegenheid
Onderwerp       :  aanbieding advies
Uw kenmerk      :  DGV/BMO-U-932542
Ons kenmerk     :  U 947/AB/jt/543-X2
Bijlagen        :  1
Datum           :  19 april 2000
Bij brief van 3 december 1993, nr. DGV/BMO-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 repro-
tox-lijst. Op deze lijst komen stoffen die volgens de richtlijnen van de Europese Unie in-
gedeeld moeten worden in categorie 1 of 2 wat betreft effecten op de voortplanting. De
Gezondheidsraad is verzocht om voor stoffen een classificatie volgens de EU-criteria
voor te stellen.
In 1996 heb ik hiervoor de Commissie Reproductietoxische stoffen ingesteld.
Hierbij bied ik u - gehoord de Beraadsgroep Gezondheid en Omgeving - een publikatie
van de commissie aan over ethanol (alcohol). Deze publikatie is heden ter kennisname
aan de Minister van Volksgezondheid Welzijn en Sport en aan de Minister van Volks-
huisvesting, Ruimtelijke Ordening en Milieubeheer gestuurd.
Hoogachtend,
w.g.
prof. dr JJ Sixma
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<pre>Ethanol
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. 2000/01OSH, The Hague, 19 April 2000
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<pre>Preferred citation:
Health Council of the Netherlands: Committee for Compounds toxic to reproduction. Et-
hanol; Evaluation of the effects on reproduction, recommendation for classification. The
Hague: Health Council of the Netherlands, 2000; publication no. 2000/01OSH.
all rights reserved
ISBN: 90-5549-318-X
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<pre>    Contents
    Samenvatting 8
    Executive summary 9
1   Scope 10
1.1 Background 10
1.2 Committee and procedure 10
1.3 Additional considerations 11
1.4 Labelling for lactation 12
1.5 Data 13
1.6 Presentation of conclusions 13
1.7 Final remark 13
2   Ethanol 14
2.1 Introduction 14
2.2 Human studies 14
2.3 Conclusion 17
    References 19
    Contents                       7
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<pre>  Annexes 23
A The committee 24
B Comments on the public draft 26
C Directive (93/21/EEC) of the European Community 27
D Abbreviations 33
  Contents                                           8
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<pre>Samenvatting
Op verzoek van de Minister van Sociale Zaken en Werkgelegenheid beoordeelt de Ge-
zondheidsraad de effecten op de reproductie van stoffen waaraan mensen tijdens de be-
roepsuitoefening kunnen worden blootgesteld. De Commissie Reproductietoxische stof-
fen, een commissie van de Raad, adviseert een classificatie van reproductietoxische stof-
fen volgens Richtlijn 93/21/EEC van de Europese Unie. In het voorliggende rapport
heeft de commissie ethanol onder de loep genomen.
De aanbevelingen van de commissie zijn:
    Voor effecten op de fertiliteit, adviseert de commissie ethanol in categorie 1 (Stoffen
    waarvan bekend is dat zij bij de mens de vruchtbaarheid schaden) te classificeren
    en met R60 (kan de vruchtbaarheid schaden) te kenmerken.
    Voor ontwikkelingsstoornissen, adviseert de commissie om ethanol in categorie 1
    (Stoffen waarvan bekend is dat zij bij de mens ontwikkelingsstoornissen veroorza-
    ken) te classificeren en met R61 (kan het ongeboren kind schaden) te kenmerken.
    Voor effecten tijdens lactatie, adviseert de commissie om ethanol tevens met R64
    (kan schadelijk zijn via de borstvoeding) te kenmerken.
Samenvatting                                                                                9
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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 ethanol.
The committee’s recommendations are:
    For effects on fertility, the committee recommends that ethanol should be classified
    in category 1 (Substances known to impair fertility in humans) and labelled with
    R60 (may impair fertility).
    For developmental toxicity, the committee recommends to classify ethanol in catego-
    ry 1 (Substances known to cause developmental toxicity in humans) and labelled
    with R61 (may cause harm to the unborn child).
    For effects during lactation, the committee recommends that ethanol should be label-
    led with R64 (may cause harm to breastfed babies).
Executive summary                                                                        10
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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 re-
        quested the Health Council of the Netherlands to classify compounds toxic to reproduc-
        tion. The classification is performed according to the guidelines of the European Union
        (Directive 93/21/EEC) by the Health Council’s Committee for Compounds Toxic to Re-
        production. 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 and 2) of the European Union.
1.2     Committee and procedure
        The present document contains the classification of ethanol 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 Mrs ir IDH Waalkens-
        Berendsen at the Department of Neurotoxicology and Reproduction Toxicology of the
        TNO Nutrition and Food Research Institute, Zeist, The Netherlands, by contract with
        the Ministry of Social Affairs and Employment. The classification is based on the evalu-
        ation of published human and animal studies concerning adverse effects with respect to
        fertility and development and lactation of the above mentioned compound.
        Scope                                                                                    11
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<pre>    Classification and labelling 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 ef-
                     fects (R63)
     No classification for effects on fertility or development
     Labelling for lactation:
                     May cause harm to breastfed babies (R64)
                     No labelling for lactation
    In April 1999, the President of the Health Council released a draft of the report for pu-
    blic review. The individuals and organisations that commented on the draft report are lis-
    ted 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 pa-
    rental and developmental effects observed, their specificity and adversity, and the dosa-
    ges at which the various effects occur. The directive necessarily leaves room for inter-
    pretation, 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 expo-
         sure to the substance and impaired fertility or subsequent developmental toxic ef-
         fects 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).
         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 stu-
         dies, need not necessarily lead to a category 2 classification.
    Scope                                                                                                  12
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<pre>         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 oc-
         cur 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 ef-
         fects occur in the presence of maternal toxicity, they will be considered as a conse-
         quence 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 reversibili-
         ty 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 Labelling for lactation
    The recommendation for labelling substances for effects during lactation is also based on
    Directive 93/21/EEC. The Directive defines that substances which are absorbed by wo-
    men and may interfere with lactation or which may be present (including metabolites) in
    breast milk in amounts sufficient to cause concern for the health of a breastfed child,
    should be labelled with R64. Unlike the classification of substances for fertility and de-
    velopmental effects, which is based on a hazard identification only (largely independent
    of dosage), the labelling 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 labelled 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 compound as potentially toxic to the breastfed child when exposu-
    re to this compound via the milk results in an intake exceeding an exposure limit for the
    general population, eg the acceptable daily intake (ADI).
1.5 Data
    Literature searches were conducted in the on-line databases Toxline and Medline, star-
    ting from 1966 up 1995. 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
*   Organisation for Economic Cooperation and Development
    Scope                                                                                        13
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<pre>    of most recent reviews were consulted. References are divided in literature cited and lite-
    rature consulted but not cited. Before finalising the public draft the committee performed
    an additional literature search in Medline and Toxline for the period 1995 to 1998. The
    results of this search were no reason for the committee to adjust the recommendations.
         The committee chose to describe human studies in the text, starting with review arti-
    cles. Of each study the quality of the study design (performed according to international-
    ly acknowledged guidelines) and the quality of documentation are considered.
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 emphasises 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 organisations.
*   for definitions see Tox95
    Scope                                                                                       14
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<pre>Chapter 2
        Ethanol
2.1     Introduction
         Name                 :    Ethanol
         CAS-no               :    64-17-5
         Use                  :    stimulant, desinfectant, solvent
         Synonym              :    alcohol
         Mol weight           :    46
         Chem formula         :    C2H5OH
2.2     Human studies
        Fertility studies
        Chopra et al (Cho73) studied 13 male patients, 35 to 59 years of age, who had typically
        clinical features of chronic hepatic cirrhosis after chronic alcohol abuse. Six patients had
        gynecomastia and 10 out of 12 patients had atrophic testis; The testis of one patient
        could not be palpated because of massive ascites and scrotal oedema. The serum
        oestradiol-17ß was elevated in 8 out of 13 patients. Serum luteinizing hormone (LH)
        was above the normal range in 7 out of 13 patients.
             Galvào-Teles et al (Gal73) studied 25 men with chronic liver disease; 8 men were
        chronic alcoholics. The plasma levels of 17ß-hydroxy-androgens, were significantly lo-
        Ethanol                                                                                      15
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<pre>wer in the males with liver disease than in controls; this fall was most striking in the pa-
tients with alcoholic cirrhosis. Serum LH levels were increased in males with liver di-
sease. Decreased libido, gynecomastia and small testis were found in 5, 4 and 4 out of 8
alcoholics, respectively. These clinical features were found in higher frequency in males
with alcoholic cirrhosis; the authors presumed that this may be due to the greater reduc-
tion in unbound plasma androgens. In this study non-age-matched normal young men
were used as controls.
     Kent et al (Ken73) studied 22 men, 39 to 67 years of age, with a history of chronic
alcoholism and hepatic insufficiency. Serum oestradiol, testosterone (T), follicle-stimula-
ting hormone (FSH) and LH were measured. Only levels of testosterone were signifi-
cantly different from those obtained in normal subjects. Eight males showed unilateral or
bilateral small testis. Fifteen males reported a loss of libido.
     Van Thiel et al (Thi78a) studied the effects of alcohol use on the hypothalamic-pi-
tuitary axis in 22 chronic alcoholic men aged 21-64 years and 14 healthy non-alcoholic
men aged 18-35 years. Gynecomastia, testicular atrophy, impotence and reduced libido
were found in 11, 12, 16 and 17 of the 22 alcoholic men, respectively. FSH, LH and
TSH levels were increased in alcoholic men, whereas testosterone (T), triiodothyronine
(T3) and thyroxine (T4) concentrations were decreased, when compared to the normal
controls.
     Pajarinen et al (Paj94) studied the effects of alcohol on spermatogenesis in a pro-
spective autopsy study in 32 controls aged 55-61 years and 44 heavy drinkers aged
50-55 years; users of tranquilizers and diuretics were excluded. Sudden cardiac death,
respiratory infections and other diseases were the primary cause of death. Spermatogenic
arrest was found in 19 and 52 % of the controls and heavy drinkers, respectively. Five
heavy drinkers had Sertolicell-only (SCO) syndrome. The mean testicular weight of the
heavy drinkers was slightly lower than of the controls.
     Spermatogenesis and testicular morphology of 195 men were studied; the men were
categorized in a control group (<10 g alcohol per day, n=48) and 4 consumption groups
(group I: 10-40 g alcohol per day, n=42; group II: 40-80 g alcohol per day, n=31; group
III: 80-160 g alcohol per day, n=35 and group IV: >160 g alcohol per day, n=39)
(Paj96). The groups had a slight difference in age; age of the control men was 55-60 ye-
ars and of the highest dose group 48-54 years. Partial spermatogenic arrest was found in
33, 36, 42, 54 and 64 % of the control and consumption groups, respectively. SCO was
detected in 1, 3 and 3 men of the groups with the highest alcohol consumption (group II,
III and IV, respectively). A reduction was found in testicular weight for the two groups
(III and IV) with the highest alcohol use.
     Vilalta et al (Vil97) studied the effect of ethanol in 38 chronic alcoholics without
chronic liver disease (reported ethanol consumption of about 200 g alcohol per day) and
19 age-matched controls. In alcoholics a significant increase in LH and FSH hormone
Ethanol                                                                                      16
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<pre>  and a decrease in free androgen index* were observed. Seminal studies indicate sperm
  counts and motility were decreased in alcoholics whereas morphological abnormalities
  were increased when compared to controls.
       An increase in dysmenorrhea, heavy menstrual flow and premenstrual discomfort
  was found by Wilsnack et al in a survey in 2552 women with increasing number of alco-
  holic drinks per day (Wil84). Becker et al studied the menstrual pattern, gynaecological
  disorders and infertility in 51 chronic alcoholic women and 51 controls and found that
  the alcoholic women were more prone to menstrual abnormalities and were at greater
  risk of gynaecological interventions, while they did not seem to have reduced fertility
  (Bec89).
       Grodstein et al (Gro94) interviewed 1050 women from 7 infertility clinics and 3833
  women who recently gave birth; they found an increase in infertility with alcohol use,
  due to disturbed ovulation or to endometriosis.
  Remark
  Alcohol induced sexual disfunction was initially attributed to liver disease (Cho73;
  Gal73; Ken73). However, additional studies were performed and it became clear that al-
  cohol itself was the principle cause of the effects on fertility (Ban87; Thi81). Alcohol
  can induce testicular failure in the absence of alcohol induced liver disease.
  Developmental toxicity
  Alcohol-dependent women have been reported to give birth to children with a combina-
  tion of anomalies, which is known as the foetal alcohol syndrome (FAS) (Lem68,
  Jon73a,b and Ros80). FAS is characterized by a spectrum of clinical features including
  prenatal and postnatal growth deficiency, morphological anomalies including distinctive
  facial appearance, skeletal abnormalities, cardiac defects, central nervous system dys-
  function, including cognitive disabilities (Jon86, Gor90, Fro92 and Rob94).
       FAS occurred in children of women with clearly identified drinking habits (Sok92).
  In some studies, the prevalence of FAS among alcohol-dependent women was as high as
  26% (Sei78), and in others as low as 2% (Sok80). In an extensive review, Meyer descri-
  bed the behaviourial teratology of alcohol and concluded that there is considerable evi-
  dence for identifying alcohol as a behavioural teratogen in humans and animals
  (Mey86). More recently, Jacobson et al and Streissguth et al described neurobehaviouri-
  al effects of prenatal alcohol exposure (Jac93a,b and Stre94).
* free androgen index = (total testosterone/ total sex steroid hormone binding globulin)*100
  Ethanol                                                                                    17
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<pre>    Lactation
    Binkiewicz et al (Bin78) reported a breast-fed infant with increased levels of cortisol in
    the blood and a clinical pattern which closely resembled Cushing syndrome. During
    pregnancy the mother refrained from alcohol consumption. However, after birth she re-
    sumed drinking “in order to promote milk production”. In a random sample of breast
    milk 1 g alcohol/l was detected.
         Lawton (Law85) analysed samples of breast milk and blood at fixed intervals after
    the ingestion of alcohol by 8 nursing mother. The results showed that alcohol appeared
    quickly in both fore- and hind-milk at a level equivalent to or higher than the correspon-
    ding blood samples.
         Little et al (Lit89) studied in 400 infants the relation of the mother’s use of alcohol
    during breast feeding to the infant’s development at one year of age (299 infants from
    mothers with an absolute daily alcohol consumption of less than 1/2 oz. ethanol and 101
    infants from mothers consuming more than 1/2 oz.). They found that ethanol ingested
    through breast milk had a slight but significant detrimental effect on motor development,
    but not on mental development in breast-fed infants.
         Mennella et al (Men91) studied the effects of short-term alcohol consumption on fla-
    vour and odour of breast-milk and the feeding behaviour of their infants. Short-term al-
    cohol consumption significantly and consistently increased the perceived intensity of the
    odour of human milk by a panel of adults. The infants sucked more frequently during the
    first minutes of feeding in cases where their mothers had consumed alcohol, but they
    consumed significantly less milk during the testing sessions in which their mothers drank
    alcoholic beverages.
         Mennella and Gerrish (Men98) showed that short-term exposure to small amounts of
    alcohol in breast milk produced distinctive changes in the infant’s sleep-wake patterning.
2.3 Conclusion
    Ethanol consumed in the form of alcoholic beverages affected human male fertility as
    concluded from effects as testicular atrophy, decreased libido and testosterone levels,
    and increased oestrogen levels. In addition, human female fertility was affected, as con-
    cluded from disturbances in the menstrual cycle.
         Therefore, based on the human data, especially on the effects on the male reproduc-
    tive system, the committee recommends to classify ethanol in category 1 (substances
    known to impair fertility in humans) and to label the compound with R60 (may impair
    fertility).
         Ethanol causes multiple congenital anomalies in humans (retarded growth, dysfunc-
    tion central nervous system, external malformations), when exposure occurs during pre-
    Ethanol                                                                                      18
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<pre>natal development. The incidence, nature and extent of these anomalies are dependent
amongst others on time, duration and level of exposure during pregnancy.
     The committee is of the opinion that a causal relationship exists between human ex-
posure to ethanol and developmental effects and therefore recommends to classify etha-
nol in category 1 (substances known to cause developmental toxicity in humans) and to
label the compound with R61 (may cause harm to the unborn child). This is irrespective
the maternal (toxic) effects (see additional considerations, paragraph 1.3).
Ethanol consumed during lactation is excreted in breast milk and affects infant’s sleep-
wake patterning, motor development and can cause pseudo-Cushing syndrome. Therefo-
re, the committee recommends to label ethanol with R64 (May cause harm to breastfed
babies) as well.
Proposed classification for effects on fertility
Category 1, R 60.
Proposed classification for developmental toxicity
Category 1, R 61.
Proposed labelling for effects during lactation
R 64.
For the committee,
The Hague, 19 April 2000
dr ASAM van der Burght,                   dr BJ Blaauboer,
scientific secretary                      chairman
Ethanol                                                                                  19
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<pre>       References
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       of alcoholic versus non alcoholic liver disease. Q J Med 1987; 63(240):305-313.
Bec89  Becker U, Tønnesen H, Kaas-Claesson N, et al. Menstrual disturbances and fertility in chronic alcoholic
       women. Drug Alcohol Dependence 1989; 24: 75-82.
Bin78  Binkiewicz A, Robinson MJ Senior B. Pseudo-Cushing syndrome caused by alcohol in breast milk. J Pe-
       diatr 1978; 93: 965-967.
Cho73  Chopra IJ, Tulchinsky D, Greenway FL. Estrogen-androgen imbalance in hepatic cirrhosis. Studies in 13
       male patients. Ann Intern Med 1973; 79: 198-203.
Fro92  Froster UG, Baird PA. Congenital defects of the limbs and alcohol exposure in pregnancy: Data from a
       population based study. Am J Med Genet 1992; 44: 782-785.
Gal73  Galvào-Teles DC, Anderson CW, Burke JC, et al. Biologically active androgens and oestradiol in men
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Gor90  Gorlin RI, Cohen MM, Levin LS. Teratogenic agents. In: Syndromes of the head and neck. New York:
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Gro94  Grodstein F, Goldman MB, Cramer DW. Infertility in women and moderate alcohol use. Am J Publ He-
       alth 1994; 84: 1429-1432.
Jac93a Jacobson JL, Jacobson SW, Sokol RJ, et al. Teratogenic effects of alcohol on infant development. Alcohol
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Jac93b Jacobson SW, Jacobson JL, Sokol RJ, et al. Prenatal alcohol exposure and infant information processing
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Jon73a Jones KL, Smith DW, Ulleland CN, et al. Pattern of malformation in offspring of chronic alcoholic wo-
       men. Lancet 1973; i: 1267-1271.
       References                                                                                               20
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<pre>Jon73b Jones KL, Smith DW. Recognition of the fetal alcohol syndrome in early infancy. Lancet 1973; ii:
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Jon86  Jones KL. Fetal alcohol syndrome. Pediatr Rev 1986; 8: 122-126.
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Lit89  Little RE, Anderson KW, Ervin CH, et al. Maternal alcohol use during breast-feeding and infant mental
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Men91  Mennella JA, Beauchamp GK. The transfer of alcohol to human milk. Effects on flavor and the infant’s
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Men98  Mennella JA, Gerrish CJ. Effects of exposure to alcohol in mother’s milk on infant sleep. Pediatrics
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Mey86  Meyer LS, Riley EP. Behavioral Teratology of Alcohol. In: Riley EE, Vorhees CV, ed. Handbook of Be-
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Paj94  Pajarinen JT, Karhunen PJ. Spermatogenic arrest and ‘Sertoli cell-only” syndrome- commmon
       alcohol-induced disorders of the human testis. Int J Androl 1994; 17: 292-299.
Paj96  Pajarinen J, Karhunen PJ, Savolainen P, et al. Moderate alcohol consumption and disorders of human
       spermatogenesis. Alcohol Clin Exp Res 1996; 20: 332-337.
Rob94  Robin NH, Zackai EH. Unusual cranofacial dysmorphia due to prenatal alcohol and cocaine exposure.
       Teratology 1994; 50: 160-164.
Ros80  Rosett ML. A clinical perspective of the fetal alcohol syndrome. Alcohol Clin Exp Res 1980; 4: 199-122.
Sei78  Seidenberg J, Majewski F. Zur Haufigkeit der Alcoholembryopathis in den verschiedenen Phasen der
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       References                                                                                               23
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<pre>A The committee
B Comments on the public draft
C Directive (93/21/EEG) of the European Community
D Abbreviations
  Annexes
                                                  24
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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 Neonatology; Erasmus University, Rotterdam
         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 Clinical Genetics/Teratology; Erasmus University, Rotterdam
         JHJ Copius Peereboom-Stegeman
         Toxicologist; Catholic University Nijmegen, Nijmegen
         AH Piersma
         Reproductive toxicologist; National Institute of Public Health and the Environment,
         Bilthoven
         A Stijkel
         Toxicologist; Environmental Awareness Foundation, ’s-Graveland
         PJJM Weterings
         Toxicologist; Weterings Consultancy BV, Rosmalen
         ASAM van der Burght, scientific secretary
         Health Council of the Netherlands, The Hague
      The committee                                                                          25
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<pre>The first draft of the present document was prepared by IDH Waalkens-Berendsen, from
the TNO Nutrition and Food Research Institute in Zeist, by contract with the Ministry of
Social Affairs and Employment.
Secretarial assistance: E Vandenbussche-Parméus.
Lay-out: J van Kan.
The committee                                                                            26
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<pre>Annex B
      Comments on the public draft
      A draft of the present report was released in 1999 for public review. The following per-
      sons and organisations have commented on the draft document:
          L Appelman, C Braun, E Houthoff
          Akzo Nobel, Arnhem
          C Jeukenne,
          Ethyl Alcohol Group, Bruxelles, Belgium
          JR Kelsey
          BP Chemicals Limited, Hull, United Kingdom
          H Lindemann
          Bayer AG, Wuppertal, Germany
          JASJ Razenberg
          Nederlandse Vereniging van Zeepfabrikanten, Zeist
          EC Rietveld
          Diosinth bv, Akzo Nobel, Oss
          CJ Halm
          FME-CWM, Zoetermeer
      Comments on the public draft                                                             27
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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                                                         28
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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 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 resuts 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 conse-
     quence of the other toxic effects, but where the evidence is insufficient to place the substance in Ca-
     tegory 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                                                              29
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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 head-
ings 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 in-
Directive (93/21/EEC) of the European Community                                                            30
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<pre>      terfere 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 de-
      velopment, 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 (te-
      ratogenic effects), functional defects, peri-postnatal defects, and impaired postnatal mental or physi-
      cal 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 ani-
mal 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 simi-
lar 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 le-
vels 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 neces-
sarily 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                                                                 31
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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 appropri-
ate.
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 eviden-
ce 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 stu-
dies 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 associa-
ted with marked maternal toxicity. The route of exposure is also important. In particular, the injection of
irritant material intraperitoneally may result in local damage to the uterus and its contents, and the re-
sults of such studies must be interpreted with caution and on their own would not normally lead to classi-
fication.
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 possibili-
ty that the effects may have been due to non-specific influences such as generalised toxicity cannot be ex-
cluded.
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                                                                32
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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 Repro-
duction’, 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 po-
     tentially toxic levels in breast milk, and/or
b    on the basis of results of one or two generation studies in animals which indicate the presence of ad-
     verse effects on the offspring due to transfer in the milk, and/or
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                                                             33
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<pre>Annex D
      Abbreviations
                 Abbreviations used:
                            body weight
                            day
                            female(s)
                            intraperitoneal
                            intravenous
                            male(s)
                            number
                            no observed adverse effect level
                            Organisation for Economic Cooperation and Development
                            postnatal
                            week
      Abbreviations                                                               34
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<br><br>