<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>Tetrachloroethylene (PER)
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 ‘Tetrachloroethylene (PER)’
Uw kenmerk          : DGV/MBO/U-932542
Ons kenmerk         : U 99/AvdB/ra/543-N6
Bijlagen            :1
Datum               : 18 februari 2003
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 tetrachloorethyleen (PER). Dit advies is
opgesteld door de Commissie Reproductietoxische 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) 340 7520                                                   Telefax (070) 340 75 23
E-mail: A.vd.Burght@gr.nl                                                 www.gr.nl
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<pre>Tetrachloroethylene (PER)
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. 2003/04OSH, The Hague, February 18, 2003
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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.
Tetrachloroethylene (PER); Evaluation of the effects on reproduction, recommendation
for classification. The Hague: Health Council of the Netherlands, 2003; publication no.
2003/04OSH.
all rights reserved
ISBN: 90-5549-467-4
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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 Labelling for lactation 11
1.5 Data 11
1.6 Presentation of conclusions 12
1.7 Final remark 12
2   Tetrachloroethylene 13
2.1 Introduction 13
2.2 Human studies 13
2.3 Animal studies 18
2.4 Conclusion 22
    References 26
    Contents                       5
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<pre>  Annexes 30
A De committee 31
B Comments on the public draft 33
C Directive (93/21/EEC) of the European Community 34
D Fertility and developmental toxicity studies 40
E Abbreviations 43
  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 tetrachloorethyleen onder de loep genomen. De aanbevelingen van
de commissie zijn:
• Voor effecten op de fertiliteit meent de commissie dat er onvoldoende geschikte
    humane gegevens beschikbaar zijn en dat voldoende diergegevens laten zien dat
    tetrachloorethyleen de fertiliteit niet schaadt. Zij adviseert daarom om
    tetrachloorethyleen niet te classificeren.
• Voor effecten op de ontwikkeling adviseert de commissie tetrachloorethyleen in
    categorie 3 (stoffen die in verband met hun mogelijke voor de ontwikkeling
    schadelijke effecten reden geven tot bezorgdheid voor de mens) te classificeren en
    met R63 (mogelijk gevaar voor beschadiging van het ongeboren kind) te
    kenmerken.
• Voor effecten tijdens lactatie, adviseert de commissie om tetrachloorethyleen 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 tetrachloroethylene.
The committee’s recommendations are
• For effects on fertility, the committee recommends not to classify
    tetrachloroethylene on the basis of a lack of sufficient human data and sufficient
    animal data which show that no classification is indicated.
• For developmental toxicity, the committee recommends to classify
    tetrachlororethylene in category 3 (substances which cause concern for humans
    owing to possible developmental effects) and to label tetrachloroethylene with R63
    (possible risk of harm to the unborn child).
• For effects during lactation, the committee is of the opinion that due to a lack of
    appropriate data tetrachloroethylene should not be labelled.
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 tetrachloroethylene 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
        APM Wolterbeek and ir DH Waalkens-Berendsen, of 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 evaluation of published
        Scope                                                                                  9
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<pre>    human and animal studies concerning adverse effects with respect to fertility and
    development and lactation of the above mentioned compound.
    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
                       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 organisations 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).
    • 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.
    Scope                                                                                                    10
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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
         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 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
    women 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 developmental effects, which is based on a hazard identification only
    (largely independent of dosage), the labelling for effects during lactation is based on a
    risk characterisation 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 concentration of a compound as potentially toxic to the breastfed
    child when this concentration leads to exceedence of the 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,
    starting from 1966 up 2000. Literature was selected primarily on the basis of the text of
*   Organisation for Economic Cooperation and Development
    Scope                                                                                       11
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<pre>    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. 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. 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 summarised 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 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                                                                                     12
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<pre>Chapter 2
        Tetrachloroethylene
2.1     Introduction
        Name              :  Tetrachloroethylene
        CAS-no            :  127-18-4
        Synonyms          :  Tetrachloroethene, perchloroethylene, perchlor, PER, 1,1,2,2-tetrachloroethylene
        Use               :  organic solvent, dry cleaning, degreasing
        Mol weight        :  165.8
        Chem formula      :  C2Cl4
        Conversion factor :  1 ppm = 6.89 mg/m3 (101 kPa, 25ºC)
2.2     Human studies
        Fertility
        Taskinen et al. (Tas89) conducted a nested case-control study with 120 cases of
        spontaneous abortion and 251 controls. This study was based on a file of 6000 Finnish
        male workers who had been biologically monitored for exposure to six organic solvents
        (styrene, xylene, toluene, tetrachloroethylene, trichloroethylene and 1,1,1-
        trichloroethane) at the Finnish Institute of Occupational Health during 1965-1983.
        Information about their marriages and their wives’ pregnancies and spontaneous
        abortions were obtained from national registries; data on paternal occupational exposure
        to solvents were collected by means of a questionnaire sent to workers and covering the
        Tetrachloroethylene                                                                                   13
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<pre>period of spermatogenesis. The incidence of spontaneous abortions among wives of men
occupationally exposed to organic solvents was statistically significantly increased
(cases 103, referents 182; crude odds ratio 2.7 (95% CI 1.3-5.6)). No effects on the
incidence of spontaneous abortions among wives of men occupationally exposed to
tetrachloroethylene (cases n=4, referents=17; crude odds ratio 0.5 (95% CI 0.2-1.5)) or
halogenated hydrocarbons was observed.
     Zielhuis and Van Der Gulden (Zie89) investigated the effect of tetrachloroethylene
on the menstrual cycle in a small exploratory study. A self-administered questionnaire
was used to obtain information about the menstrual disorders. The questionnaires of 68
‘exposed’ dry-cleaning workers and 76 ‘reference’ laundry workers were used for
analysis. There was no difference between the groups in mean cycle length. However,
the incidences of dysmenorrhoea, unusual cycle length, menorrhagia and premenstrual
syndrome were higher among dry-cleaning workers than among laundry workers. To the
committee’s opinion the significance of these findings is limited due to small sample
size and the lack of exposure data.
     Eskenazi et al. (Esk91a) studied the semen quality of 34 men exposed to
tetrachloroethylene (dry-cleaning workers) and 48 laundry workers who were not
exposed to tetrachloroethylene. As an index of exposure expired air levels of
tetrachloroethylene were measured. Although no difference was observed between the
two groups in the average number of sperm cells (> 80 million cells/ml), the incidence
of men who were oligospermic (< 20 million cells/ml) was relative high (ca. 25%) in
both groups. Furthermore, only subtle differences in sperm quality were observed
between the groups.
     In a second study of Eskenazi et al. (Eks91b), the pregnancy outcomes of the wives
of the dry-cleaning workers and of the laundry workers who participated in the study
described above (Eks91a) were examined. In total 17 partners of dry-cleaning workers
and 32 partners of laundry workers participated in this study. The number of pregnancies
and the standardized fertility ratios were similar between the two groups. Moreover,
there was no difference in the incidence of spontaneous abortions between the groups.
However, wives of dry-cleaning workers were more than twice as likely to have a
history of attempting to become pregnant for more than 12 months or to have sought
care for an infertility problem. This difference was not statistically significant.
Furthermore, data about the correlation between length of time to conception and
tetrachloroethylene exposure were unreliable and no association could be established
between the length of time to conception and semen quality.
     In a retrospective study, time to pregnancy was studied among women biologically
monitored for exposure to six organic solvents (styrene, xylene, toluene,
tetrachloroethylene, trichloroethylene and 1,1,1-trichloroethane) at the Finnish Institute
of Occupational Health during 1965-1983 (Sal95). In this study, 197 women
Tetrachloroethylene                                                                        14
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<pre>participated. More than half of the subjects (105) were exposed to organic solvents
during their time to pregnancy. Nearly a quarter were highly exposed (handling solvents
daily or 1-4 days a week supported by individual exposure measurements). Daily or high
solvent exposure, adjusted for potential confounding factors, was significantly
associated with reduced fecundity (incidence density ratio [IDR] of clinical pregnancies
was 0.41 (CI 0.27-0.62)). The IDR’s for workers exposed to tetrachloroethylene were
0.63 (CI 0.34-1.17) (low exposure, n=13) and 0.69 (CI 0.31-1.52) (high exposure, n=7).
Development
Hemminki et al. (Hem80) compared the incidence of spontaneous abortions among
Finnish chemical workers in 1973-1976 with that of the general population. The
information about the workers was obtained from files of the Union of Chemical
Workers (n=9000) and the information about abortions was obtained from the Hospital
Discharge Registry of the National Board of Health. The incidence of spontaneous
abortions among laundry workers was statistically significantly increased when
compared to the incidence of spontaneous abortions among all women in Finland. Data
about exposure levels were not presented.
     Lindbohm et al. (Lin84) analysed the incidence of spontaneous abortions between
1973-1976 after occupational exposure (to solvents, automobile exhaust fumes,
polycyclic aromatic hydrocarbons, metals, textile dust, animal microorganisms and
other chemicals) of women and their husbands. Information about the occupations was
obtained from the 1975 national populations and housing census and the information
about abortions was obtained from the Finnish Hospital Discharge Registry of the
National Board of Health. No effect on the incidence of spontaneous abortions was
observed among solvent exposed women (n=730 pregnancies; adjusted odds ratio 0.79
(95% CI 0.58-1.07)) and among the wives of solvent exposed husbands (n=1316
pregnancies; adjusted odds ratio 0.86 (95% CI 0.69-1.08)). The incidence of
spontaneous abortions among female laundry workers was statistically significantly
increased (n=416 pregnancies; adjusted odds ratio 1.48 (95% CI 1.09-2.02)). Data about
exposure levels were not presented.
     Bosco et al. (Bos87) interviewed 67 female workers in 53 dry-cleaning shops in
Rome, Italy. The women reported 102 pregnancies of which 56 occurred during periods
of their life of employment in dry-cleaning shops and 46 during periods they were
housewives. Although the incidence of spontaneous abortions among women working
in dry-cleaning shops was 4 times higher than among housewives, no statistically
significant differences were observed in the incidences of low birth weights,
spontaneous abortions, still births and congenital birth defects between the two groups.
Mean trichloroacetic acid (an urinary metabolite of tetrachloroethylene but also of
Tetrachloroethylene                                                                      15
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<pre>trichloroethylene) levels in the urine among dry cleaners were four times higher than
among women doing only ironing or among controls. However, in all groups the
metabolite levels were low, suggesting rather low exposure levels.
     McDonald et al. (Don87) performed a large cross-sectional study among 56067
Canadian women who delivered or were treated for a spontaneous abortion in 11
Montreal hospitals between1982-1984. All women were interviewed in detail regarding
their occupational, social and personal characteristics in their most recent and past
pregnancies (104649 pregnancies in total). The data were analysed in relation to 4 main
adverse pregnancy outcomes; spontaneous abortion, stillbirth, congenital defects and
low birth weight. The expected numbers of these 4 adverse pregnancy outcomes were
calculated and compared with the observed numbers. In this cohort, 202 pregnancies
occurred in women working in laundries or dry-cleaning shops. For none of the above
mentioned adverse pregnancy outcomes, the observed to expected ratio was statistically
significantly increased.
     Kyyrönen et al. (Kyy89) defined a cohort of 5700 female dry-cleaning and laundry
workers from the registers of the Union of Chemical Workers and of the Municipal
Workers Union of Finland for the period of 1973-1983. Linking this file of study
subjects with the files of the Hospital Discharge Register and the Finnish Register of
Congenital Malformations resulted in a final study population of 130 cases of
spontaneous abortion (and 289 controls) and 24 cases of malformations (and 93
controls). Statistical analysis showed a statistically significant association between the
incidence of spontaneous abortion and high exposure (work tasks included dry cleaning
for at least one hour daily on average or when the women reported handling of
tetrachloroethylene at least once a week) to tetrachloroethylene (9 cases, 6 controls;
adjusted odds ratio 3.4 (95% CI 1.0-11.2)). No effect of tetrachloroethylene exposure on
the incidence of congenital malformations was observed.
     In the study of Taskinen et al. (Tas89, for a description see section fertility), no
association was observed between paternal exposure to solvents and the incidence of
congenital malformations. Furthermore, no significant effect on the incidence of
spontaneous abortions was observed after maternal exposure to organic solvents (cases
n=11, referents n=18; adjusted OR 1.2 (95% CI 0.5-2.7)).
     Ahlborg (Ahl90) investigated the risk of adverse pregnancy outcome (spontaneous
abortion, perinatal death, congenital malformations and low birth weight) in two cohorts
of women engaged in laundry or dry-cleaning work. A primary study consisted of 48
cases and 110 referents and a complementary study consisted of 68 cases and 131
referents (these women were identified in the Swedish Medical Birth Registry and in the
Swedish Registry of Congenital Malformations). Statistical analysis of the total material
did not show any effect after low (adjusted odds ratio 1.1 (95% CI 0.6-2.2)) or high
Tetrachloroethylene                                                                        16
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<pre>(adjusted odds ratio 1.1 (95% CI 0.5-2.2)) tetrachloroethylene exposure during the first
trimester on the incidence of adverse pregnancy outcomes.
     Lindbohm et al. (Lin90) identified a cohort of women who were biologically
monitored for exposure to organic solvents between 1965-1983. Pregnancies occurring
in this group between 1973-1983 were identified from the Finnish Register of
Congenital Malformations. The final study material included 73 cases of spontaneous
abortion and 167 controls. The incidence of spontaneous abortions in the group of
women exposed to organic solvents (57%) during the first trimester of pregnancy was
increased when compared to the control group (42%, odds ratio 2.2 (95% CI 1.2-4.1)).
The incidence of spontaneous abortions in cases and controls exposed to
tetrachloroethylene was 11% and 9%, respectively (odds ratio 1.4 (95% CI 0.4-4.2)).
The odds ratios for the low- and high-exposure groups were 0.5 (95% CI 0.1-2.9) and
2.5 (95% CI 0.6-10.5), respectively. The odds ratio for spontaneous abortion for dry-
cleaning workers exposed to tetrachloroethylene was 2.7 (95% CI 0.7-11.2), for other
work in dry cleaning plants the odds ratio was 0.6 (95% CI 0.1-5.5) and for other work
were women are exposed to tetrachloroethylene the odds ratio was 1.3 (95% CI 0.3-6.6).
     Windham et al. (Win91) performed a case control study in California using women
who had a spontaneous abortion at less than 20 weeks gestation each matched to two
controls who had have a live birth. A significant association was observed between the
incidence of spontaneous abortions and exposure to tetrachloroethylene (crude odds
ratio 4.7 (95% CI 1.1-21.1)). However, these results were based on only 5 cases and 2
controls, and 4 of these women were also exposed to trichloroethylene.
     Doyle et al. (Doy97) performed a retrospective occupational study of reproductive
outcome in 7305 women who were currently or previously employed in dry cleaning or
laundry units in the United Kingdom. Data about exposure concentrations to
tetrachloroethylene were not presented. The rate of spontaneous abortion varied
according to the type of work the women did during the pregnancy or in the three
months before conception: being lowest for pregnancies not exposed to either dry
cleaning or laundry work (10.9%), higher for those exposed to laundry work (13.4%)
and higher still for those exposed to dry cleaning work (14.8%). Within the group of
pregnancies exposed to dry cleaning, the proportion was higher if the women reported
that she works as an operator at the time of pregnancy (17.1%) rather than as a non-
operator (11.6%). Adjusted odds ratios for the period 1980-1995 showed that the risk
was over 50% higher in operators than non-operators (P=0.04).
Lactation
Bagnell et al. (Bag77) reported a case of a 6 weeks old breast-fed infant suffering from
obstructive jaundice and hepatomegaly. The mother was exposed to tetrachloroethylene
Tetrachloroethylene                                                                      17
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<pre>    as a result of lunching with her husband at the dry cleaning plant where he was
    employed. One hour after her lunch visit the breast milk of the mother contained 10 mg
    tetrachloroethylene/l. Avoidance of exposure to solvent vapours for the next 24 hours
    allowed the breast milk concentration to decrease to 3 mg/l. Cessation of breastfeeding
    resulted in rapid improvement of the infant’s condition. Data about exposure levels were
    not presented.
         Schreiber (Sch92, Sch93) modelled the infant exposure to tetrachloroethylene by
    breast milk feeding based on a variety of maternal occupational and residential
    inhalation exposure scenarios. The predicted concentration of tetrachloroethylene in
    breast milk of women ranged from 857-8440 µg/l for women occupationally exposed to
    tetrachloroethylene. For women exposed to tetrachloroethylene in residences near dry
    cleaners, the predicted breast milk concentrations of tetrachloroethylene ranged from
    16-3000 µg/l and exposure to indoor residential background concentrations of
    tetrachloroethylene resulted in a predicted breast milk concentration of 1.5 µg
    tetrachloroethylene/l. These breast milk concentrations resulted in infant exposure levels
    of 0.0001 mg/kg body weight/day (1.5 µg/l milk) or 0.82 mg/kg body weight/day (8440
    µg/l milk) assumed that a 7.2 kg infant ingests 700 ml milk a day.
         Fisher et al. (Fis97) studied the human blood/air and milk/air partition coefficient
    (PC) in human blood and human milk samples. The objective of this study was to
    evaluate the potential chemical exposure of a nursing infant by ingestion of
    contaminated milk from a mother who was occupationally exposed to vapours; To
    estimate infant exposure, a generic human pharmacokinetic (PB-PK) lactation model
    was developed. The model was based on an 8-hour exposure period of the mother to a
    constant vapour concentration equal to the threshold limit value for tetrachloroethylene
    of 25 ppm (= 172 mg/m3). The experimentally determined blood/air and milk/air PC
    values were used in the PB-PK lactation model. The predicted amount of
    tetrachloroethylene ingested by a nursing infant over a 24-hour period was 1.36 mg in
    0.92 l (1.48 mg/l).
2.3 Animal studies
    Tables 1 and 2 (annex D) summarize the fertility and developmental studies with
    tetrachloroethylene in experimental animals.
    Fertility studies
    Beliles et al. (Bel80) exposed rats and mice to 0, 100 or 500 ppm of tetrachloroethylene
    (0, 689, 3445 mg/m3) for 5 consecutive days, 7 hours/day. An increased proportion of
    sperm with aberrant morphology was found in mice (but not in rats) after exposure to
    Tetrachloroethylene                                                                        18
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<pre>500 ppm 4 weeks after exposure (19.7% in tetrachloroethylene group and 6% in control
group). In mice, 10 weeks after exposure, there were no statistically significant
differences in the proportion of abnormal sperm between the control group and the
groups treated with tetrachloroethylene. In a dominant lethal assay performed on the
rats, no adverse effects were observed.
     Tinston (Tin95) performed a two-generation study, based on a standard protocol.
Alpk:APfSD rats were exposed by inhalation to 0, 100, 300 or 1000 ppm
tetrachloroethylene (0, 689, 2067, 6890 mg/m3) 5 days/week, 6 hours/day for 11 weeks
prior to mating. During and following mating, F0-males were exposed daily (6 hours/
day) until termination and F0-females were exposed until gestation day (GD) 20. One
F1A litter was produced; dams together with their litter were exposed daily from
postnatal day (PN) 6 to 29. The second generation parents (F1) were selected from the
F1A litters on PN 29 and were exposed to tetrachloroethylene for at least 11 weeks prior
to mating. Two litters F2A and F2B were produced in the second generation. F2A litters
were exposed from PN 6-29 (0 and 100 ppm) or PN 7 to 29 (300 ppm). Dams and litters
of the 1000 ppm group were not exposed. F2B litters were generated by mating males
and females of the control, 300 and 1000 ppm groups. There was no exposure of the
dams and F2B litters during lactation. An F2C generation was obtained after mating F1
males of the control and 1000 ppm to non exposed females. Although in the 1000 ppm
group of the F0 generation, some statistically significant reductions in body weight were
observed during the premating, gestation and lactation periods, these effects were only
marginal. In the F1-generation a more pronounced effect on body weight was observed
in this group mainly due to the low pup weight on PN 29 (initial weight at the start of the
premating period). During the first 2 weeks of exposure to 1000 ppm in each generation
(F0 parents and F1A pups) a decreased activity and reduced response to sound was
observed. These signs were not present approximately 30 minutes after the end of
exposure. In a few animals of the 1000 ppm group clinical observations such as
salivation, breathing irregularities, piloerection and tip-toe gait were observed. Kidney
and liver weight of the males of the 1000 ppm group were significantly increased. In the
1000 ppm group, histological changes (slight nuclear pleomorphism) were observed in
the kidneys of the males in both generations and in the females of the F0-generation. A
statistically significant dose-related reduction in the testis weight was observed in the
300 and 1000 ppm group in the second generation, but there were no associated
histopathological changes in the 1000 ppm group. There were no effects on fertility in
any of the exposed groups from either generation.
Tetrachloroethylene                                                                         19
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<pre>Developmental toxicity
Tinston (1995) performed a two-generation study, based on a standard protocol.
Alpk:APfSD rats were exposed by inhalation to 0, 100, 300 or 1000 ppm
tetrachloroethylene (0, 689, 2067, 6890 mg/m3) 5 days/week, 6 hours/day for 11 weeks
prior to mating. During and following mating, F0-males were exposed daily (6 hours/
day) until termination and the F0-females were exposed until gestation day (GD) 20.
One F1A litter was produced; dams together with their litter were exposed daily from
postnatal days (PN) 6 to 29. The second generation parents (F1) were selected from the
F1A litters on PN 29 and were exposed to tetrachloroethylene for at least 11 weeks prior
to mating. Two litters F2A and F2B were produced in the second generation. F2A litters
were exposed from PN 6-29 (0 and 100 ppm) or PN 7 to 29 (300 ppm). Dams and litters
of the 1000 ppm group were not exposed. F2B litters were generated by mating males
and females of the control, 300 and 1000 ppm groups. There was no exposure of the
dams and F2B litters during lactation. An F2C generation was obtained after mating F1
males of the control and 1000 ppm to non exposed females. Although in the 1000 ppm
group of the F0 generation some statistically significant reductions in body weight were
observed during the premating, gestation and lactation periods, these effects were only
marginal. In the F1-generation a more pronounced effect on body weight was observed
in this group mainly due to the low pup weight on PN 29 (initial weight at the start of the
premating period). During the first 2 weeks of exposure to 1000 ppm in each generation
(F0 parents and F1A pups) a decreased activity and reduced response to sound was
observed. These signs were not present approximately 30 minutes after the end of
exposure. In a few animals of the 1000 ppm group clinical observations such as
salivation, breathing irregularities, piloerection and tip-toe gait were observed. In the
1000 ppm group of the first generation a slight effect was observed on the number of
pups born alive and pup survival (PN 5-22). Pups of the 1000 ppm group showed signs
of sedation after exposure on PN 6 up to PN 29. Pup weights of the 300 and 1000 ppm
were reduced when compared to the controls. In the second generation in the F2A and
F2B litters of the 1000 ppm group a statistically significant effect was observed on the
proportion of pups born alive and pup survival (PN 1-5 and 5-22). The total number of
pups born (live and dead pups) per litter in the 1000 ppm group in the F2A litters and
more pronounced in the F2B litters was decreased; the authors did not calculate this
parameter nor performed statistics (F2A: control group 11.9 versus 1000 ppm group
10.1; F2B control group 10.6 versus 1000 ppm group 7.9). Pup weights of F2A and F2B
litters were decreased in the 1000 ppm group. No significant effects were observed in
the F2C litters; this indicates that the effects observed in the 1000 ppm group were not
male mediated.
Tetrachloroethylene                                                                         20
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<pre>     Schwetz et al. (Sch75) studied the developmental effects after inhalation of
tetrachloroethylene (300 ppm=2067 mg/m3) during gestational days 6-15, for 7 hours/
day in Sprague Dawley rats and Swiss Webster mice. Increased maternal relative liver
weights of mice and slight but statistically significant decreases in rat body weights
were observed. In mice, a decrease in fetal body weight, retarded ossification of the
skull bones and sternebrae was observed. In rats, the resorption rate in the
tetrachloroethylene group was increased to 9% versus 4% in the controls. These effects
might be caused by maternal toxicity or by chance, since, for some parameters, a high
variance between 2 described control groups was observed.
     Organic materials concentrated from the drinking waters of five US cities selected
as representative of the major sources of raw water were administered to groups of
pregnant CD-1 mice from GD 7-14 by gavage at dose levels representative for 300,
1000 and 3000 times the anticipated human exposure to these materials (Kav79). The
tetrachloroethylene exposure level in the highest dose group was calculated to be 0.007
mg/kg body weight /day. In the drinking-water concentrates also other compounds, e.g.
chloroform [calculated exposure level 7.1 mg/kg body weight], were present. The dams
were killed on GD 18 and the fetuses were examined for skeletal and visceral anomalies
(Kav79). Except from slight effects on body weights and relative liver weight, no
maternally toxic effects were observed. Furthermore, no effects were observed on the
fetuses.
     Beliles et al. (Bel80, see also the section about fertility) found no maternal toxicity
or developmental effects after exposure by inhalation to 500 ppm (= 3445 mg/m3)
tetrachloroethylene, 7 hours /day, at gestational days 0-18 or 6-18, with or without a 3-
week pregestational exposure period in Sprague Dawley rats, except for a increased
maternal kidney weight in the group treated premating and during gestational days 6-18.
     The same investigators (Bel80) also exposed female New Zealand White rabbits by
inhalation to 500 ppm tetrachloroethylene (7 hours/day, gestational days 0-21 or 7-21,
with or without a 3-week pregestational exposure). No maternal toxicity, fetal toxicity or
teratogenic effects were reported.
     In a behavioural study, Nelson et al. (Nel80) exposed pregnant Sprague-Dawley rats
to 0, 100 and 900 ppm (0, 689, 6201 mg/m3) of tetrachloroethylene for 7 hours/day on
gestational days 7-13 or 14-20. Various behavioural tests were performed on the
offspring on postnatal days 4-56 and histological and biochemical examinations of the
pups brain was performed. Exposure to 900 ppm (both periods) caused decreased
maternal weight gain, reduced food consumption. Inconsistent results were obtained in
the behavioural tests and biochemical analysis of the brain of 21 day old pups
demonstrated significant reductions in the levels of acetylcholine for the group whose
dams were exposed during days 7-13 of gestation.
Tetrachloroethylene                                                                          21
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<pre>         Smith et al. (Smi89) exposed Long Evans rats to 0, 330, 800, 1200 or 1800 mg/kg
    trichloroacetic acid (a metabolite of tetrachloroethylene) by gavage on days 6-15 of
    gestation. Maternal weight gain was reduced at 800, 1200 and 1800 mg/kg and a dose-
    related increase in spleen and kidney weights was observed which was statistically
    significant at all dose levels. Embryolethality was significantly increased in the three
    highest dose groups. Foetal weight and foetal length were statistically significantly
    dose-related decreased in all treatment groups. The incidence of soft tissue
    malformations, mainly in the cardiovascular system, was dose-related and statistically
    significantly increased in all dose groups. The incidence of skeletal malformations was
    statistically significant increased in the 1200 and 1800 mg/kg groups.
    Lactation
    No animal studies on the effects on lactation were found.
2.4 Conclusion
    Occupational exposure to mixtures of organic solvents has been shown to increase the
    incidence of spontaneous abortions among wives of exposed men (Tas89) and to
    decrease fecundity of exposed women (Sal95). However, in the study of Taskinen et al.
    (1989) no effect of tetrachloroethylene exposure on spontaneous abortions was
    observed. In the study of Sallmén et al. (Sal95) an effect of tetrachloroethylene exposure
    on fecundity was observed but the groups were very small (n=7 or 13) and no dose
    response relationship was observed. Zielhuis and Van der Gulden (Zie89) observed an
    increased incidence of menstrual disorders among dry-cleaning workers but the
    significance of these findings was limited due to the small sample size and lack of
    exposure data. In the studies of Eskenazi et al. (Esk91a, Esk91b) subtle effects on sperm
    parameters were observed in dry-cleaning workers (Esk91a) but there were no effects on
    fertility (Esk91b). Although effects were observed on fertility in men, it is not clear
    whether the described effects are due to tetrachloroethylene exposure alone, or to a
    mixture of compounds. For this reason, the committee recommends not to classify
    tetrachloroethylene with respect to effects on fertility because of a lack of appropriate
    human data.
         In the animal studies, Beliles et al. (Bel80) found an increased incidence of aberrant
    sperm morphology in mice (but not rats), 4 weeks after tetrachloroethylene exposure.
    However, after 10 weeks no effect was observed. In addition, in the two-generation
    study of Tinston et al. (Tin95), no effect of tetrachloroethylene on fertility was observed
    (but maternal toxicity was observed).
    Tetrachloroethylene                                                                         22
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<pre>     In conclusion, based on the data from animal studies, the committee is of the
opinion that sufficient data show that no classification for effects of tetrachloroethylene
on fertility is indicated.
Hemminki et al. (Hem80) and Lindbohm et al. (Lin84) reported an increased incidence
of spontaneous abortions among laundry workers. However, no data about
tetrachloroethylene-exposure levels in the laundries were presented in these studies
(tetrachloroethylene is particularly used by dry-cleaning workers and to a lesser extent
in laundries). Bosco et al. (Bos87), Mc Donald et al. (Don87), Taskinen et al. (Tas89),
Ahlborg et al. (Ahl90), Lindbohm et al. (Lin90) observed no statistically significant
adverse effects on pregnancy outcome. In the study of Kyyrönen et al. (Kyy89) and of
Windham et al. (Win91) a significant association was observed between (high) exposure
to tetrachloroethylene and the incidence of spontaneous abortions. However, the results
of both studies were based on relatively small groups and in the study of Windham et al.
(Win91) women reported that they were also exposed to trichloroethylene. Doyle et al.
(Doy97) showed that women working in dry-cleaning shops, and especially those who
were working as an operator, had an increased risk for having a spontaneous abortion.
However, since exposure levels of tetrachloroethylene were not measured and the data
were not corrected for confounding factors such as heavy lifting this study showed only
an association between job and incidence of spontaneous abortions.
     In conclusion, the committee is of the opinion that although effects were observed
on development in man, it is not clear whether the described effects are due to
tetrachloroethylene exposure alone, or to a mixture of compounds.
     In animal studies, Schwetz et al. (Sch75) observed effects of inhalatory
tetrachloroethylene exposure (300 ppm) on ossification in mice and on the incidence of
resorption in rats. However, these effects were observed at dose levels which induced
maternal toxic effects as well. In the study of Beliles et al. (Bel80), no significant
developmental effects after inhalatory tetrachloroethylene exposure (500 ppm) were
observed in rats and rabbits. In a two-generation study of Tinston et al. (Tin95),
tetrachloroethylene had an effect on the number of F1- and F2-pups born alive, pup
survival and pup body weights. Furthermore, the total number of F2-pups born (live and
dead pups) per litter was decreased. In this study general toxicity (effect on body weight
(F0 and F1) and histopathological effects on kidneys (only F0)) was observed in the F0-
and F1-male parents and F0-females. Nelson et al. (Nel80) observed inconsistent effects
on behavioural parameters and on biochemical parameters of the brain in the offspring
of rats exposed to tetrachloroethylene at dose levels inducing maternal toxic effects.
Tetrachloroethylene                                                                         23
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<pre>     In conclusion, in view of the animal studies, the committee recommends to classify
tetrachloroethylene in category 3 (‘substances which cause concern for humans owing
to possible developmental toxic effects’) and to label with R63 (may cause harm to the
unborn child).
From the study of Fisher et al. (a pharmacokinetic lactation model), a concentration of
1.48 mg tetrachloroethylene/l breast milk was predicted (Fis97). The committee is of the
opinion that this (predicted) tetrachloroethylene concentration in human breast milk can
only be used as an indication for the possible concentration of the compound in breast
milk, because the model is not yet sufficiently validated. The committee concludes that
the predicted exposure level is no reason for labelling. In studies of Schreiber et al.
(Sch92, Sch93), a maximal level of tetrachloroethylene in breast milk was predicted ( in
a model) to be 8.44 mg/l. In addition, in the study of Bagnell et al. (Bag77) 10 mg
tetrachloroethylene per litre breast milk was related to clinical signs observed in a 6-
weeks old breast-fed infant.
     No additional experimental data are available about the concentration of
tetrachloroethylene in human breast milk and about the possible effects during lactation.
Therefore the committee concluded that a lack of appropriate data precludes assessment
of tetrachloroethylene for labelling for effects during lactation.
Proposed classification for fertility
A lack of appropriate human data preclude the assessment of tetrachloroethylene and
sufficient animal data show that no classification for tetrachloroethylene is indicated for
effects on fertility.
Proposed classification for developmental toxicity
Category 3, R63.
Proposed labelling for effect during lactation
Lack of appropriate data precludes assessment of tetrachloroethylene for labelling for
effects during lactation.
Tetrachloroethylene                                                                         24
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<pre>Additional consideration
The committee would like to emphasise that several human studies considered here in
view of tetrachloroethylene exposure give reason for concern with respect to effects on
fertility and development. However, it is not clear in these studies whether exposure
involved pure tetrachloroethylene or a mixture of solvents containing
tetrachloroethylene. Therefore, the EU Classification and Labelling guideline does not
warrant a classification of tetrachloroethylene on the basis of these human studies.
However, the committee emphasises that there is clearly cause for concern for effects on
fertility and development after exposure to mixtures of solvents containing
tetrachloroethylene.
Tetrachloroethylene                                                                      25
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<pre>       References
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       tetrachloroethylene. Am. J. Ind. Med. 1990; 17: 567-575.
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<pre>Hem80 Hemminki K, Franssilla E, Vainio H. Spontaneous abortions among female chemical workers in Finland.
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WHO84 World Health Organization. Tetrachloroethylene. Environmental Health Criteria 1984; 31.
      References                                                                                               29
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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
                                                  30
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<pre>Annex A
      De committee
      •  BJ Blaauboer, chairman
         Toxicologist, Institute for Risk Assessment Sciences, Utrecht
      •  AM Bongers, advisor
         Ministry of Social Affairs and Employment, Den Haag
      •  HFP Joosten
         Toxicologist, NV Organon, Department of Toxicology and Drug Dispositn, 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
      •  ASAM van der Burght, scientific secretary
         Health Council of the Netherlands, Den Haag
      De committee                                                                           31
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<pre>The first draft of the present document was prepared by APM Wolterbeek and DH
Waalkens-Berendsen, from the TNO Nutrition and Food Research Institute in Zeist, by
contract with the Ministry of Social Affairs and Employment.
Secretarial assistance: A Aksel.
Lay-out: J van Kan.
De committee                                                                        32
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<pre>Annex B
      Comments on the public draft
      A draft of the present report was released in 2002 for public review. The following
      persons and organisations have commented on the draft review:
      • V Digernes, Federation of Norwegian Process Industries, Norway
      Comments on the public draft                                                        33
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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.
      Directive (93/21/EEC) of the European Community                                                             34
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<pre>Category 2:
Substances which should be regarded as if they impair fertility in humans:
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 sec-
     ondary 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 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                                                                 35
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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 interfere
Directive (93/21/EEC) of the European Community                                                               36
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<pre>       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 devel-
       opment, 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 develop-
       ment 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                                                                   37
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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).
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.
Directive (93/21/EEC) of the European Community                                                                 38
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<pre>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 poten-
     tially 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                                                                39
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<pre>Annex        D
             Fertility and developmental toxicity
             studies
Table 1.1 Fertility studies with tetrachloroethylene in experimental animals.
authors    species            experimental period/      dose and route general toxicity        effects on reproductive   remark
                              design                                                           organs/effects on repro-
                                                                                               duction
Beliles et SpragueDawley 7 h/d for 5 consecutive 0, 689 and             not presented          No effect on sperm head
al. (1980) rats(n=?)          days                      3445 mg/m3                             morphology
                                                        by inh
Beliles et CD-1 mice(n=?) 7 h/d for 5 consecutive 0, 689 and            not presented          Increased anomalies in
al. (1980)                    days                      3445 mg/m3                             sperm head morghology
                                                        by inh                                 after 4 w. in 3445 mg/m3
                                                                                               group.
Tinston    A1p1: APfSD        11 weeks prior to mat-    0, 689, 2067 or 6890 mg/m3             2067 mg/m3 : reduced tes- two-gener-
(1995)     rats (male and     ing, mating, GD 0-20      6890 mg/m3      group:decreased BW     tis weight F1-males; no   ation study
           females 24/sex/    andPN 6-29 (see text      6h/day; prior   in F0- and F1-genera-  effect on fertility 6890
           group)             for exposure during       to mating 5d/   tion; increased kid-   mg/m3 : reduced testis
                              lactation) Males of F0    week and daily  ney and liver weights; weight F1-males; no his-
                              and F1 generation         during mating,  histological changes   topathological changes;
                              exposed for 19 and 35     gestation and   in kidneys in males of no effect on fertility
                              w, respectively before    lactation by    both generations and
                              sacrifice                 inh             in females of the F0-
                                                                        generation
bw = body weight h=hour d= day w=week inh=inhalation gav=gavage n=number GD=gestation day
             Fertility and developmental toxicity studies                                                                         40
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<pre>Table 2.1 Developmental toxicity studies with tetrachloroethylene in experimental animals.
authors          species            experimental      dose and route    general toxicity   developmental          remarks
                                    period/design                                          toxicity
Schwetz et       Swiss Webster-     GD 6-15; sacri- 0 and 2067 mg/ relative liver          decreased fetal
al.(1975)        mice(n=17)         fice day 18       m3 7 h/day by     weight increased   weight, delayed
                                                      inh                                  ossification skull
                                                                                           bones and sterne-
                                                                                           brae
Schwetz et       Sprague Dawley GD 6-15; sacri- 0 and 2067 mg/ decreased body              increased no.
al.(1975)        rats (n=17)        fice day 21       m3, 7h/day by     weight             resorptions
                                                      inh.
Kavlock et       CD-1 mice          GD 7-14; sacri- by gav, see                            no effects             300, 1000 and
al.(1979)        (number of lit-    fice day 18       remark                                                      3000 x the human
                 ters: 11-72)                                                                                     exposure to the
                                                                                                                  levels in drinking
                                                                                                                  water; the highest
                                                                                                                  dose corresponded
                                                                                                                  to 0.007 mg/kg bw
Beliles et       Sprague Dawley GD 0-18 or 6-18 0 and 3445 mg/          no maternal toxic- 3445 mg/m3: no
al.(1980)        rats (n=19-24) with or without m3 7h/day by            ity except for     fetal toxicity and
                                    3-wk premating; inh.                increased kidney teratogenicity
                                    sacrifice day 21                    weight in group
                                                                        GD 6-18 with 3-
                                                                        wk premating
                                                                        exposure
Beliles et       New Zealand        GD 0-21 or 7-21 0 and 3445 mg/ no maternal toxic- 3445 mg/m3 : no
al.(1980)        White rabbits      with or without m3 7h/day by        ity                effects fetal toxicity
                                    3-wk premating; inh                                    and teratogenicity
                                    sacrifice day 30
bw = body weight h=hour d= day w=week inh=inhalation gav=gavage n=number GD=gestation day
            Fertility and developmental toxicity studies                                                                           41
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<pre>Table 2.2 Developmental toxicity studies tetrachloroethylene in experimental animals.
authors       species       experimental           dose and route    general toxicity      effects on reproductive remarks
                            period/design                                                  organs/effects on repro-
                                                                                           duction
Nelson et     Sprague       GD 7-13 or 14-20       0, 689 and 6201 decreased maternal      GD 7-13, 6201 mg/m3        None of the
al(1980)      Dawley rats                          mg/m3 7h/day      weight gain, reduced  decreased performance      differences
              (n=19)                               by inh.           food consumption      in some behavioural        observed
                                                                                           tests; reduced levels of   were consis-
                                                                                           acetylcholine in the       tent in time or
                                                                                           brain 21-day old pups      impressive
                                                                                           GD 14-20, 6201 mg/m3
                                                                                           decreased performance
                                                                                           of pups in some behav-
                                                                                           ioral tests; in other test
                                                                                           superior performance
Tinston(1995) A1p1;         11 weeks prior to      0, 689, 2067 or   6890 mg/m3 group:     6890 mg/m3: decreased
              APfSD rats    mating, mating, GD     6890 mg/m3 6h/    decreased BW in F0-   number of pups born
              (male and     0-20 and PN 6-29       day; prior to     and F1-generation;    and decreased pup sur-
              females 24/   (see text for expo-    mating 5d/week    increased kidney and  vival 2067 and 6089 mg/
              sex/group)    sure during lacta-     and daily dur-    liver weights; histo- m3: reduced pup weights
                            tion)                  ing mating, ges-  logical changes in
                            Males of F0 and F1     tation and        kidneys in males of
                            generation exposed     lactation by inh. both generations and
                            for 19 and 35 w,                         in females of the F0-
                            respectively before                      generation
                            sacrifice
bw = body weight h=hour d= day w=week inh=inhalation gav=gavage n=number GD=gestation day
            Fertility and developmental toxicity studies                                                                           42
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<pre>Annex E
      Abbreviations
      Abbreviations used:
      bw         body weight
      d          day
      F          female(s)
      i.p.       intraperitoneal
      i.v.       intravenous
      M          male(s)
      n          number
      NOAEL      no adverse effect level
      OECD       Organisation for Economic Cooperation and Development
      PN         postnatal
      Abbreviations                                                    43
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<br><br>