<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>Diethyleneglycol (mono)alkylethers
Evaluation of the effects on reproduction, recommendation for classification
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<pre></pre>

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<pre>Gezondheidsraad                                      Voorzitter
Health Council of the Netherlands
Aan de Staatssecretaris Sociale Zaken en Werkgelegenheid
Onderwerp                   : Aanbieding advies ‘Diethyleneglycol (mono)alkylethers’
Uw kenmerk                  : DGV/MBO/U-932542
Ons kenmerk                 : U-1849/AvdB/fs/543-E7
Bijlagen                    :1
Datum                       : 22 december 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 be-
hoeve 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 diethyleenglycol (mono)alkylethers. Dit advies is
opgesteld door de Commissie Reproductietoxische stoffen van de Gezondheidsraad en beoordeeld door
de Beraadsgroep Gezondheid en Omgeving. Ik wil u erop wijzen dat de commissie onder meer
adviseert om diethyleenglycol (mono)methylether (DEGME) wat betreft de effecten op de
ontwikkeling in categorie 2 te classificeren. Dit advies van de commissie wijkt af van het standpunt van
de Europese Commissie, die DEGME in categorie 3 heeft geclassificeerd. Dit verschil in inzicht heeft
echter geen gevolgen voor het opnemen van DEGME op de hierboven genoemde lijst van voor de
voortplanting giftige stoffen.
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- m a i l : A . v d . B u r g h t @ g r . n l                                    www.gr.nl
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<pre>Diethyleneglycol (mono)alkylethers
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. 2003/10OSH, The Hague, 22 December 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 and Food Quality. The Council can publish advi-
sory reports on its own initiative. It usually does this in order to ask attention for devel-
opments 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 avail-
able to the public.
This report can be downloaded from www.healthcouncil.nl.
Preferred citation:
Health Council of the Netherlands. Committee for Compounds toxic to reproduction.
Diethyleneglycol (mono)alkylethers. The Hague: Health Council of the Netherlands,
2003; publication no. 2003/10OSH.
all rights reserved
ISBN: 90-5549-508-5
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<pre>    Contents
    Samenvatting 9
    Executive summary 11
1   Scope 13
1.1 Background 13
1.2 Committee and procedure 13
1.3 Additional considerations 14
1.4 Labelling for lactation 15
1.5 Data 16
1.6 Presentation of conclusions 16
1.7 Final remark 16
2   Diethyleneglycol (mono)methylether (DEGME) 17
2.1 Introduction (HCN96) 17
2.2 Human studies 18
2.3 Animal studies 18
2.4 Conclusions 22
3   Diethyleneglycol (mono)ethylether (DEGEE) 25
3.1 Introduction (HCN96) 25
3.2 Human studies 26
    Contents                                      7
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<pre>3.3 Animal studies 26
3.4 Conclusions 29
4   Diethyleneglycol (mono)alkylethers (DEGBE) 31
4.1 Introduction (HCN96) 31
4.2 Human studies 32
4.3 Animal studies 32
4.4 Conclusion 34
    References 37
    Annexes 41
A   The committee 43
B   Comments on the public draft 45
C   Directive (93/21/EEC) of the European Community 47
D   Fertility and developmental toxicity studies 53
E   Abbreviations 59
8   Diethyleneglycol (mono)alkylethers
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<pre>Samenvatting
Diethyleenglycol (mono)alkylethers worden door de industrie voornamelijk als
oplosmiddel. Op verzoek van de Minister van Sociale Zaken en Werkgelegenheid
beoordeelt de Gezondheidsraad 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 voor drie diethyleenglycol (mono)alkylethers,
te weten diethyleenglycol (mono) methyl ether, diethyleenglycol (mono)ethylether,
diethyleenglycol (mono)n-butylether onder de loep genomen.
De aanbevelingen van de commissie zijn:
• Diethyleenglycol (mono)methylether
    • Voor effecten op de fertiliteit meent de commissie dat er onvoldoende geschikte
      humane gegevens beschikbaar zijn en dat voldoende diergegevens laten zien dat
      diethyleenglycol (mono)methylether de fertiliteit niet schaadt. Daarom adviseert
      zij diethyleenglycol (mono)methylether niet te classificeren.
    • Voor effecten op de ontwikkeling adviseert de commissie diethyleenglycol
      (mono)methylether te calssificeren in categorie 2 (stoffen die dienen te worden
      beschouwd alsof zij bij de mens ontwikkelingsstoornissen veroorzaken) en met
      T;R61 te kenmerken.
    • Voor effecten tijdens lactatie adviseert de commissie om diethyleenglycol
      (mono)methylether niet te kenmerken wegens onvoldoende geschikte gegevens.
Samenvatting                                                                            9
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<pre>   •   Diethyleenglycol (mono)ethylether
       • Voor effecten op de fertiliteit meent de commissie dat er onvoldoende geschikte
         humane gegevens beschikbaar zijn en dat voldoende diergegevens laten zien dat
         diethyleenglycol (mono)ethylether de fertiliteit niet schaadt. Daarom adviseert zij
         diethyleenglycol (mono)ethylether niet te classificeren.
       • Voor effecten op de ontwikkeling van het nageslacht meent de commissie dat er
         onvoldoende geschikte humane gegevens beschikbaar zijn en dat voldoende dier-
         gegevens laten zien dat diethyleenglycol (mono)ethylether de ontwikkeling van het
         nageslacht niet schaadt. Daarom adviseert zij diethyleenglycol (mono)ethylether
         niet te classificeren.
       • Voor effecten tijdens lactatie adviseert de commissie om diethyleenglycol
         (mono)ethylether niet te kenmerken wegens onvoldoende geschikte gegevens.
   •   Diethyleenglycol (mono)n-buthylether
       • Voor effecten op de fertiliteit meent de commissie dat er onvoldoende geschikte
         humane gegevens beschikbaar zijn en dat voldoende diergegevens laten zien dat
         diethyleenglycol (mono)n-buthylether de fertiliteit niet schaadt. Daarom adviseert
         zij diethyleenglycol (mono)n-buthylether niet te classificeren.
       • Voor effecten op de ontwikkeling van het nageslacht meent de commissie dat er
         onvoldoende geschikte humane gegevens beschikbaar zijn en dat voldoende dier-
         gegevens laten zien dat diethyleenglycol (mono)n-buthylether de ontwikkeling van
         het nageslacht niet schaadt. Daarom adviseert zij diethyleenglycol (mono)n-
         buthylether niet te classificeren.
       • Voor effecten tijdens lactatie adviseert de commissie om diethyleenglycol
         (mono)n-buthylether niet te kenmerken wegens onvoldoende geschikte gegevens.
10 Diethyleneglycol (mono)alkylethers
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<pre>Executive summary
Diethyleneglycol (mono)alkylethers are mainly used as solvents or intermediates. 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 the following three
Diethyleneglycol (mono)alkylethers: diethyleneglycol (mono)methylether, diethylene-
glycol (mono)ethylether and diethyleneglycol (mono)n-butylether.
The committees recommendations are:
• Diethyleneglycol (mono)methylether (DEGME)
    • For effects on fertility, the committee recommends not classifying DEGME on the
      basis of a lack of appropriate human data and sufficient animal data which show
      that no classification is indicated.
    • For developmental toxicity, the committee recommends classifying DEGME in
      category 2 (substances which should be regarded as if they cause developmental
      toxicity to humans) and labelling DEGME with T;R61.
    • For effects during lactation, the committee is of the opinion that due to a lack of
      appropriate data DEGME should not be labelled.
Executive summary                                                                         11
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<pre>   •   Diethyleneglycol (mono)ethylether (DEGEE)
       • For effects on fertility, the committee recommends not classifying DEGEE on the
         basis of a lack of appropriate human data and sufficient animal data which show
         that no classification is indicated.
       • For developmental toxicity, the committee recommends not classifying DEGEE on
         the basis of a lack of appropriate human data and sufficient animal data which
         show that no classification is indicated.
       • For effects during lactation, the committee is of the opinion that due to a lack of
         appropriate data DEGEE should not be labelled.
   •   Diethyleneglycol (mono)n-butylether (DEGBE)
       • For effects on fertility, the committee recommends not classifying DEGBE on the
         basis of a lack of appropriate human data and sufficient animal data which show
         that no classification is indicated.
       • For developmental toxicity, the committee recommends not classifying DEGBE
         on the basis of a lack of appropriate human data and sufficient animal data which
         show that no classification is indicated.
       • For effects during lactation, the committee is of the opinion that due to a lack of
         appropriate data DEGBE should not be labelled.
12 Diethyleneglycol (mono)alkylethers
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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 repro-
        duction. The classification is performed by the Health Council’s Committee for com-
        pounds 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 three Diethyleneglycol (mono)alky-
        lethers: Diethyleneglycol (mono)methylether, Diethyleneglycol (mono)ethylether, and
        Diethyleneglycol (mono)n-butylether by the Health Council’s Committee for com-
        pounds toxic to reproduction. The members of the committee are listed in Annex A. The
        first draft of this report was prepared by dr J Krüse and dr JAGM van Raaij of the
        OpdenKamp Registration & Notification, The Hague, The Netherlands, by contract with
        the Ministry of Social Affairs and Employment. The classification is based on the evalu-
        Scope                                                                                    13
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<pre>    ation of published 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 2003, 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 direc-
    tive, 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).
14  Diethyleneglycol (mono)alkylethers
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<pre>    •    Adverse effects in a reproductive or developmental study, in the absence of data on
         parental toxicity, occurring at dose levels which cause severe toxicity in other stud-
         ies, need not necessarily lead to a category 2 classification.
    •    If, after prenatal exposure, small reversible changes in foetal growth and in skeletal
         development (e.g. wavy ribs, short rib XIII, incomplete ossification) in offspring
         occur in a higher incidence than in the control group in the absence of maternal
         effects, the substance will be classified in category 3 for developmental toxicity. If
         these effects occur in the presence of maternal toxicity, they will be considered as a
         consequence of this and therefore the substance will not be classified for develop-
         mental toxicity (see Annex C, 4.2.3.3 developmental toxicity final paragraph).
    •    Clear adverse reproductive effects will not be disregarded on the basis of reversibil-
         ity per se.
    •    Effects on sex organs in a general toxicity study (e.g. in a subchronic or chronic tox-
         icity 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 metabo-
    lites) 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 inde-
    pendent of dosage), the labelling for effects during lactation is based on a risk character-
    isation 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 is above an exposure limit for the general population, eg
    the acceptable daily intake (ADI).
*   Organisation for Economic Cooperation and Development
    Scope                                                                                        15
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<pre>1.5 Data
    Literature searches were conducted in the online databases Toxline and Medline, start-
    ing from 1966 up 2003. Literature was selected primarily on the basis of the text of the
    abstracts. Publications cited in the selected articles, but not selected during the primary
    search, were reviewed if considered appropriate. In addition, handbooks and a collection
    of most recent reviews were consulted.
         Human studies on Diethyleneglycol (mono)alkylethers regarding its effects on fer-
    tility and development are described in the text. Of each study the quality of the study
    design (performed according to internationally acknowledged guidelines) and the qual-
    ity 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 tox-
         icity.
    • 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 characterisation,
    human exposure assessment and recommendations of other organisations.
*   for definitions see Tox95
16  Diethyleneglycol (mono)alkylethers
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<pre>Chapter 2
        Diethyleneglycol (mono)methylether
        (DEGME)
2.1     Introduction (HCN96)
        Name                  :    Diethyleneglycol monomethylether
        synonyms              :    2-(2-methoxyethoxy)-ethanol, Dìglycol monomethyl ether, Dowanol® DM
                                   Glycol Ether, ethylene diglycol monomethyl ether, MECB, Methoxydigly-
                                   col, ß-methoxy-ß'-hydroxydiethyl ether, Methyl Carbitol® Solvent, poly-
                                   solv DM
        CAS-no                :    111-77-3
        EC no                 :    203-906-6
        Examples of use       :    Solvent for coatings and ink, fuel additive,
        Mol weight            :    120.15
        Molecular formula     :    CH -(O-CH -CH ) -OH
                                       3       2     2 2
        Chem formula          :    CH O
                                     5 12 3
        Structural formula    :
                                                      3                       o
        Conversion factor     :    1 ppm = 5.0 mg/m at 760 mm Hg and 20 C
                                           3
                                   1 mg/m = 0.2 ppm
        The European Union has proposed not to classify DEGME with respect to the effects on
        fertility. For effects on development, the European Union has proposed classifying
        DEGME in category 3 and labeling the compound with Xn;R63.
        Diethyleneglycol (mono)methylether (DEGME)                                                         17
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<pre>2.2 Human studies
    Fertility
    No publications were found concerning the effects on fertility of DEGME in humans.
    Developmental studies
    No publications were found concerning the effects on development of DEGME in
    humans.
    Lactation
    No publications were found concerning the effects on lactation of DEGME in humans.
2.3 Animal studies
    Tables 1 and 2 (Annex D) summarize the fertility and developmental studies with
    DEGME in laboratory animals, respectively.
    Fertility
    No data were available concerning functional fertility effects.
    Male and female Fischer rats (10/sex/group) were exposed subchronically by inhalation
                                                                        3
    to DEGME vapour at concentrations of 0, 150, 500 or 1.080 mg/m (0, 30, 100 or 216
    ppm) 6 hours per day, 5 days/week, for 13 weeks (Mil85). Following exposure, all ani-
    mals were weighed, sacrificed and subjected to a complete gross pathological and histo-
    pathological examination, including testis, epididymis, seminal vescicle, prostate,
    coagulating gland, ovary, oviduct, uterus, cervix and vagina. There were no exposure
    related mortalities during the course of the study. Furthermore, no apparent differences
    in body weights, absolute and relative organ weights between control and treated groups
    of animals were observed. No effects of the treatment were seen in haematology, clini-
    cal chemistry analyses, urinalyses and in the gross pathological and histopathological
    examinations (Mil85).
18  Diethyleneglycol (mono)alkylethers
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<pre>       In a study of Nagano et al. (Nag84), DEGME (0 and 2% (~3000 mg/kg bw*) in the
  drinking water) was administered to male mice (JCL-ICR) for 25 days. The animals (5/
  group) were necropsied at the end of administration. Testicular weight and the combined
  weight of seminal vesicles and coagulating gland were measured. Also a white blood
  cell count was performed at the time of necropsy. No statistically significant differences
  in these parameters were noted when compared to the control group. In addition, no gen-
  eral toxicity was observed. The observed slight decrease in testicular weight in the treat-
  ment group was only observed in one animal.
       In a subchronic study of Hobson et al. (Hob86), Hartley guinea pigs were dermally
  exposed (under occlusion) to DEGME (99% pure) at doses of 0, 40, 200 and 1000 mg/
  kg bw/day during 90 days (5 days/week, 6 hour/day). At the medium and high dose, the
  spleen weights were decreased. At the highest dose level, a statistically significant
  increase in serum lactate dehydrogenase (LDH) was observed. A mild fatty change in
  the liver was observed in all test treatment groups but not in the controls. DEGME expo-
  sure did not result in testicular lesions, nor were body weight and the relative and abso-
  lute weights of the testes, seminal vesicles and the prostate affected.
       In a study by Cheever et al. (Che88), male Sprague-Dawley rats were treated daily
  with oral doses of 5.1 mmol/kg bw DEGME (613 mg/kg bw) for up to 20 days. Selected
  animals were killed at 2-day intervals on days 3 through 21. No gross or histopathologi-
  cal testicular changes were observed when compared to controls. Further, no early
  deaths or overt signs of toxicity were observed.
       In a time course study, male Wistar rats (4-8/group) were daily administered oral
  doses of 2000 mg/kg bw/day DEGME by gavage for 1, 2, 5 and 20 days (Kaw90). After
  sacrifice, the weights of the liver, kidney, spleen, thymus, heart, lung and testis were
  determined. After one day, the relative thymus weight was decreased whereas the rela-
  tive kidney weight was increased after 2 days. Statistically significant decreases in rela-
  tive weights of the liver, spleen, thymus and testis were reported after 5 days of dosing.
  The decrease in thymus and testis weights was more pronounced after 20 days of treat-
  ment. In an accompanying dose-response study with oral doses of 0, 500, 1000 and 2000
  mg/kg bw/day (4-8/group) during 20 days only the weights of the testis and the thymus
  were reported. No effect on testis weight was observed at doses of 500 and 1000 mg/kg,
  but at 1000 mg/kg the relative thymus weight was decreased. Animals treated with 2000
  mg/kg bw/day DEGME showed a significant decrease in body weight gain (Kaw90).
* calculated: using weight of male mice 30-35 mg, drinking 5 ml water per day.
  Diethyleneglycol (mono)methylether (DEGME)                                                  19
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<pre>   Developmental toxicity
   In an in vivo mouse screening bioassay for reproductive toxicity, fifty pregnant mice
   (CD-1) were orally administered (by gavage) 0 or 4000 mg DEGME/kg bw per day dur-
   ing day 6 to 13 of gestation (vaginal plug = day 0) (Sch84). There was a significant
   reduction in viable litters, number of live pups per litter and survival over postpartum
   days 1-3. Furthermore, the pup weight gain was significantly reduced. However, no rou-
   tine examinations of the pups for malformations or skeletal anomalies were performed.
   Moreover, five dams died.
        DEGME was subsequently tested in a conventional study by Hardin et al. (Har85,
   Har86), in which Sprague-Dawley rats were exposed by gavage. Doses of 0, 720, or
   2165 mg/kg bw were administered per day from gestation day 7 to 16. The rats were
   sacrificed on day 21 of gestation. At 2165 mg/kg bw, a significant reduction of foetal
   body weights and number of live implantations was observed. An increasing percentage
   of rib variations (9.1, 42.9 and 80%) and cardiovascular malformations (0, 4.8 and
   71.4%) was observed by increasing the doses. At 720 mg/kg, there was no gross evi-
   dence of foetotoxicity, although the average foetal body weight was slightly reduced.
   Although no maternal toxicity was observed after exposure to 720 mg/kg, a statistically
   significant reduction in maternal body weight (on day 21) and food consumption (first 5
   days of dosing) was observed after exposure to 2165 mg/kg bw per day.
        Based on the results of a dose range finding study, female New Zealand White rab-
   bits (25/group) were dermally exposed (under occlusion) to undiluted DEGME at doses
   of 0, 50, 250, and 750 mg/kg bw/day from gestation days 6 to 18 (Sco86). On gestation
   day 29, caesarian section was performed, followed by examination of the foetuses for
   external, visceral, and skeletal alterations. In the highest dose group, maternal toxicity
   was observed, characterized by decreased weight gain (during pregnancy day 9-11) and
   slight haematologic changes (ie decrease in red blood cells and packed cell volume val-
   ues). Two of the 25 animals in the group died. A slight (but not significant) increase in
   embryonic resorptions was observed. An increased incidence of developmental varia-
   tions was observed in foetuses from the highest dose group as well. These foetal alter-
   ations were mild forelimb flexure, slight-to-moderate dilation of the renal pelvis,
   retrocaval ureter, cervical spurs and delayed ossification of the skull and sternebral
   bones. However, the authors were of the opinion that these effects were not severe, par-
   ticularly in view of the relatively high incidence of various spontaneous malformations
   occurring in this species. At 250 and 50 mg/kg, no clinical signs of treatment related
   maternal toxicity were observed. Delayed ossification of the skull and cervical spurs
   were observed at 250 mg/kg. No adverse developmental effects were observed at the
   lowest dose (50 mg/kg) (Sco86).
20 Diethyleneglycol (mono)alkylethers
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<pre>     In a dose-finding study, Yamano et al. (Yam93) exposed female Wistar rats by gav-
age to daily doses of 0, 125, 250, 500, 1000, 2000, 3000 and 4000 mg/kg bw/day
DEGME (4-6/group). The non-pregnant rats were treated for 11 consecutive days and
pregnant rats from day 7-17 of gestation. The non-pregnant rats showed a significant
decrease in body weight gain and food consumption at doses above 3000 mg/kg bw and
a lowering of urinary pH at all doses. Furthermore, decreased relative weights of thymus
and pituitary gland, decreased white and red blood cell counts and hemoglobin concen-
trations and hematocrit levels were also observed at these levels. There were no signs of
hepatoxicity, but at the highest dose, relative kidney weight and plasma BUN (blood
urea nitrogen) levels were slightly increased, indicating weak nephrotoxicity. In preg-
nant rats, maternal body weight gain and food consumption were decreased above dose
levels of 2000 and 3000 mg/kg bw, respectively. At 2000 mg/kg bw, the number and
body weight of live fetuses were decreased, while the number of dead or resorbed
fetuses increased. At higher doses, all litters were totally resorbed.
     Following this dose-finding study, female Wistar rats (14/group) were administered
DEGME doses of 0, 200, 600 and 1800 mg/kg bw/day by gavage from day 7 through 17
of gestation (Yam93). On day 20 of gestation, dams were sacrificed. At 600 mg/kg,
dams were not affected, but foetal body weights were decreased, and foetal thymus and
ossification were adversely affected. At 1800 mg/kg, maternal body weight gain, food
consumption and maternal thymus weights were decreased, and visceral malformations
of the cardiovascular system were observed in 28% of the foetuses. External malforma-
tions (mostly anasarca and anury) were observed in 14.1% of the foetuses at 1800 mg/
kg, but not at lower doses. Dilated renal pelvis was noted in 52.8 % of the foetuses at the
highest dose. Degree of ossification was considerably affected. No significant skeletal
malformations were observed.
     In the same experiment, eight dams per group were administered doses of 0, 200,
600 and 1800 mg DEGME/kg bw/day by gavage from day 7 through 17 of gestation.
The duration of the gestation was determined and litters were examined immediately
after delivery (for litter size, stillborn and live born, sex and external anomalies). On day
4 after birth, culling was performed to leave eight pups per litter. Pups were nursed by
their own mothers for 21 days and pups and dams were thereupon sacrificed. In the
highest dose group, the duration of gestation of prolonged by about 2 days and the num-
ber of pups was significantly decreased. The viability of the neonates was markedly
affected by the treatment with DEGME and the number of live pups on day 4 after birth
divided by the number of live born pups in each group were 92/100, 95/101, 58/93, and
2/37 for doses of 0, 200, 600 and 1800 mg/kg, respectively. Body weight gain of pups
during 21 days after birth was unaffected at 200 mg/kg bw, but slightly decreased at a
dose of 600 mg/kg bw in each sex. No significant effects of DEGME on pups were
found in the skeletal observations on day 21 postnatal.
Diethyleneglycol (mono)methylether (DEGME)                                                    21
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<pre>    Lactation
    No studies on effects on lactation were available.
2.4 Conclusions
    No human data are available concerning the effects of DEGME on fertility.
         Kawamoto et al. (1990) observed a small effect of exposure to 2000 mg/kg bw
    DEGME on testes weight (Kaw90). However, a decreased bodyweight gain and relative
    thymus weight were observed at this dose level. No effects on funtional fertility were
    found. Nagano et al. (Nag84), Miller et al. (Mil85) and Hobson et al. (Hob86) did not
    observe any effects on fertility after exposure to high concentrations of DEGME (up to
    1000-3000 mg/kg/day) in rats, mice and guinea pigs. No general toxicity was observed
    as well.
         Based on these results, the committee is of the opinion that a lack of appropriate
    human data preclude the assessment of DEGME for effects on fertility and that suffi-
    cient animal data show that no classification for effects on fertility is indicated.
    No human data are available concerning the effects of DEGME on development.
         Yamano et al. (Yam93) observed decreased foetal body weight, decreased vialibil-
    ity of the pups and affected thymus and ossification in rats after exposure to 600 mg
    DEGME/kg bw, in the absence of maternal toxicity. After comparable oral doses (720
    mg DEGME/kg bw), Hardin et al. (Har85, Har86) found rib variations and dilated renal
    pelvis in rats in the absence of maternal toxicity. Exposure to higher concentrations
    resulted in more pronounced developmental effects (decreased number of live pups and
    cardiovasular malformations), however maternal toxicity was observed as well.
         In addition, Schuler et al. (Sch84) found a significant reduction of viable litters,
    number of live pups per litter, pup survival and a decreased foetal body weight in mice.
    However, these effects were observed in the presence of severe maternal toxicity. Based
    on the studies of Hardin et al. (Har85, Har86) and Yamano et al. (Yam93), the commit-
    tee recommends to classify DEGME in category 2 ( substances which should be
    regarded as if they cause developmental toxicity to humans) and to label the compound
    with T;R61 (may cause harm to the unborn child).
    No chemical analysis for the presence of DEGME or its metabolites in human or animal
    milk has been performed. Moreover, no studies were available concerning the effects on
    lactation. Therefore, a lack of appropriate data precludes the assessment of DEGME for
    labelling for effects during lactation.
22  Diethyleneglycol (mono)alkylethers
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<pre>Proposed classification for fertility
A lack of appropriate human data preclude the assessment of DEGME for fertility and
sufficient animal data show that no classification on fertility is indicated
Proposed classification for developmental toxicity
Category 2, T;R61
Proposed labelling for effects during lactation
A lack of appropriate data precludes the assessment of DEGME for labelling for effects
during lactation
Diethyleneglycol (mono)methylether (DEGME)                                             23
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<pre>24 Diethyleneglycol (mono)alkylethers</pre>

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<pre>Chapter 3
        Diethyleneglycol (mono)ethylether
        (DEGEE)
3.1     3.1.Introduction (HCN96)
        Name               : Diethyleneglycol monoethylether
        synonyms           : 2-(2-ethoxyethoxy)-ethanol, APV, Carbitol®, Carbitol® cellosolve, Carbitol®
                             Solvent, diethylen glycol ethyl ether, diglycolmonoethyl ether, dioxitol, Dow-
                             anol® DE Glycol Ether, ethoxydiglycol, ethyl carbitol, ethyl diethylen glycol,
                             ethylene diglycol monoethyl ether, >Losungsmittel APV, polysolv, Solvosol,
                             Transcutol.
        CAS-no             : 111-90-0
        EC no              : 203-919-7
        Examples of use    : Solvent for manufactoring industries
        Mol weight         : 134.19
        Molecular formula :  C H -(O-CH -CH ) -OH
                               2 5        2     2 2
        Chem formula       : CH O
                               6 14 3
        Structural formula :
                                                 3                        o
        Conversion factor  : 1 ppm = 5.58 mg/m at 760 mm Hg and 20 C
                                     3
                             1 mg/m = 0.179 ppm
        Diethyleneglycol (mono)ethylether (DEGEE)                                                           25
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<pre>3.2 Human studies
    Fertility
    No publications were found concerning the effects on fertility of DEGEE in humans.
    Developmental studies
    No publications were found concerning the effects on development of DEGEE in
    humans.
    Lactation
    No publications were found concerning the effects on lactation of DEGEE.
3.3 Animal studies
    Tables 3 and 4 (Annex D) summarize the fertility and developmental studies with
    DEGEE in laboratory animals, respectively.
    Fertility
    In a feeding study, Wistar rats (12/sex/group) were given diets containing 0.0, 0.25, 1.0
    and 5.0% DEGEE (2.5 g/kg feed, 10 g/kg feed, 50 g/kg feed) for 90 days. At the highest
    dose, growth and food intake of both sexes were significantly reduced and one male
    died. Haemotological examinations, performed at week 6 and 12, showed no changes at
    any dose level. At autopsy, no abnormalities were noticed in gross appearance of the
    liver, kidneys, brain, spleen, heart, adrenals or gonads. At the highest dose level,
    increases were observed in the relative weights of the kidney in both sexes and of the
    testes. Further, histopathological examination showed hydropic degeneration in the kid-
    neys of two males and one female, testicular oedema in five males, and a slight to mod-
    erate fatty change in the liver of most animals. No effects were observed at the lower
    dose levels. The test substance contained 0.4% ethylene glycol as an impurity (Hal66).
         Morrissey et al. (Mor89) summarized the results of 48 Continuous Breeding Repro-
    duction Studies of the NTP, one concerning DEGEE. These studies were described by
    Chapin et al. (Cha97) in more detail. The general study design and applied methods for
    the Reproductive Assessment by Continuous Breeding (RACB) study consists of four
    “Tasks”. Task 1 is a 14 day dose-finding study, using six exposure groups (8 mice/
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<pre>group/sex). The endpoints were clinical signs, mortality, body weight gain, and con-
sumption of food and water. In the continuous breeding phase (Task2), a control group
(n=40 animals per sex) and three treatment groups (n=20/sex) were used. Mice were
exposed to DEGEE for a 7-day premating period, and thereupon randomly grouped as
mating pairs. Exposure levels were 0.25, 1.25 and 2.50% in feed or water, correspond-
ing to approximately 0.69, 3.24 and 6.20 g/kg bw /day, respectively. During cohabita-
tion for 98 days, they were treated continuously. For all newborns during this treatment,
data were collected on body weight, proportion of males, number of litters per pair and
number of live and dead pups, within a period of 12 hours after birth. After the 98-day
cohabitation period, the pairs were separated, but the treatment was continued. During
the next 21 days, any final litters were delivered and kept for at least 21 days (weaning).
If fertility is impaired in this task, a crossover mating trial of the F0 animals is per-
formed to determine the affected sex (Task 3). Task 4 assesses the fertility and reproduc-
tive performance of the F1 generation (offspring from Task 2), which is also
continuously exposed to the test substance. In Task 2, no significant effects were
observed on other fertility parameters, eg fertility index, mean number of litter/ live
pups per pair and sex ratio of pups born alive. In addition, an offspring assessment of
reproductive function (Task 4) was performed. Therefore, the mothers were dosed
through weaning and F1 mice were dosed until mated at 74 ± 10 days of age. Male off-
spring were mated to female offspring from the same treatment group (20/group/sex),
and the F2 litters were examined for litter size, sex and pup weight. Only the highest
dose level of 2.5% in feed or water (corresponding to approximately 7.1 g/kg bw/day)
was tested. In this case, no effects were observed on mating/fertility index. There was a
34% reduction in the percent of sperm that were motile, however, this was observed in
the presence of 12% increase in liver weight and a 6% decease in brain weight. Since no
significant adverse effects on fertility were observed in the continuous breeding phase
(Task 2), no crossover mating trial (Task 3) was performed (Mor89, Cha97).
     The reproductive toxicity of DEGEE in CD-1 mice was assessed by Williams et al.
(Wil90), by using a Reproductive Assessment by Continuous Breeding (RACB) proto-
col. Males and females (20/sex/group, 40 controls/sex) were treated with DEGEE via
their drinking water resulting in dose levels of 0, 440, 2200, or 4400 mg/kg bw/day.
Males and females were exposed separately during a premating period of 7 days and
then continuously for 14 weeks as mating pairs. In the highest dose group the number of
parental females with copulatory plugs was 84% of that in the control group (difference
not statistically significant). At a dose level of 4400 mg/kg bw, female pup weights
(adjusted for litter size) were reduced. DEGEE had no effect on several fertility parame-
ters of the F0 or F1 generation mice (number of pairs with at least one litter, number of
litters per pair, live pups per litter, proportion of pups born alive, or sex males/total of
pups born alive), although a 34% decrease in cauda epidymal sperm motility was
Diethyleneglycol (mono)ethylether (DEGEE)                                                    27
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<pre>   observed in F1 males at 4400 mg/kg bw DEGEE. Further, adult F1 males and females
   showed a statistically significant increase in relative liver weight and slight decrease in
   brain weight at this dose level. Since the effects of DEGEE on the fertility and reproduc-
   tive performance of the F0 mice during Task 2 were minimal, Task 3 was not per-
   formed.
   Developmental toxicity
   In an in vivo mouse screening bioassay for reproductive toxicity, fifty pregnant mice
   (CD-1) were orally administered by gavage doses of 0 and 5500 mg/kg bw/day DEGEE
   during days 6-13 of gestation (vaginal plug = day 0). There were no effects on the num-
   ber of viable litters, live born pups per litter and weight gain, and on the percentage of
   pup survival from days 1 through 3 of age. Pup birth weight was slightly (but signifi-
   cantly) decreased. However, no routine examinations of the pups for malformations or
   skeletal anomalies were performed. Seven of the treated dams died (Sch84).
        In an inhalation study by Nelson et al. (Nel84), Sprague-Dawley rats were exposed
                                                                            3
   during gestation days 7-15 to concentrations of 100 ppm (558 mg/m ) DEGEE for 7 h/
   day. Dams were sacrificed on day 20. Foetuses were individually weighed, and two-
   thirds of them were examined for soft-tissue anomalies; the other one-third were exam-
   ined for skeletal defects. Data were analysed on a litter basis. No embryotoxicity, mater-
   nal toxicity, foetotoxicity or teratogenicity (visceral or skeletal defects) was seen using
   this study protocol.
        Dermal exposure of Sprague-Dawley rats during gestation days 7-16 to 0.35 ml/day
   (2.6 mmol) DEGEE 4 times/day (about 6000 mg/kg bw/day) resulted in some slight
   skeletal effects in the foetuses, such as fused and misshapen vertebrae and centra and
   extra ribs. However, no increase in the total incidence of skeletal malformations was
   observed, nor in the incidence of visceral defects. In maternal animals, treatment weight
   gain and extragestational body weight gain (extragestational body weight minus day 5
   body weight) were less when compared with the water control animals (Har84).
        Morrissey et al. (Mor89) summarized the results of 48 Continuous Breeding Repro-
   duction Studies of the NTP, one concerning DEGEE. These studies were described by
   Chapin et al. (Cha97) in more detail. The general study design and applied methods for
   the Reproductive Assessment by Continuous Breeding (RACB) study consists of four
   “Tasks”. Task 1 is a 14 day dose-finding study, using six exposure groups (8 mice/
   group/sex). The endpoints were clinical signs, mortality, body weight gain, and con-
   sumption of food and water. In the continuous breeding phase (Task2), a control group
   (n=40 animals per sex) and three treatment groups (n=20/sex) were used. Mice were
   exposed to DEGEE for a 7-day premating period, and thereupon randomly grouped as
   mating pairs. Exposure levels were 0.25, 1.25 and 2.50% in feed or water, correspond-
28 Diethyleneglycol (mono)alkylethers
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<pre>    ing to approximately 0.69, 3.24 and 6.20 g/kg bw /day, respectively. During cohabita-
    tion for 98 days, they were treated continuously. For all newborns during this treatment,
    data were collected on body weight, proportion of males, number of litters per pair and
    number of live and dead pups, within a period of 12 hours after birth. After the 98-day
    cohabitation period, the pairs were separated, but the treatment was continued. During
    the next 21 days, any final litters were delivered and kept for at least 21 days (weaning).
    If fertility is impaired in this task, a crossover mating trial of the F0 animals is per-
    formed to determine the affected sex (Task 3). Task 4 assesses the fertility and reproduc-
    tive performance of the F1 generation (offspring from Task 2), which is also
    continuously exposed to the test substance. In Task 2, the mean live pup weight per litter
    was reduced for female pups at the highest dose level and for male pup only at the low-
    est dose (the mean live pup weight per litter was adjusted for the total number of live
    and dead pups per litter by analysis of covariance). In addition, an offspring assessment
    of reproductive function (Task 4) was performed. Therefore, the mothers were dosed
    through weaning and F1 mice were dosed until mated at 74 ± 10 days of age. Male off-
    spring were mated to female offspring from the same treatment group (20/group/sex),
    and the F2 litters were examined for litter size, sex and pup weight. Only the highest
    dose level of 2.5% in feed or water (corresponding to approximately 7.1 g/kg bw/day)
    was tested. In this case, no effects were observed on mean number of live pups and
    mean live pup weight (Mor89, Cha97).
    Lactation
    No publications were available describing studies which allow for the evaluation of the
    effects of DEGEE on lactation.
3.4 Conclusions
    No human data are available concerning the effects of DEGEE on fertility.
         The effect on testes weight observed by Hall et al. (Hal66) in rats after exposure to
    DEGEE is accompanied by other toxic effects. In addition, DEGEE contained ethylene
    glycol as impurity which might have affected the results, since this compound is known
    to be a reproductive toxicant (Hal66). Furthermore, Williams et al. (Wil90) only found a
    decrease (34%) in cauda epidymal sperm motility in mice after an high dose of 4.4 g/kg
    bw at which an increased liverweight was observed as well.
         Based on the results of Williams et al. (Wil90), the committee is of the opinion that
    a lack of appropriate human data preclude the assessment of DEGEE for effects on fer-
    tility and sufficient animal data show that no classification for effects on fertility is indi-
    cated.
    Diethyleneglycol (mono)ethylether (DEGEE)                                                       29
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<pre>   No human data are available concerning the effects of DEGEE on development.
       The results of an oral preliminary in vivo screening bioassay with mice showed a
   slightly (but significantly) decreased foetal body weight after exposure to DEGEE
   (Sch84). However, maternal death was observed as well in 7 of 50 animals. In a dermal
   study with rats, Hardin et al. found slight skeletal effects in the presence of maternal
   toxicity (decreased weight gain) (Har84). In an inhalation study with rats (Nel84), no
   effects were observed on development, however no maternal toxicity was observed as
   well.
       The committee is therefore of the opinion that a lack of appropriate human data pre-
   clude the assessment of DEGEE for effects on development and sufficient animal data
   show that no classification for effects on development is indicated.
   A lack of appropriate data precludes the assessment of DEGEE for labelling for effects
   during lactation.
   Proposed classification for fertility
   A lack of appropriate human data preclude the assessment of DEGEE for fertility and
   sufficient animal data show that no classification on fertility is indicated
   Proposed classification for developmental toxicity
   A lack of appropriate human data preclude the assessment of DEGEE for development
   and sufficient animal data show that no classification on developmental toxicity is indi-
   cated
   Proposed labelling for effects during lactation
   A lack of appropriate data precludes the assessment of DEGEE for labelling for effects
   during lactation
30 Diethyleneglycol (mono)alkylethers
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<pre>Chapter 4
        Diethyleneglycol (mono)n-butylether
        (DEGBE)
4.1     Introduction (HCN96)
        Name               : Diethyleneglycol (mono)n-butylether
        synonyms           : 2-(2-butoxyethoxy)-ethanol, BUCB, butoxy dithylene glycol, butoxydiglycol,
                             Butyl Carbiltol ® Solvent, O-butyl diethylene glycol, butyl dioxitol, diglycol
                             monobutyl ether, Dowanol® DB Glycol Ether, Ektasolve DB, glycol ether
                             DB, Jefferesol DB, poly-solv DB
        CAS-no             : 112-34-5
        EC no              : 203-961-6
        Examples of use    : industrial solvent, chemical and plasticizer intermediate, coalescing agent in
                             plants, diluent for hydraulic brake fluid, solvent in household cleaners
                             (Ema88)
        Mol weight         : 162.23
        Molecular formula  : C H -(O-CH -CH ) -OH
                               6 9         2     2 2
        Chem formula       : CH O
                               8 18 3
        Structural formula :
                                                  3                        o
        Conversion factor  : 1 ppm = 6.75 mg/m at 760 mm Hg and 20 C
                                     3
                             1 mg/m = 0.148 ppm
        Diethyleneglycol (mono)n-butylether (DEGBE)                                                         31
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<pre>4.2 Human studies
    Fertility
    No publications were found concerning the effects on fertility of DEGBE in humans.
    Developmental studies
    No publications were found concerning the effects on development of DEGBE in
    humans.
    Lactation
    No publications were found concerning the effects on lactation of DEGBE.
4.3 Animal studies
    Tables 5, 6 and 7 (Annex D) summarize the fertility and developmental studies and the
    lactation studies with DEGBE in laboratory animals, respectively.
    Fertility
    In an one-generation study with rats (Charles River CD), doses of 0, 250, 500 and 1000
    mg/kg bw/day DEGBE were administered by gavage to males for 60 days prior to mat-
    ing and to females from 14 days before mating until day 13 of gestation, or through
    delivery until weaning (Nol85). Treated males were mated with untreated females and
    vice versa. One-half of each group of females was sacrificed on day 13 of gestation and
    in a uterine examination the numbers of corpora lutea, implantations, resorptions, and
    viable embryos were recorded. The remaining females delivered their young and the off-
    spring were followed to weaning. Fertility of the males and females was not affected by
    the treatment (Nol85).
         Male and female rats (Sprague-Dawley) were dermally exposed under occlusion for
    13 weeks to doses of 0, 200, 600 and 2000 mg/kg bw/day (6h/day, 5 days/week)
    (Aul93). Histopathological examination revealed no changes in the testes, whereas vag-
    inal cytology indicated no adverse effect on oestrus cycling. Fertility parameters, such
    as the male and female mating indices, pregnancy rates, male fertility indices and partu-
    ration data were not adversely affected by treatment with the highest dose (Aul93). No
    effects were also observed on body weight and feed consumption.
32  Diethyleneglycol (mono)alkylethers
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<pre>Developmental toxicity
In an in vivo mouse screening bioassay for developmental toxicity 48 pregnant mice
(CD-1) were orally administered by gavage doses of 0, 500 or 2050 mg/kg bw/day dur-
ing days 6-13 of gestation (vaginal plug = day 0). At both dose levels there were no
effects on the number of viable litters, the number of live-born pups per litter, pup birth
weight and weight gain, and the percentage of pup survival from days 1 to 3 of age.
However, no examinations of the pups for malformations or skeletal anomalies were
performed. At the low dose no maternal death or changes in body weight were observed,
but at the high dose 12 of the 48 dams died (Sch84).
     Pregnant Wistar rats (20/group) received doses of 0, 25, 115 and 633 mg/kg bw/day
DEGBE via the diet during day 0 to 20 of gestation. Groups of 14-15 dams were killed
on day 20 of gestation and the remainder (5-6) was allowed to deliver spontaneously.
Pre- and post-implantation losses, number of corpora lutea, implantations and live foet-
uses per litter, sex ratio of live foetuses, foetal body weights and placental weight were
not affected by the treatment. External, skeletal and internal examinations of the foet-
uses were not revealed. Only in the lowest dose group, the degree of ossification (num-
ber of caudal vertebrae) was significantly lower than in the controls. Survival of
offspring up to 10 weeks of age was very high in all groups and body weight gain simi-
lar to that of the control groups. In the DEGBE-treated groups maternal weight gain dur-
ing pregnancy was significantly reduced, without a decrease in food intake or any
clinical sign of toxicity (Ema88).
     Nolen et al. (Nol85) studied the effects of DEGBE in female rabbits (New Zealand
White) dermally exposed from day 7-18 of gestation. Doses of 0, 100, 300 and 1000 mg/
kg bw/day were applied 4h/day without occlusion. On day 29 of gestation all females
were sacrificed. No significant differences were observed between the controls and the
treated groups in the mean numbers of corpora lutea, implants, resorptions and viable
foetuses and in the mean foetal body weight. Moreover, there were no effects on the
incidence of skeletal anomalies and gross and visceral malformations. Topical applica-
tion resulted in a dose-dependent mild skin irritation, but no other signs of toxicity
(including maternal death) were observed during the treatment.
     An additional one-generation study was performed with rats (Charles River CD) by
Nolen et al. (Nol85). DEGBE was orally intubated at doses of 0, 250, 500, or 1000 mg/
kg bw/day to male rats for 60 days prior mating and to females from 14 days prior to
mating until sacrifice. Untreated males were mated with treated females and vice versa.
One-half of each group of females was sacrificed on GD 13 and the uterine contents
were examined. The remaining females delivered their young which were followed to
weaning. No adverse effects on embryos, fetuses, or neonates were observed, except for
a slight reduction of the mean pup weights during the later stages of lactation among the
Diethyleneglycol (mono)n-butylether (DEGBE)                                                 33
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<pre>    offspring of the females in the highest dose group. The body weights of the females at
    days 1, 13, or 20 of gestation or at the weaning were not significantly different from the
    controls. There were no signs of maternal toxicity.
        Male and female rats (Sprague-Dawley) were dermally exposed under occlusion for
    13 weeks to doses of 200, 600 and 2000 mg/kg bw/day (6h/day, 5 days/week) (Aul93).
    Satellite groups of male and female rats were treated with 2000 mg/kg bw/day for 13
    weeks, subsequently mated within their dose groups, and the females were treated
    through day 20 of gestation and allowed to deliver and nurse their offspring through day
    21 of lactation (weaning). Pup body weights, pup survival and viability were not
    adversely affected by treatment with the highest dose. No effects were observed on
    maternal body weight and feed consumptions (Aul93).
    Lactation
    Male and female rats were exposed dermally under occlusion to undiluted DEGBE dur-
    ing 6 hr/day, 5 days/week for 13 weeks, at a dose of 2000 mg/kg bw/day (Aul93). The
    animals were mated within the dose groups. After mating the females were treated up to
    day 20 of gestation. Following delivery they nursed their offspring through day 21 of
    lactation (weaning). The growth and survival of pups within the treated litters was com-
    parable to the control (Aul93).
        In a one-generation study, male rats (Charles River CD) were orally dosed with 0,
    250, 500, or 1000 mg/kg bw/day for 60 days prior mating and female rats to similar
    doses from 14 days prior to mating until weaning of the offspring (Nol85). Untreated
    males were bred to treated females and vice versa. The females delivered and the off-
    spring was followed to weaning. The pups were weighed individually on days 0, 4, 7, 14
    and 21 of lactation. The mean body weight of the pups from the high dose (1000 mg/kg
    bw) was slightly (but significantly) reduced at day 14 of lactation but not significantly at
    day 21 (Nol85).
4.4 Conclusion
    No human data are available concerning the effects of DEGBE on fertility. No effects
    were observed on fertility in rats after exposure to high concentrations (up to 1000 mg/
    kg bw/day) DEGBE (Nol85). Moreover, Auletta et al. (1993) neither found any effects
    on fertility after dermal exposure to concentration up to 2000 mg/kg/day, nor on general
    body weight and feed consumption.
        Based on the results, the committee is of the opinion that a lack of appropriate
    human data preclude the assessment of DEGBE for effects on fertility and that sufficient
    animal data show that no classification for effects on fertility is indicated.
34  Diethyleneglycol (mono)alkylethers
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<pre>No human data are available concerning the effects of DEGBE on development. Schuler
et al. (Sch84) and Ema et al. (Ema88) did not find dose related effects on development,
but did observe maternal toxicity (maternal death (Sch84) and reduced maternal weight
gain (Ema88)). Nolen et al. (Nol85) studied the effects of DEGBE in rats (oral exposed)
and in rabbits (dermally exposed). No developmental effects were found, however, no
maternal toxicity was observed as well. Therefore, the committee considers the results
of Nolen et al. (Nol85) negative. In conclusion, the committee is of the opinion that a
lack of appropriate human data preclude the assessment of DEGBE for effects on devel-
opment. The studies of Schuler et al. (Sch84) and Ema et al. (Ema88) provide sufficient
animal evidence to conclude that no classification for effects on development is indi-
cated.
In a few studies (Aul93, Nol85) the pups were exposed during lactation. In the study of
Nolen et al. (Nol85), rats had a decrease in pup weight at the highest exposure level
(1000 mg/kg bw, gavage) on day 14 after birth. However, this effect was not (signifi-
cantly) present at day 21. No chemical analysis for the presence of DEGBE or its metab-
olites in animal (or human) milk has been performed. Therefore, the committee
concludes that a lack of appropriate data precludes the assessment of DEGBE for label-
ling for effects during lactation.
Proposed classification for fertility
A lack of appropriate human data preclude the assessment of DEGBE for fertility and
sufficient animal data show that no classification on fertility is indicated
Proposed classification for developmental toxicity
A lack of appropriate human data preclude the assessment of DEGBE for development
and sufficient animal data show that no classification on development is indicated
Proposed labelling for effects during lactation
A lack of appropriate data precludes the assessment of DEGBE for labelling for effects
during lactation
Diethyleneglycol (mono)n-butylether (DEGBE)                                             35
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<pre>      References
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      subchronic/reproduction study in rats. J am Coll Toxicol 1993; 12(2): 161-168.
Ben83 Benedict JH, Granville AN, Briggs DW. A percutaneous teratology study of diethylene monobutyl ether in
      rabbits.Procter and Gamble Report 1983. Cited in ECE85.
Bow95 Bowden HC, Wilby OK, Botham CA, Adam PJ, RossFW. Asssessment of the toxic and potential
      teratogenic effects of four glycol ethers and two derivatives using the hydra regeneration assay and the rat
      whole embryo culture. Toxic in Vitro 1995; 5:773-781.
Cha97 Chapin RC and Sloane RA. Reproductive assessment by continuous breeding: Evolving study dosing and
      summaries of ninety-day studies. Env. Health Persp. 1997; 105 (suppl 1):199-210.
Che80 Chernoff N, Kavlock RJ. A potential in vivo screen for the determination of teratogenic effects in mammals.
      Teratology 1980; 21 (2): 33A.
Che88 Cheever KL, Richards DE, Weigel WW, Lal JB, Dinsmore AM, Daniel FB. Metabolism of bis(2-
      methoxyethyl)ether in the adult male rat: Evaluation of the principal metabolite as a testicular toxicant.
      Toxicol Appl Pharmacol 1988; 94: 150-159.
Doe83 Doe JE, Hart D, Wickramaratne GA. The teratogenic potential of diethylene glycol monomethyl ether
      (DGME) as assayed in the post-natal development test by the subcutaneous route. Toxicologist 1983; 3:70.
Doe84 Doe JE. Further studies on the toxicology of the glycol ethers with emphasis on rapid screening and hazard
      assessment. Environ Health Perspect 1984; 57:199-206
ECE85 ECETOC Technical Report No. 17
ECE94 ECETOC Technical Report No. 64
Ema88 Ema M, Itami T, Kawasaki H. Teratology study of diethylene mono-n-butyl ether in rats. Drug Chem
      Toxicol 1988;11(2):97-111.
      References                                                                                                   37
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<pre>Gau68 Gaunt IF, Colley J, Grasso P, Landsdown ABG, Gangolli SD. Short-term toxicity of diethylene glycol
      monoethyl ether in the rat, mouse and pig. Food Cosmet Toxicol 1968; 6, 689-705.
Hal66 Hall DE, Lee FS, Austin P, Fairweather FA. Short-term feeding study with diethylene glycol monoethyl
      ether in rats. Food Cosmet Toxicol 1966; 4:263-268.
Han47 Hanzlik PJ, Lawrence WS, Fellows JK, Luduena FP, Lacqueur GL. Epidermal application of
      diethyleneglycol monoethyl ether (carbitol) and some other glycols. Absorption, toxicity and viseral
      damage. J Ind Hyg Toxicol 1947; 29, 325-341.
Har84 Hardin BD, Goad PT, Burg JR. Developmental toxicity of four glycol ethers applied cutaneously to rats.
      Environ Health Persp 1984; 57:69-74
Har85 Hardin BD, Goad PT, Burg JR. Teratogenicity of diethylene glycol monomethyl ether in the rat. Teratology
      1985;31(3) Abstract P46, 54A.
Har86 Hardin BD, Goad PT, Burg JR. Developmental toxicity of diethylene glycol monomethyl ether (diEGME).
      Fund Appl Toxicol 1986; 6:430-439.
Har87 Hardin BD, Schuler RL, Burg JR, Booth GM, Hazelden KP, MacKenzie KM, Piccirillo VJ, Smith KN.
      Evaluation of 60 chemicals in a preliminary development toxicity Test. Teratogenesis, Carcinogenesis, and
      Mutagenesis 1987; 7:29-48.
Har97 Hardy CJ, Coombs DW, Lewis DJ, Klimish HJ. Twenty-eight-day repeated-dose inhalation exposure of rats
      to diethylene glycol monoethyl ether. Fund Appl Toxicol 1997; 38:143-147.
HCN96 Health Council of the Netherlands: Dutch Expert Committee on Occupational Standards (DECOS):
      Ethyleneglycol ethers; Ethyleneglycol monomethyl ether, Ethyleneglycol monomethyl ether acetate,
      diethyleneglycol monomethyl ether, diethyleneglycol monoethyl ether, diethyleneglycol monobuthyl ether.
      The Hague: Health Council of the Netherlands, 1996; publication no. 1996/01 WGD.
Hob86 Hobson DW, D'Addario AP, Bruner RH, Uddin DE. A subchronic dermal exposure study of diethylene
      glycol monomethyl ether and ethylene glycol monomethyl ether in the male guinea pig. Fund Appl Toxicol
      1986; 6:339-348.
Joh88 Johnson EM, Newman CH, Gabel BE, Boerner TF, Dausky LA. An analysis of the hydra assays
      applicability and reliability as developmental toxicity prescreen. J Am Coll Toxicol 1988; 7(2):111-126.
Kaw90 Kawamoto T, Matsuno K, Kayama F, Hirai M, Arashidani K, Yoshikawa M, Kodama Y. Acute oral toxicity
      of ethylene glycol monomethyl ether and diethylene glycol monomethyl ether. Bull Environ Contam
      Toxicol 1990; 44:602-608.
Lam85 Lamb JC, IV. Reproductive toxicity testing: Evaluating and developing new testing systems. J Am Coll
      Toxicol 1985; 4:163-171.
Mil85 Miller RR, Eisenbrandt DL, Gushow TS, Weiss SK. Diethylene glycol monomethyl ether 13-week vapor
      inhalation toxicity study in rats. Fundam Appl Toxicol 1985; 5(6): 1174-1179.
Mor89 Morrissey RE, Lamb JC, Morris RW, Chapin RE, Gulati DK, Heindel JJ. Results and evaluations of 48
      continuous breeding reproduction studies conducted in mice. Fund Appl Toxicol 1989; 13: 747-777.
Nag84 Nagano K, Nakayama E, Oobayashi H, Nishizawa T, Okuda H, Yamazaki K. Experimental studies on
      toxicity of ethylene glycol alkyl ethers in Japan. Environ Health Perspect 1984; 57:75-84.
38    Diethyleneglycol (mono)alkylethers
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<pre>Nel82  Nelson BK, Setzer JV, Brightwell WS, Mathinos PR, Kuczuk MH, Weaver TE. Comparative inhalation
       teratogenicity of four glycol ether solvents in rats. Teratology 1982; 25:64A.
Nel84  Nelson BK, Setzer JV, Brightwell WS, Mathinos PR, Kuczuk MH, Weaver TE, Goad PT. Comparative
       inhalation teratogenicity of four glycol ether solvents and an amino acid derivative in rats. Environ Health
       Persp 1984; 57: 261-271.
Nol85  Nolen GA, Gibson WB, Benedict JH, Briggs DW, Schardein JL. Fertility and teratogenic studies of
       diethylene glycol monobutyl ether in rats and rabbits. Fund Appl Toxicol 1985; 5:1137-1143.
Proc84 Procter and Gamble. Study of fertility and genral reproductive performance in rats. Int Research Dev Corp
       Report BSBTS-796S2 , 1984. Cited in ECE85.
Ree85  Reel JR, Lawton AD, Wolkowski-Tyl R, Davis GW, Lamb JC, IV. Evaluation of a new reproductive
       toxicology protocol using diethylstilbestrol (DES) as a positive control compound. J Amer Coll Toxicol
       1985; 4:147-162.
Sch84  Schuler RL, Hardin BD, Niemeier RW, Booth G, Hazelden K, Piccirillo V, Smith K. Results of testing
       fifteen glycol ethers in a short-term in vivo reproductive toxicity assay. Environ Health Perspect 1984;
       57:141-146.
Sco86  Scortichini BH, John-Greene JA, Quast JF, Rao KS. Teratologic evaluation of dermally applied diethylene
       glycol monomethyl ether in rabbits. Fund Appl Toxicol 1986; 7:68-75.
Smy64  Smyth HF, Carpenter CP, Boyd SC. Summary of toxicological data - A 2 year study of diethylene glycol
       monoethyl ether in rats. Food Cosmet Toxicol 1964; 2: 641-642.
Ste71  Stenger EG, Aeppli, Lislott, Muller D, Peheim Eu, Thomann P. Zur Toxicologie des Athylenglykol-
       Monoathylathers. Arzneimittel Forsch 1971; 21:880. cited in Opdyke DLJ. Monographs on fragrance raw
       materials: diethylene glycol monoethyl ether. Food Chem Toxicol 1974; 12:517-518.
Tox95  Niesink RJM, de Vries J, Hollinger MA, eds. Toxicology, Principles and Applications, Boca Raton: CRC
       Press, 1995:385
Tyl84  Tyler T. Environ Health Persp 1984; 57: 185.
Uni87  Unilever research. The effect of subcutaneously administered carbitol and butyl carbitol on the pregnancy
       and offspring of the Colworth Wistar rat. Research report PES 87 1031. Unilever Research, UK 1987.
Wic87  Wickramaratne GA de S. The Chernoff-Kavloch assay: Its validation and application in rats. Teratogenesis,
       Carcinogenesis, and Mutagenesis 1987; 7:73-83.
Wil90  Williams J, Reel JR, George JD, Lamb JC. Reproductive effects of diethylene glycol monoethyl ether in
       swiss CD-1 mice assessed by a continous breeding protocol. Fund Appl Toxicol 1990; 14:622-635.
Yam93  Yamano T, Noda T, Shimizu M, Moriata S, and Nagahama M. Effects of diethyleneglycol monomethyl
       ether on the pregnancy and postnatal developments in rats. Arch Environ Contam Toxicol 1993; 24(2): 228-
       235
       Literature consulted but not referred to in the text of the report
But76  Butterworth KR, Gaunt IF, Grasso P. A 9-month toxicity study of diethyleneglycol monoethyl ether in the
       ferret. BIBRA Research Report no. 15/1975. Cited in BIBRA Bulletin 1976;15: 112. Cited in ECE85.
       References                                                                                                   39
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<pre>Cha97a Chapin RE, Sloane RA, Haseman JK. The relationship among reproductive endpoints in Swiss Mice, using
       the reproductive assessment by continuous breeding database. Fund Appl Pharmacol 1997;38:129-142.
Cha97b Chapin RE, Sloane RA. Reproductive assessment by continuous breeding: Evolving study design and
       summaries of ninety studies. Environ Health Perspect 1997; 105 Suppl 1: 199-205.
Jan96  Jankovic J, Drake F. A screening method for occupational reproductive health risk. Am Ind Hyg Ass J 1996;
       57:641-649.
Kim96  Kimmel CA. Reproductive and developmental effects of diethylene and triethylene glycol (methyl-, ethyl-)
       ethers. Occup Hyg 1996; 2:131-151.
Kod82  Kodak data summary 1982. Cited in IUCLID data set
Lam97  Lamb JC, Reel JR, Lawton AD. Diethylene glycol monoethyl ether. Environ Health Perspect 1997; 105
       Suppl 1: 209.
Mer96  The Merck Index, 12TH editition
Ree90  Rees DC, Francis EZ, Kimmel CA. Scientific and regulatory issues relevant to assessing risk for
       developmental neurotoxicity: an overview. Neurotoxicol Teratol 1990; 12: 175-181.
Smy48  Smyth HF, Carpenter CP. Further experience with the range-finding test in the industrial toxicology
       laboratory. J Ind Hyg Toxicol 1948; 30: 63-68.
40     Diethyleneglycol (mono)alkylethers
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<pre>A The Committee
B Comments on the public draft
C Directive (93/21/EEC) of the European Community
D Fertility and developmental toxicity studies
E Abbreviations
  Annexes
                                                  41
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<pre>Annex A
      The committee
      •  BJ Blaauboer, chairman
         Toxicologist, Institute of Risk Assessment Sciences, Utrecht University
      •  AM Bongers, advisor
         Ministry of Social Affairs and Employment, The Hague
      •  JHJ Copius Peereboom-Stegeman
         Toxicologist, University Medical Centre St Radboud, Nijmegen
      •  HFP Joosten
         Toxicologist, NV Organon, Department of Toxicology and Drug Disposition,
         Oss
      •  D Lindhout
         professor of Medical Genetics, paediatrician; UMC, Utrecht
      •  AH Piersma
         Reproductive toxicologist, National Institute of Public Health and the
         Environment, Bilthoven
      •  N Roeleveld
         Epidemiologist; University Medical Centre St Radboud, 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
      The committee                                                               43
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<pre>   The first draft of the present document was prepared by J Kruse and JAGM van Raaij of
   the Opdenkamp Registration and Notification, by contract with the Ministry of Social
   Affairs and Employment.
   Secretarial assistance: A Aksel and F Smith.
   Lay-out: J van Kan.
44 Diethyleneglycol (mono)alkylethers
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<pre>Annex B
      Comments on the public draft
      A draft of the present report was released in 2003 for public review. The following per-
      sons and organisations have commented on the draft review:
      • RD Zumwalde, National Institute of Occupational Safety and Health (NIOSH),
          USA.
      • E González-Fernández, Ministerio de Trabajo y Asuntos Sociales, Spain.
      • P de Kettenis, Oxygenated Solvent Producers Association (OSPA), CEFIC Sector
          Group, Belgium.
      • E Gavini, University of Milan, Italy.
      • V Foa, Department of Occupational and Environmental Health, University of Milan,
          Italy.
      Comments on the public draft                                                             45
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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                                                             47
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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 sec-
        ondary non-specific consequence of the other toxic effects.
   •    Other relevant information.
   Substances which should be regarded as if they cause developmental toxicity to humans:
   There is sufficient evidence to provide a strong presumption that human exposure to the substance may
   result in developmental toxicity, generally on the basis of:
   •    Clear results in appropriate animal studies where effects have been observed in the absence of signs of
        marked maternal toxicity, or at around the same dose levels as other toxic effects but which are not a
        secondary non-specific consequence of the other toxic effects.
   •    Other relevant information.
   Category 3:
   Substances which cause concern for human fertility:
   Generally on the basis of:
   •    Results in appropriate animal studies which provide sufficient evidence to cause a strong suspicion of
        impaired fertility in the absence of toxic effects, or evidence of impaired fertility occurring at around
        the same dose levels as other toxic effects, but which is not a secondary non-specific consequence of
        the other toxic effects, but where the evidence is insufficient to place the substance in Category 2.
   •    Other relevant information.
   Substances which cause concern for humans owing to possible developmental toxic effects:
   Generally on the basis of:
   •    Results in appropriate animal studies which provide sufficient evidence to cause a strong suspicion of
        developmental toxicity in the absence of signs of marked maternal toxicity, or at around the same dose
        levels as other toxic effects but which are not a secondary non-specific consequence of the other toxic
        effects, but where the evidence is insufficient to place the substance in Category 2.
   •    Other relevant information.
48 Diethyleneglycol (mono)alkylethers
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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                                                               49
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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
          development, both before and after birth. It includes effects induced or manifested prenatally as well as
          those manifested postnatally. This includes embrytoxic/fetotoxic effects such as reduced body weight,
          growth and developmental retardation, organ toxicity, death, abortion, structural defects (teratogenic
          effects), functional defects, peri/postnatal defects, and impaired postnatal, mental 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
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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                                                                 51
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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 indicate 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.
52 Diethyleneglycol (mono)alkylethers
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<pre>Annex         D
              Fertility and developmental toxicity
              studies
Tabel 1 Fertility studies with diethyleneglycol (mono)methylether in animals.
Authors      Species         Experimental       Dose and routeGeneral toxicity                          Effects on reproduction
                             period/design
Nag84        Mice (ICL/      25 days (daily)    2.0%            No effect on white blood cell count     No effect on testicular weight and
             ICR)                               (oral, drinking                                         combined weight of seminal vesi-
             5/group                            water)                                                  cles and coagulating gland
Hob86        Guinea pigs 13 weeks, 5 days/ 0, 40, 200,          At 200 and 1000 mg/kg a decrease of No significant effects on weights
             (Hartley)       week, 6 hr/day 1000 mg/kg          splenic weight                          of testes, seminal vesicles and
             6 males/                           bw/day          At 1000 mg/kg increase in serum         prostate.
             group (control                     (dermal under   LDH                                     No testicular lesions.
             7)                                 occlusion)      A mild fatty change in the liver in all
                                                                test treatment groups.
Che88        Rats            Up to 20 days      5.1 mmol/kg No early deaths,                            No gross or histopathological tes-
             (Sprague-       (daily); Gross and bw/day (=613 no overt signs of toxicity                 ticular changes.
             Dawley)         histopathological mg/kg bw/day)
             5 males, no     examination at 2 (oral)
             control group   day intervals from
                             days 3-21
Kaw90        Rats (Wistar) Dose-response        500, 1000,      At 2000 mg/kg : decrease in weight At 2000 mg/kg:
             4-8 males/      study              2000 mg/kg      gain.                                   decrease in relative weight of testis
             group           20 days (daily)    bw/day          At 1000 and 2000 mg/kg:                 (only the weight of the testes and
                                                (oral)          decrease in relative weight of thymus the thymus were reported)
              Fertility and developmental toxicity studies                                                                               53
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<pre>Kaw90      Rats (Wistar) Time-course          2000 mg/kg    After one day decrease in relative      after 5 and 20 days decrease in rel-
           4-8 males/     study               bw/day        weight of thymus                        ative weight of testis
           group          1,2,5 or 20 days (oral)           After 2 days increase in relative
                                                            weight of kidney
                                                            After 5 days decrease in relative
                                                            weight of liver, spleen and thymus
                                                            After 20 days decrease in relative
                                                            weight of liver and thymus
Mil85      Rats (Fischer 13 weeks, 5 days/ 0, 150, 500,     No effects on body weights, organ       No effects observed on testis, epid-
           344)           week, 6 hr/day 1080 mg/m3         weights, haemotological analyses,       idymus, seminal vescicle, pros-
           10/sex/                            (inhalation)  clinical chemistry analyses, urinaly-   tate, coagulating gland, ovary,
           group                                            ses, and gross and histopathological    oviduct, uterus, cervix and vagina
                                                            examinations                            after gross pathologic and histo-
                                                                                                    pathologic examination.
Tabel 2 Developmental toxicity studies with diethyleneglycol (mono)methylether in animals.
Authors    Species        Experimental       Dose and route General toxicity             Effects on reproduction
                          period/design
Yam93      Rats (Wistar) GD 7-17             0, 200, 600,    At 1800 mg/kg decrease of At 1800 mg/kg: Visceral malformations of
           14 females/ Sacrifice on GD 1800 mg/kg            maternal body weight gain, the cardiovascular system in 28% of the foe-
           group          20.                bw/day          food consumption, and thy- tuses.
                                             (gavage) from   mus weight                  External malformations (mostly anasarca
                                             day 7-17                                    and anury) in 14.1 % and
           8 females/                                        At 200 and 600 mg/kg no dilated renal pelvis in 52.8% of the foetuses.
           group                                             effects on dams             No significant skeletal malformations.
                          GD 7-17                                                        Gestation period prolonged by 2 days.
                          Sacrifice 21 days
                          PP                                                             At 600 mg/kg: decrease in foetal body
                                                                                         weight and adverse effects on thymus and
                                                                                         ossification.
                                                                                         At 200 mg/kg: no effects on foetuses or neo-
                                                                                         nates
Sch84,     Mice           GD 6-13            0, 4000 mg/kg 5 dams (10%) died             Significant reduction in number of viable lit-
Har87       (CD-1)        (vaginal plug =    bw/day          Maternal weight change      ters (5/32), number of live pups, per litter,
           50 females/    day 0)             (gavage)        affected                    pup weight gain and pup survival over days
           group                                                                         1-3 PP.
Har86      Rats (Sprague- GD 7-16 ,          0,1000, 1495,   At 5175 mg/kg maternal      Dose related increase in visceral and skeletal
           Dawley)        sacrifice on day   2235, 3345,     mortality (2/9) and reduc-  malformations.
           9 females/     21                 5175 mg/kg      tion of extra gestational   At 3345 and 5175 mg/kg respectively 5/5
           group          (dose finding      bw/day          body weight gain.           and 6/9 litters totally resorbed.
                          study);            (oral)                                      At 2235 and 3345 mg/kg decreased foetal
                          Chernoff – Kav-                                                weight.
                          lock assay                                                     No routine examinations of the pups for
                                                                                         malformations or skeletal anomalies were
                                                                                         performed.
54          Diethyleneglycol (mono)alkylethers
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<pre>Har86        Rats (Sprague- GD 7-16 ,           0,720, 2165      No maternal toxicity.        At 2165 mg/kg decreased foetal weight and
             Dawley)         sacrifice on day mg/kg bw/day At 2165 mg/kg decreased            litter size and increased incidence of rib and
             12-13 females/ 21                  (oral)           maternal weight,             cardiovascular malformations.
             group           Teratology study                                                 At 720 mg/kg increased incidence of rib
                                                                                              malformations
Sco86        Rabbits (New    GD 6-18            0, 50, 250, 750  No treatment related clini- At 750 mg/kg:
             Zealand         Sacrifice on GD mg/kg bw/day        cal signs of maternal toxic- slight embryotoxicity, slight increase in
             White)          29 (caesarian sec- (dermal)         ity at 50 and 250 mg/kg. embryonic resorptions
             25 females/     tion)                               At 750 mg/kg decreased In foetuses: mild forelimb flexure, slight-to-
             group                                               weight gain, concurrent      moderate dilation of the renal pelvis, retro-
                                                                 physiologic decrease in red caval ureter,cervical spurs and delayed ossi-
                                                                 blood cells and packed cell fication of the skull and sternebral bones
                                                                 volume valus
                                                                                              At 250 mg/kg: slight foetotoxicity (delayed
                                                                                              ossification of the skull and cervical spurs)
                                                                                              At 50 mg/kg: no embryonic and foetal
                                                                                              effects
Tabel 3 Fertility studies with diethyleneglycol (mono)ethylether in animals.
Authors      Species          Experimental period/designDose and route           General toxicity          Effects on reproduction
Hal66        Rats (Wistar) 90 days                        0.25, 1 , 5 %          At 5%:                    At 5%:
             12/sex/group                                 (oral feed);           Reduced growth rate, Increase in relative testes weight,
                                                                                 reduced appetite,         testicular oedema
                                                          test compound con- hydropic degeneration
                                                          taminated with 0.4% of kidney, fatty
                                                          ethylene glycol        changes in the liver.
Mor89        Mice             Exposure of breeding pairs In task 2:                                        In task 2 (continuous breeding
             (CD-1)           during 14 weeks (pre-       0, 690, 3240, 6200                               phase):
             20/sex/          ceeded by exposure during mg/kg bw /day                                      At 6200 mg/kg reduction in the
             group            a premating period of 7     (feed or water)                                  mean live pup weight per litter
             controls 40/sex days)                                                                         for female pups.
                              Reproductive Assessment                                                      Only at 690 mg/kg reduction in
                              by Continuous Breeding In task 4 only 7080                                   the mean live pup weight per lit-
                              (RACB) protocol.            mg/kg bw /day (feed                              ter for male pups.
                                                          or water)                                        In task 4 (offspring assessment of
                                                                                                           reproductive function):
                                                                                                           No effects.
Wil90        Mice             Exposure of breeding pairs 0, 440, 2200, 4400                                No effects on the reproduction in
             (CD-1)           during 14 weeks (pre-       mg/kg bw/day                                     the F0 and F1 generations.
             20/sex/          ceeded by exposure during (drinking water)                                   At 4400 mg/kg:
             group            a premating period of 7                                                      Decrease in sperm motility.
             controls 40/sex days)                                                                         In F1 males and females increase
                              Reproductive Assessment                                                      of liver weight and decrease of
                              by Continuous Breeding                                                       brain weight.
                              (RACB) protocol.
              Fertility and developmental toxicity studies                                                                                55
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<pre>Tabel 4 Developmental toxicity studies with diethyleneglycol (mono)ethylether in animals.
Authors       Species                Experimental period/design Dose and route           General toxicity     effects on reproduction
Sch84, Har87 Mice (CD-1) 50          GD 6-13                       55000 mg/kg bw / body weight gain No effect on viable litters, pup
              females/group                                        day (gavage)          reduced;             survival, body weight, body
                                                                                         maternal death 14% weight gain
                                                                                         (7/50)
                                                                                                              No routine examinations for
                                                                                                              malformations or skeletal
                                                                                                              anomalies
Har84         Rats                   GD 7-16                       0, 0.35 ml, 4 times/ Treatment weight      No increase in visceral
              (Sprague_Dawley) Necropsy on day 21                  day, corresponding gain and extrages-      defects.
              13 females                                           to approximately tational body             Slight skeletal effects in the
              17 controls                                          6000 mg/kg bw/ weight gain s               foetuses: Fused and misshapen
                                                                   day                   reduced.             vertebrae and centra and extra
                                                                   (dermal)                                   ribs. However, no increase in
                                                                                                              total incidence of skeletal mal-
                                                                                                              formations. No embryo- or
                                                                                                              foetotoxicity or teratogenicity.
Nel84         Rats                   GD 7-15                       0, 100 ppm (highest No maternal toxic- No embryotoxicity, foetotoxi-
              (Sprague_Dawley)       7 hours/day                   level that could be ity                    cty or teratogenicity (visceral
              15 females/            Sacrifice of dams on GD 20. generated)                                   or skeletal defects)
              group                  Foetuses individually
                                     weighed, fixed and examined (inhalation)
                                     for soft-tissue anomalies and
                                     skeletal defects.
Tabel 5 Fertility studies with diethyleneglycol (mono)buthylether in animals.
Authors       Species               Experimental period/     Dose and route       General toxicity            Effects on reproduction
                                    design
Aul93         Rats (CD)             6h/day, 5 days/week 13 200, 600, 2000 mg/ Dermal irritation; inci- No adverse effects on repro-
              25 /sex/group         weeks prior to mating kg bw/day               dence, severity and, time ductive performance or fertil-
                                    and to GD 20 in          (dermal)             of onset dose dependent, ity in any group.
                                    females;                                      more severe in females; No histopathological changes
                                                                                  no systemic toxicity at the in the testes observed.
                                    Method used:                                  highest dose (2000 mg/kg Vaginal cytology indicated no
                                    OECD Guide line 415                           bw)                         adverse effect on oestrous
                                                                                                              cycling
Nol85         Rats (Charles River males: 60 days prior to 250, 500, 1000 mg/ No effect on body                No effects on fertility
              CD)                   mating                   kg bw/day (gavage)weights of the females at
              25males/sex/ group females: 14 days prior                           days 1, 13, or 20 of gesta-
                                    to mating untill GD13                         tion or weaning
56            Diethyleneglycol (mono)alkylethers
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<pre>Tabel 6 Developmental toxicity studies with diethyleneglycol (mono)buthylether in animals.
Authors        Species              Experimental period/   Dose and route     General toxicity          Effects on reproduction
                                    design
Sch84, Har87 Mice (CD-1) 50         GD 6-13                500, 2050 mg/kg    At 500 mg/kg no mor- No effect on viable litters, pup
               females/group                               bw/day (gavage)    tality, no effect on body survival, body weight, body
                                                                              weight.                   weight gain.
                                                                              At 2050 mg/kg mater- No routine examinations for
                                                                              nal death 25% (12/48). malformations or skeletal
                                                                                                        anomalies
Nol85          Rabbits (New         GD 7-18 (sacrifice on 100, 300, 1000 mg/ Mild skin irritation at    No effects
               Zealand White)       day 29)                kg bw/day          300 and 1000 mg/kg,
               20 females/ group                           (dermal)           no mortality
Nol85          Rats (CD)            14 days to GD 13, 14   250, 500, 1000 mg/ No effects                No foetal effects; decrease in
               22-24 females /      days to 21 days PP     kg bw.day                                    pup weight on day 14 PP at
               group                (killed day 21)        (oral)                                       1000 mg/kg bw
Tabel 7 Lactation studies with diethyleneglycol (mono)buthylether in animals.
Authors        Species              Experimental period/   Dose and route     General toxicity          Effects on reproduction
                                    design
Nol85          Rats (CD)            14 days to GD 13, 14   250, 500, 1000 mg/ No effects                Decrease in pup weight on day
               22-24 females /      days to 21 days PP     kg bw/day                                    14 PP at 1000 mg/kg bw
               group                (killed day 21)
Aul93          Rats (CD)            6h/day, 5 days/week 13 2000 mg/kg bw/     Dermal irritation; inci- Growth and survival of pups
               25 /sex/group        weeks prior to mating day                 dence, severity and,      within the treated litters com-
                                    and to GD 20 in        (dermal)           time of onset dose        parable to control
                                    females                                   dependent, more severe
                                                                              in females.
                                                                              No systemic toxicity at
                                                                              2000 mg/kg bw
Ema88          Rats (Wistar)        GD 0-20 (killed day 20)25, 115, 633 mg/kg reduced weight gain at No effects of lactation on sur-
               5-6 females / group Weaning on day 21       bw/day             all doses                 vival rate and growth of the
                                    after birth.           (oral)                                       offspring
             Fertility and developmental toxicity studies                                                                            57
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<pre>58 Diethyleneglycol (mono)alkylethers</pre>

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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                                                          59
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<pre>60 Diethyleneglycol (mono)alkylethers</pre>

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<br><br>