<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>Advisory Reports Areas of activity The Health Council’s task is to advise ministers and parliament on issues in the field of public health. Most of the advisory opinions that the Council produces every year are prepared at the request of one of the ministers. In addition, the Health Council issues unsolicited advice that has an ‘alerting’ function. In some cases, such an alerting report leads to a minister requesting further advice on the subject. Health Council of the Netherlands www.healthcouncil.nl Optimum healthcare What is the optimum result of cure and care in view of the risks and opportunities? Environmental health Which environmental influences could have a positive or negative effect on health? Prevention Which forms of prevention can help realise significant health benefits? Healthy working conditions How can employees be protected against working conditions that could harm their health? Healthy nutrition Which foods promote good health and which carry certain health risks? Innovation and the knowledge infrastructure Before we can harvest knowledge in the field of healthcare, we first need to ensure that the right seeds are sown. Health Council of the Netherlands Bisphenol A diglycidyl ether Evaluation of the carcinogenicity and genotoxicity 2013/25 2013/25 Evaluation of the carcinogenicity and genotoxicity 620167_V23_GR-Paars_Om_EN.indd Alle pagina's 30-09-13 10:31</pre>

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<pre>Bisphenol A diglycidyl ether
    Evaluation of the carcinogenicity and genotoxicity
</pre>

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<pre></pre>

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<pre>Aan de minister van Sociale Zaken en Werkgelegenheid
Onderwerp              : aanbieding advies Bisphenol A diglycidyl ether
Uw kenmerk             : DGV/BMO-U-932542
Ons kenmerk            : U-7910/BV/fs/246-Y18
Bijlagen               :1
Datum                  : 18 oktober 2013
Geachte minister,
Graag bied ik u hierbij het advies aan over de gevolgen van beroepsmatige blootstelling aan
bisfenol A diglycidylether.
Dit advies maakt deel uit van een uitgebreide reeks waarin kankerverwekkende stoffen wor-
den geclassificeerd volgens richtlijnen van de Europese Unie. Het gaat om stoffen waaraan
mensen tijdens de beroepsmatige uitoefening kunnen worden blootgesteld.
      Dit advies is opgesteld door een vaste subcommissie van de Commissie Gezondheid en
beroepsmatige blootstelling aan stoffen (GBBS), de Subcommissie Classificatie van carci-
nogene stoffen. Het advies is getoetst door de Beraadsgroep Gezondheid en omgeving van
de Gezondheidsraad.
Ik heb dit advies vandaag ter kennisname toegezonden aan de staatssecretaris van Infra-
structuur en Milieu en aan de minister van Volksgezondheid, Welzijn en Sport.
Met vriendelijke groet,
prof. dr. W.A. van Gool,
voorzitter
Bezoekadres                                                             Postadres
Rijnstraat 50                                                           Postbus 16052
2515 XP Den               Haag                                          2500 BB Den     Haag
E - m a i l : b . v. d . v o e t @ g r. n l                             w w w. g r. n l
Te l e f o o n ( 0 7 0 ) 3 4 0 7 4 4 7
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<pre></pre>

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<pre>Bisphenol A diglycidyl ether
Evaluation of the carcinogenicity and genotoxicity
to:
the Minister of Social Affairs and Employment
No. 2013/25, The Hague, October 18, 2013
</pre>

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<pre>The Health Council of the Netherlands, established in 1902, is an independent
scientific advisory body. Its remit is “to advise the government and Parliament on
the current level of knowledge with respect to public health issues and health
(services) research...” (Section 22, Health Act).
     The Health Council receives most requests for advice from the Ministers of
Health, Welfare & Sport, Infrastructure & the Environment, Social Affairs &
Employment, Economic Affairs, and Education, Culture & Science. The Council
can publish advisory reports on its own initiative. It usually does this in order to
ask attention for developments or trends that are thought to be relevant to
government policy.
     Most Health Council reports are prepared by multidisciplinary committees of
Dutch or, sometimes, foreign experts, appointed in a personal capacity. The
reports are available to the public.
                 The Health Council of the Netherlands is a member of the European
                 Science Advisory Network for Health (EuSANH), a network of science
                 advisory bodies in Europe.
                 The Health Council of the Netherlands is a member of the International Network
                 of Agencies for Health Technology Assessment (INAHTA), an international
                 collaboration of organisations engaged with health technology assessment.
 I NA HTA
This report can be downloaded from www.healthcouncil.nl.
Preferred citation:
Health Council of the Netherlands. Bisfenol A diglycidyl ether - Evaluation of
the carcinogenicity and genotoxicity. The Hague: Health Council of the
Netherlands, 2013; publication no. 2013/25.
all rights reserved
ISBN: 978-90-5549-971-7
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<pre>   Contents
   Samenvatting 9
   Executive summary 11
   Scope 13
.1 Background 13
.2 Committee and procedures 13
.3 Data 14
   General information 15
.1 Identity and physico-chemical properties 15
.2 IARC classification 16
   Carcinogenicity studies 17
.1 Observations in humans 17
.2 Carcinogenicity studies in animals 17
.3 Summary of the carcinogenicity studies 27
   Genotoxicity 29
.1 Gene mutation assays 29
.2 Cytogenetic assays 30
   Contents                                    7
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<pre> .3 Miscellaneous 33
 .4 Summary of the genotoxicity studies 34
    Classification 35
 .1 Evaluation of data on carcinogenicity and genotoxicity 35
 .2 Recommendation for classification 36
    References 37
    Annexes 41
A   Request for advice 43
B   The Committee 45
C   The submission letter 47
D   Comments on the public review draft 49
E   IARC Monograph 51
F   Carcinogenicity studies in animals 59
G   Carcinogenic classification of substances by the Committee 61
    Bisphenol A diglycidyl ether
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<pre>Samenvatting
Op verzoek van de minister van Sociale Zaken en Werkgelegenheid evalueert en
beoordeelt de Gezondheidsraad de kankerverwekkende eigenschappen van stof-
fen waaraan mensen tijdens het uitoefenen van hun beroep kunnen worden bloot-
gesteld. De evaluatie en beoordeling worden verricht door de Subcommissie
Classificatie van carcinogene stoffen van de Commissie Gezondheid en beroeps-
matige blootstelling aan stoffen van de raad, hierna kortweg aangeduid als de
commissie. In het voorliggende advies neemt de commissie bisfenol A diglyci-
dylether onder de loep.
Bisfenol A diglycidylether en zijn oligomeren zijn de hoofdbestanddelen van
epoxyharsen. De epoxyharsen op basis van bisfenol A diglycidylether worden
wijd gebruikt als beschermingslagen, met inbegrip van verven, in versterkt plas-
tic laminaat en mengsels, in het bewerken, gieten en vormen van harsen, in kleef-
stoffen, en in bevloering.
     Op basis van de beschikbare gegevens is de commissie van mening dat de
gegevens over bisfenol A diglycidylether als zuivere stof niet voldoende zijn om
de kankerverwekkende eigenschappen te evalueren (categorie 3).* Overigens
maakt de commissie zich zorgen over de mogelijke carcinogeniteit van niet vol-
ledig gezuiverd (technische kwaliteit) bisfenol A diglycidylether.
Volgens het classificatiesysteem van de Gezondheidsraad (zie bijlage G).
Samenvatting                                                                      9
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<pre>0 Bisphenol A diglycidyl ether</pre>

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<pre>Executive summary
At request of the Minister of Social Affairs and Employment, the Health Council
of the Netherlands evaluates and judges the carcinogenic properties of
substances to which workers are occupationally exposed. The evaluation is
performed by the Subcommittee on the Classification Carcinogenic Substances
of the Dutch Expert Committee on Occupational Safety of the Health Council,
hereafter called the Committee. In this report, the Committee evaluated
bisphenol A diglycidyl ether.
Bisphenol A diglycidyl ether and its oligomers are major components of epoxy
resins. Epoxy resins based on bisphenol A diglycidyl ether are widely used in
protective coatings, including paints, in reinforced plastic laminates and
composites, in tooling, casting and moulding resins, in bonding materials and
adhesives, and in flooring and aggregates.
    The Committee is of the opinion that the available data on pure bisphenol A
diglycidyl ether are insufficient to evaluate the carcinogenic properties
(Category 3).* In addition the Committee is of the opinion that exposure to
technical grades of bisphenol A diglycidyl ether may pose concern for potential
carcinogenic effects.
According to the classification system of the Health Council (see Annex G).
Executive summary                                                               11
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<pre>2 Bisphenol A diglycidyl ether</pre>

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<pre> hapter 1
        Scope
1.1     Background
        In the Netherlands a special policy is in force with respect to occupational use
        and exposure to carcinogenic substances. Regarding this policy, the Minister of
        Social Affairs and Employment has asked the Health Council of the Netherlands
        to evaluate the carcinogenic properties of substances, and to propose a
        classification (see Annex A). In addition to classifying substances, the Health
        Council also assesses the genotoxic properties of the substance in question. The
        assessment and the proposal for a classification are expressed in the form of
        standard sentences (see Annex G).
        This report contains the evaluation of the carcinogenicity of bisphenol A
        diglycidyl ether.
1.2     Committee and procedures
        The evaluation is performed by the Subcommittee on Classification of
        Carcinogenic Substances of the Dutch Expert Committee on Occupational Safety
        of the Health Council, hereafter called the Committee. The members of the
        Committee are listed in Annex B. The submission letter (in English) to the
        Minister can be found in Annex C.
        Scope                                                                            13
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<pre>        In May 2013 the President of the Health Council released a draft of the report
    for public review. The individuals and organisations that commented on the draft
    are listed in Annex D. The Committee has taken these comments into account in
    deciding on the final version of the report.
1.3 Data
    The evaluation and recommendation of the Committee is based on scientific
    data, which are publicly available. The starting points of the Committees’ reports
    are, if possible, the monographs of the International Agency for Research on
    Cancer (IARC). This means that the original sources of the studies, which are
    mentioned in the IARC-monograph, are reviewed only by the Committee when
    these are considered most relevant in assessing the carcinogenicity and
    genotoxicity of the substance in question. In the case of bisphenol A diglycidyl
    ether, such an IARC-monograph is available of which the summary and
    conclusion is inserted in Annex E.
        A search was performed for more recently published data from the online
    databases Medline, Toxline, Chemical Abstracts, RTECS and ECHA. The last
    updated online search was in August 2013.
 4  Bisphenol A diglycidyl ether
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<pre> hapter     2
            General information
2.1         Identity and physico-chemical properties
            The data have been retrieved from the IARC evaluation of Bisphenol A
            diglycidyl ether,1,2 the European Substance Information System (ESIS, which
            can be accessed via http://esis.jrc.ec.europa.eu/) and the Hazardous Substances
            Data Bank (HSDB, which can be accessed via http://toxnet.nlm.nih.gov/cgi-bin/
            sis/htmlgen?HSDB).
 hemical name           : 2,2’-[(1-methylethylidene)bis(4,1-phenyleneoxymethylene)]bis-(orixane)
 AS registry number     : 1675-54-3
 INECS number           : 216-823-5
 ynonyms                : 4,4’-Bis(2,3-epoxypropoxy)diphenyldimethylmethane; 2,2-bis(para-(2,3-
                          epoxypropoxy)phenyl)propane; 2,2-bis(4-(2,3-epoxypropyloxy)phenyl)propane; bis(4-
                          glycidyloxyphenyl)dimethylmethane; 2,2-bis(para-glycidyloxyphenyl)propane; 2,2-bis(4-
                          glycidyloxyphenyl)propane; bis(4-hydroxyphenyl)dimethylmethane diglycidyl ether; 2,2-
                          bis(para-hydroxyphenyl)propane diglycidyl ether; 2,2-bis(4-hydroxyphenyl)propane diglycidyl
                          ether; BPDGE; dian diglycidyl ether; diglycidyl bisphenol A; diglycidyl bisphenol A ether;
                          bisphenol A diglycidyl ether; diglycidyl diphenylolpropane ether; diglycidyl ether of 2,2-bis(para-
                          hydroxyphenyl)propane; diglycidyl ether of 2,2-bis(4-hydroxyphenyl)propane; diglycidyl ether of
                          bisphenol A; diglycidyl ether of 4,4'-isopropylidenediphenol; para,para'-
                          dihydroxydiphenyldimethylmethane diglycidyl ether; 4,4'-dihydroxydiphenyldimethylmethane
                          diglycidyl ether; diomethane diglycidyl ether; 4,4'-isopropylidenebis[1-(2,3-
                          epoxypropoxy)benzene]; 4,4'-isopropylidenediphenol diglycidyl ether; oligomer 340.
Appearance              : A medium viscosity, unmodified liquid epoxy resin
            General information                                                                                          15
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<pre>Use                       : Bisphenol A diglycidyl ether and its oligomers are major components of epoxy resins. Epoxy
                            resins based on bisphenol A diglycidyl ether are widely used in protective coatings, including
                            paints, in reinforced plastic laminates and composites, in tooling, casting and moulding resins, in
                            bonding materials and adhesives, and in flooring and aggregates.
Chemical formula          : C21H24O4
 tructural formula        :                              CH3
                                    CH2 O                C               O   CH2
                            O                                                       O
                                                         CH3
Molecular weight          : 340.42
Boiling point             : no data
Melting point             : 8-12ºC
 apour pressure           : 1.1.10-7 mmHg
 apour density (air = 1)  : no data
 olubility                : 0.7 mg/L at 25ºC (in water)
Conversion factor         : mg/m3 =         0.072 ppm at 25ºC and 101.3 kPa
                            ppm =           13.92 mg/m3 at 25ºC and 101.3 kPa
 U Classification         : Eye Irrit. 2: H319 (Causes serious eye irritation)
100% solution)              Skin Irrit. 2: H315 (Causes skin irritation)
                            Skin Sens.1: H317 (May cause an allergic skin reaction)
2.2           IARC classification
              There is limited evidence in experimental animals for the carcinogenicity of
              bisphenol A diglycidyl ether and bisphenol A diglycidyl ether is mutagenic to
              bacteria. Based on this information IARC has classified bisphenol A diglycidyl
              ether as not classifiable as to its carcinogenicity to humans (Group 3) (see
              Annex E).
 6            Bisphenol A diglycidyl ether
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<pre> hapter 3
        Carcinogenicity studies
3.1     Observations in humans
        No information on human studies related to the carcinogenicity of bisphenol A
        diglycidyl ether has been retrieved from the IARC monographs.1,2 No additional
        human studies in the period after the IARC monograph were retrieved from the
        literature.
3.2     Carcinogenicity studies in animals
        The information on bisphenol A diglycidyl ether in animal studies is selected
        from the IARC monographs,1,2 the EFSA review (2004)3 and the ECHA
        website.4 No studies on inhalation exposure were available. The Committee is
        aware that only a limited number of animal studies exists using pure (analytical
        grade) bisphenol A diglycidyl ether while all other studies use technical grade
        material, containing various impurities. Moreover, in a number of studies the test
        material was inadequately described.
        Oral exposure
        In the study by Hine et al. (1958)5 (cited in IARC1), groups of 30 male Heston A
        strain mice were fed a diet containing 2% bisphenol A diglycidyl ether (no
        further details regarding the test material are available) or a normal diet. The
        Carcinogenicity studies                                                            17
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<pre>  study was terminated after 11 months. The incidences of pulmonary tumours in
  survivors were 12/23 in the epoxy resin-treated group and 15/29 in the untreated
  control group. No lung tumour was observed in mice that died during the study.
  The other organs were not examined for tumours. [The IARC Working Group
  noted the inadequate description of the test material and that the study was not
  designed to investigate carcinogenicity in tissues other than lungs.]
  Stebbins and Dryzga (2003)6 (cited in EFSA3 and ECHA4) administered pure
  bisphenol A diglycidyl ether (purity >99%) to groups of 65 male and 65 female
  Fischer 344 rats by oral gavage. Bisphenol A diglycidyl ether was suspended in
  Tween_ 80 and methylcellulose and given at dose levels of 0 (controls), 2, 15, or
  100 mg/kg/day for up to two years. Ten rats per sex and per dose level were
  necropsied after one year of treatment (chronic toxicity group), and 50 rats per
  sex per dose level were dosed for up to two years (oncogenicity group). Daily
  examinations and periodic body weight and feed consumption were monitored
  throughout the study. Clinical pathology examinations (haematology, clinical
  chemistry, electrolytes, and urinalysis) were conducted at regular intervals
  throughout the study. Ophthalmic examinations were conducted on all rats before
  the start of the study and on all surviving rats prior to the scheduled necropsies.
  Histopathological examination of an extensive set of organs was performed on
  all control and high-dose level rats and all rats removed from the study early.
  Histopathological examination of survivors from the low and intermediate dose
  levels was limited to the liver, kidneys, lungs, spleen, and relevant gross lesions.
  The study was performed in compliance with Good laboratory Practice,
  following the OECD guideline 453 on chronic toxicity/carcinogenicity studies.
       After 24 months there were no statistically significant differences in
  mortality among study groups.
       Males given 15 or 100 mg/kg/day had treatment-related statistically
  significant decreases in body weights and body weight gains. After one year of
  dosing, body weight gains for males given 15 or 100 mg/kg/day were 4.0% and
  12.9% lower than controls. At study termination body weights of the males given
  15 or 100 mg/kg/day were 3.5% and 7.4% lower than controls, respectively.
  There were no treatment-related effects on body weights of males given 2 mg/kg/
  day nor of females from any dose group.
       Males given 100 mg/kg/day and females given 15 or 100 mg/kg/day had
  treatment-related, statistically significant increases in serum cholesterol after 3
  and 12 months of bisphenol A diglycidyl ether administration. In addition, there
  was a treatment-related, non-statistically identified increase in serum cholesterol
8 Bisphenol A diglycidyl ether
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<pre>of males given 100 mg/kg/day at 24 months. No treatment related alterations
were observed in haematology, urinalysis and electrolytes.
    Males and females given 100 mg/kg/day had treatment-related, statistically
significant increases in coecal size and weight. There were no histopathologic
alterations in the enlarged caecums. The coecal enlargement was interpreted to
be non-adverse, and reflective only of a physiologic adaptive change in the
caecum. Males given 100 mg/kg/day also had a treatment related, statistically
significant decreases in absolute and relative spleen weights. Very slight atrophy
of the red pulp of the spleen was noted in these animals, and interpreted to be
reflective of lower body weight gain rather than a primary toxic effect.
    No increase in neoplasms was observed in either male or female rats at any
dose level. The authors conclude that bisphenol A diglycidyl ether did not show
oncogenic potential under the conditions of this study.
Dermal exposure
In a study by Peristianis et al. (1988)7 (cited in IARC1) groups of 50 male and 50
female CF1 mice, six weeks of age, received applications of 0.2 ml of a 1% or
10% solution of pure (analytical grade) bisphenol A diglycidyl ether in acetone
on shaved back skin twice a week for two years. In addition, a control group of
100 male and 100 female mice was treated with acetone. A positive control
group of 50 males and 50 females received an application of ß-propiolactone in
acetone.
    Survival of both male and female mice was not affected by treatment with the
pure epoxy resin when compared to the acetone controls and was considerably
less than survival in the positive (ß-propiolactone) controls.
    Treatment with the pure epoxy resin did not lead to the development of any
epidermal tumours in both male and female animals (Annex F, Table 1). No
epidermal tumour was observed in the acetone controls (Annex F, Table 1). Two
dermal tumours (haemanchiosarcomas) were seen in the high-dose males (Annex
F, Table 1). One male mouse in the acetone control group developed a dermal
tumour (fibrosarcoma) of the treated site (Annex F, Table 1). In the positive
control groups (treated with ß-propiolactone) a large number of skin tumours
was observed in both males (132 tumours in 30 of 50 animals) and and females
(63 tumours in 13 of 50 animals). These tumours were generally malignant
epithelial tumours and, with a lower incidence, mesenchymal tumours.
    The incidence of systemic tumours was generally comparable to those seen
in control mice. However, in female mice a slight increase was observed for the
incidence of thymic lymphosarcomas (2 of 50 animals after low-dose treatment
Carcinogenicity studies                                                            19
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<pre>  (1%) and 5 of 50 animals after high-dose (10%) treatment, compared with 6 of
  100 females in the acetone control group). [The Committee is aware that only a
  very small amount of bisphenol A diglycidyl ether is able to penetrate human,
  mouse and rat skin unchanged, and is metabolized to its corresponding -diol
  (Boogaard et al. (2000).8]
  Stebbins and Baker (1998)9 (cited in EFSA3 and ECHA4) evaluated pure
  bisphenol A diglycidyl ether (purity 99.3%) for chronic toxicity and
  oncogenicity potential following two years of repeated dermal administration.
  Groups of 70 male B6C3F1 mice/dose level were dosed dermally with bisphenol
  A diglycidyl ether in acetone solutions at concentrations of 0, 0.005%, 0.5%, or
  5.0% (w/v). The dosing volume was 50 ml/application which corresponded to
  approximate dosages of 0, 0.1, 10 or 100 mg Bisphenol A diglycidyl ether/kg
  body weight per application. Each dose group followed a 3 applications/week
  (monday, wednesday, friday) dosing regimen. Twenty mice/dose level were
  necropsied after one year of exposure, while the remaining 50 mice/dose level
  were necropsied after two years of exposure or until removal from study due to
  death or moribund condition. Data were collected on the following: clinical
  appearance and behavior, dermal irritation at the test site, body weights, food
  consumption, clinical pathology, organ weights, gross pathology, and
  histopathology.
      Bisphenol A diglycidyl ether applied to the skin of male B6C3F1 mice three
  times per week for two years at dosages of 0.1,10 or 100 mg/kg/application
  caused no apparent systemic toxicity. Slight to severe epidermal hyperplasia,
  slight to moderate chronic or chronic-active dermal inflammation, and epidermal
  crusts were observed histopathologically at dosages of 10 and 100 mg/kg/
  application. In addition, epidermal ulcers accompanied the dermal inflammation
  in a few animals given 10 or 100 mg/kg/application. There were no treatment-
  related dermal alterations in mice given 0.1 mg/kg/application.
      One mouse given 10 mg/kg/application had a squamous cell carcinoma of the
  skin at the test material application site. The single occurrence of a squamous cell
  carcinoma at the test site of this mid-dose animal was not an indicator of
  oncogenic potential, because there were no tumors at the test material application
  sites of animals from the high-dose group. The occurrence of one squamous cell
  carcinoma was also within the historical control incidence range of epidermal
  squamous cell tumors occurring in B6C3F1 mouse oncogenicity studies
  performed by this laboratory.
0 Bisphenol A diglycidyl ether
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<pre>    Dermal application of Bisphenol A diglycidyl ether at doses up to 100 mg/
kg/application for two years produced neither systemic toxicity nor oncogenicity
in any tissue in the male B6C3F1 mouse.
    Crissmann and Jeffries (1998)10 (cited in EFSA3 and ECHA4) applied pure
bisphenol A diglycidyl ether (purity 99.3%) to the unoccluded skin of female
Fischer 344 rats five times per week for up to two years at dosages of 0, 1, 100,
and 1,000 mg/kg/application.
    Animals receiving 1,000 mg/kg/application gained weight more slowly than
control animals during the first few months of the study; but at the end of two
years there were no differences in body weights, body weight gains, or food
consumption.
    The only in-life observations attributed to treatment were an increase in the
number of 1,000 mg/kg/application dose group rats with periocular soiling and
urine soiling in the perineal area.
    Histopathologically, there was dose-related mild chronic dermatitis at the
dermal test site of rats in the 100 and 1,000 mg/kg/application groups. In the liver
there was centrilobular hepatocyte hypertrophy at the 1,000 mg/kg/application
dose, and an increase in several types of foci of cellular alteration at 100 and
1,000 mg/kg/application. Liver effects were also observed as mild elevations in
several clinical chemistry enzymes in rats given 1,000 mg/kg/application.
    The incidence of epithelial neoplasms in and around the mouth, although not
statistically different from concurrent controls, was slightly higher than observed
in historical controls. These neoplasms were attributed to embedded hair foreign
bodies in oral tissues and peri-oral skin, and thus were considered an artifact of
the study methodology. Thus, there were no neoplasms in any tissue that were
statistically increased or directly attributable to the effects of the test material.
    Under the conditions of this 2-year dermal ononcogenicity bioassay,
bisphenol A diglycidyl ether at doses up to 1,000 mg/kg/application did not
cause neoplasia in any tissue in female Fischer 344 rats.
In the abovementioned study by Peristianis et al. (1988)7 (cited in IARC1) two
technical grade preparations of bisphenol A diglycidylether (EPON 828,
containing 29 mg/kg epichlorohydrin and Epikote 828, containing 3 mg/kg
epichlorohydrin) were also included.
    Treatment of both male and female mice with EPON or Epikote did not affect
the survival of the animals when compared to the acetone-treated control. ln
animals treated with EPON 828, one skin carcinoma occurred in high-dose males
and one fibrosarcoma of the subcutis in a high-dose female (Annex F, Table 1).
Carcinogenicity studies                                                               21
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<pre>      ln Epikote 828-treated mice, one squamous cell papilloma of the skin was
  observed in a low-dose male and three basal-cell carcinomas, one in a low-dose
  and one in a high-dose male and one in a high-dose female (Annex F, Table 1). ln
  addition, one sebaceous-gland adenoma was observed in a high-dose male
  (Annex F, Table 1).
      The incidence of systemic tumours in all treatment groups was generally
  comparable to those seen in control mice. However, in males treated with 1 and
  10 % EPON 828 a slight increase in the incidence of kidney tumours, mainly
  carcinomas, was observed (0 of 50 and 8 of 50 males respectively, with 6 of 99
  males in the acetone control group). Moreover, in female mice, treated with
  Epikote 828 a slight increase in the incidence of both lymphoreticular/
  haematopoietic tumours and reticulum-cell sarcoma was observed. The treatment
  with 1 and 10% Epikote 828 resulted in the development of lymphoreticular/
  haematopoietic tumours in 14 of 50 females and in 24 of 50 females respectively,
  with 27 out of 100 females in the acetone control group). In addition, in female
  mice, reticulum-cell sarcoma’s developed in 11 of 50 and 15 of 50 animals after
  treatment with 1 and 10% respectively (with 16 of 100 females in the control
  group).
  In a study by Holland et al.(1979)11 (cited in IARC1) groups of 40 female and 40
  male C3H and 20 female and 20 male C57BL/6 mice, ten to 12 weeks of age,
  received applications of 5, or 25 mg of technical grade bisphenol A diglycidyl
  ether (containing 10% (w/w) of an epoxidised polyglycol (mol wt >500) and
  small amounts of phenyl glycidyl ether) in acetone on their shaved back skin
  three times a week for 24 months. Vehicle controls were treated with acetone.
  After the 24-month exposure period, all surviving mice were weighed and the
  average weight of treated animals was compared with that of the controls.
      In C3H mice, no significant change in average terminal body weight was
  observed. Survival in control, mid, and high dose groups, respectively, was 23,
  21, and 21 in males and 21, 23, and 18 in females, and no skin tumours were
  observed.
      In C57BL/6 mice, significant weight loss was observed in high-dose males.
  Survival in control, mid, and high dose groups, respectively, was 20, 17, and 15
  in males and 15, 15, and 13 in females. Skin tumours ocurred in low-dose and
  high-dose males (1 papilloma and 6 carcinomas, respectively, with no tumours in
  the control) and in high-dose females (1 papilloma and 1 carcinoma, with no
  tumours in the low dose and control group).
      It was also examined in this study whether bisphenol A diglycidyl ether
  penetrated the skin and could lead to the development of tumours in other organs.
2 Bisphenol A diglycidyl ether
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<pre>The incidence of histologically confirmed tumours observed at death is given in
Annex F (Table 2) for both C3H and C57BL/6 mice. The tumour incidence
fluctuated greatly and was either uncorrelated with dose or was comparable to
that in the control. [The IARC Working Group noticed the increased incidence of
lung tumours in female C3H mice, a finding that was not further discussed in the
paper by Holland et al.11]
In the same study of Holland et al. (1979)11 (cited in IARC1) groups of 40 male
and 40 female C3H mice and 20 male and 20 female C57BL/6 mice, ten to 12
weeks of age, received 15, or 75 mg per week of a mixture of equal parts of
technical grade bisphenol A diglycidyl ether and bis(2.3-epoxycyclopentyl)ether
in acetone on their shaved back skin for 24 months. Vehicle controls were treated
with acetone.
    Survival of C3H mice at 24 months was 22, 20 and 23 for males and 23, 23
and 19 for females in the control, low and high-dose groups, respectively. Skin
tumours occurred in 14 low-dose males (four papillomas and ten carcinomas)
and 32 high-dose males (13 papillomas and 19 carcinomas), in five low-dose
females (three papillomas and two carcinomas) and in 19 high-dose females (12
papillomas and seven carcinomas). One skin papilloma was observed in control
females, and no skin tumour was seen in control males.
    In C57BL/6 mice, survival at 24 months was 20, 15 and four for males and
15, 14 and four for females in the respective dose groups. The difference
between control and high-dose groups was statistically significant (p < 0.05).
Skin tumours (mostly carcinomas) were observed in one low-dose and 17 high-
dose males and in two low-dose (one papilloma and one carcinoma) and 15 high-
dose (two papillomas and 13 carcinomas) females, but not in controls of either
sex. When tested alone at the same dose levels, each substance revealed a much
lower tumour response, indicating a synergistic effect of the compounds when
tested as a mixture.
In another study, Zakova et al. (1985)12 (cited in IARC1), groups of 50 male and
50 female CF1 mice, six weeks old, received applications of 0, 1, or 10%
(equivalent to 2 and 20 mg) Araldite GY 250 (technical grade; main component,
bisphenol A diglycidyl ether; containing 4.3 mg/kg epichlorohydrin as a
contaminant) in 0.2 mL acetone on shaved back twice a week for two years.
There was no effect on survival; no skin tumour was observed on the site of
application, and there was no significant difference in the occurrence of other
tumours. A positive control group that received skin applications of a 2%
solution of β-propiolactone showed high incidences of malignant skin tumours.
Carcinogenicity studies                                                           23
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<pre>  Hine et al. (1958)5 (cited in IARC1) studied the effect of bisphenol A diglycidyl
  ether (no further details regarding the test material are available) on skin of male
  C3H mice. Groups of 30 male C3H mice (with body weights of 16-18 g)
  received skin applications of 0.2 mL of a 0.3% solution weekly or a 5% solution
  of bisphenol A diglycidyl ether in acetone once or three times weekly for 24
  months. A control group of 30 male animals received 0.2 mL acetone alone, and
  a positive control group was treated weekly with a 0.3% solution of 20-
  methylcholanthrene in acetone. No skin tumour occurred in any of the treated
  mice. The group treated with 20-methylcholanthrene showed a high incidence in
  malignant skin tumours (19/20) within six months. [The IARC Working Group
  noted the inadequate description of the test material.]
  In a study by Weil et al. (1963)13 (cited in IARC1) a group of about 40 C3H mice
  (exact number and sex not specified), aged 13 weeks, received skin applications
  of undiluted bisphenol A diglycidyl ether (purity and dose not specified) on
  shaved back skin for life (maximum, 23 months). After 16 months of treatment,
  at which time 32 mice were still alive, a single skin papilloma occurred; no other
  skin tumour appeared during the experiment. The authors stated that in a second,
  similar experiment, no skin tumour was observed (details not given). [The IARC
  Working Group noted that the amount of test substance per application was not
  given and that untreated controls were not included in the experiment.]
  In the abovementioned study of Hine et al. (1958)5 (cited in IARC1) each of 16
  male albino rabbits (strain and age not specified) received skin applications (site
  not specified) of 0.5 mL acetone thrice weekly, a 0.3% solution in acetone once
  per week, a 5% solution of bisphenol A diglycidyl ether (no further details
  regarding the test material are available) once or three times per week and a 0.3%
  solution of 20-methylcholanthrene in acetone. At 24 months, 13/16 rabbits were
  still alive. Skin tumours were seen only at 20-methylcholanthrene treated sites.
  [The IARC Working Group noted the inadequate description of the test material.]
  Subcutaneous injection
  In the study of Hine et al. (1958)5 (cited in IARC1) groups of 30 male Long-
  Evans rats (with body weights of 80-100 g) were given three weekly
  subcutaneous injections of bisphenol A diglycidyl ether (no further details
  regarding the test material are available) dissolved in propylene glycol (50%
  solution; total dose, 2.58 g/kg bw). A negative control group was injected with
  propylene glycol alone, and a positive control group received three injections of
4 Bisphenol A diglycidyl ether
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<pre>1,2,5,6,-dibenzanthracene. The experiment was terminated after 24 months, at
which time survival was 17, 14 and four animals in the negative control, epoxy
resin and positive control groups, respectively. The numbers of malignant
tumours at the site of injection were 0, 4 (fibrosarcomas) and 17 (mainly
fibrosarcomas or sarcomas), respectively. [The IARC Working Group noted the
inadequate description of the test material.]
Carcinogenicity of metabolites
A dose of approximately 55 mg/kg bw [14C]bisphenol A diglycidyl ether to mice
was well absorbed after administration by either the oral or dermal route. Most of
the orally administered material was excreted within 24 h. After eight days, 79%
was recovered from faeces and 10% from urine following oral dosing. Following
dermal dosing, 67% and 11% of the radioactivity could be recovered from the
application site after 24 h and 8 days, respectively. Bisphenol A diglycidyl ether
is rapidly metabolized in mice, the major route involving hydration to the
corresponding bis-diol, which occurs both enzymatically, through the epoxide
hydrolase, and nonenzymatically. This hydration is followed by monooxy-
genase-mediated dealkylation to form a phenol and glyceraldehyde. It also
appears that bisphenol A diglycidyl ether may be directly oxidized with the
release of glycidaldehyde (Figure 1). Urinary and faecal metabolites include
glucuronides and sulfates of the bis-diol and corresponding carboxylic acids
(IARC 19891, 19992). As the epoxy hydrolase activity for polycyclic aromatic
hydrocarbons in liver and skin of man is greater than in mouse and rat, metabolic
deactivation of bisphenol A diglycidy ether can also be expected in man.3
Carcinogenicity of glycidaldehyde and glyceraldehyde
Glycidaldehyde is classified by IARC (see Annex E) as possibly carcinogenic to
humans (Category 2B) on the basis of sufficient evidence in experimental
animals (IARC 197614, 198715, 19992): glycidaldehyde is carcinogenic in mice
by skin application and by subcutaneous injection and in rats. It produced
malignant tumours at the site of application in both species. No epidemiological
data relevant to the carcinogenicity of glycidaldehyde are available.
     For glyceraldehyde no experimental and human data regarding
carcinogenicity are found in the literature and no IARC classification is
available.
Carcinogenicity studies                                                            25
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<pre>igure 1 Two possible routes of oxidative dealkylation of the glycidyl moiety of bisphenol A diglycidyl ether (IARC, 1999).2
          Carcinogenicity of epichlorohydrin
          Technical grade preparations of Bisphenol A diglycidyl ether may contain
          epichlorohydrin (Peristianis et al. (1988))7. The carcinogenicity of
          epichlorohydrin has been evaluated by IARC (197614, 198715, 19992). They
          concluded that there is inadequate evidence in humans for the carcinogenicity of
          epichlorohydrin but sufficient evidence for the carcinogenicity in experimental
          animals. As overall evaluation IARC considered epichlorohydrin probably
          carcinogenic to humans (Group 2A) by IARC. Previously, the Dutch Expert
6         Bisphenol A diglycidyl ether
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<pre>    Committee on Occupational Standards (DECOS) has concluded that
    epichlorohydrin is a genotoxic carcinogen (WGD86)16 and calculated additional
    lifetime cancer risks (No. 2000/10OSH).17
3.3 Summary of the carcinogenicity studies
    No human data on the carcinogenicity of bisphenol A diglycidyl ether are
    available.
    The experimental study in CF1 mice by Peristianis et al. (1988)7, represents the
    oldest 2 year skin application study that tested pure (‘analytical grade’) bisphenol
    A diglycidyl ether. No increase in the incidence of skin tumours was observed
    under these conditions, only a slight increase in the incidence of thymic
    lymphosarcomas was observed in female CF1 mice, a strain known for its high
    background of this tumour type. A more recent two-year dermal study in
    B6C3F1 mice by Stebbins and Baker (1998)3,9 produced no clear evidence of any
    oncogenic activity of pure bisphenol A diglycidyl ether. The single squamous
    cell carcinoma detected at the test site in one mid-dose animal cannot be
    interpreted as evidence for an oncogenic potential because no tumours had
    occurred at the test site in any other dose group and this incidence falls within the
    historical control rate. In a two-year study in F344 rats by Crissman and Jeffries
    (1998)3,10 with pure bisphenol A diglycidyl ether no skin carcinogenic effects
    were observed but there was evidence of hepatotoxicity. The observed squamous
    cell carcinomas of the oropharyngeal region were all associated with the
    presence in the carcinoma cells of rat hair as intracellular foreign body inclusion.
         The only reliable oral study in Fisher 344 rats receiving daily administration
    of pure bisphenol A diglycidy ether by gavage for two-years showed no
    oncogenic potential in the gastrointestinal tract or in other tissues (Stebbins and
    Dryzga, 2003).3,4,6
    In the 2 year skin application study with mice by Peristianis et al.7, additionally
    two technical grades of bisphenol A diglycidyl ether were tested. One of the two
    investigated technical grades induced a slight increase in the incidence of
    epidermal tumours and slight increases in the incidences of kidney tumours in
    male mice, whereas the other technical grade induced a slight increase in the
    incidence of lymphoreticular/ haematopoietic tumours and reticulum cell
    sarcoma’s in female mice. A role for epichlorohydrin, a contaminant of the
    technical-grade preparations, may not be excluded in these observations.
    Carcinogenicity studies                                                               27
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<pre>      Apart from this study by Peristianis et al.7 quite a number of experimental
  studies also investigated the carcinogenicity of technical grades bisphenol A
  diglycidyl ether, most also being of limited design. Five of these studies
  concerned skin application in mice, and limitations in the design of these studies
  comprised the small number of animals used, the use of only a single dose level,
  or microscopical examination of only a single or a couple of organs or tissues for
  tumour formation. In the study by Holland et al.11, application of a high dose
  resulted in an increased incidence of epidermal tumours in only one of two
  strains tested. The incidence of systemic tumours in this study11 fluctuated
  greatly and was either uncorrelated with dose or comparable to the control with a
  possible exception for lung tumors in one of the strains tested. No increase in the
  incidence of skin tumours was observed in the other, limited, studies. Also, no
  skin tumours were observed following 2 year application of technical-grade
  bisphenol A diglycidyl ether to the skin of rabbits5.
8 Bisphenol A diglycidyl ether
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<pre> hapter 4
        Genotoxicity
4.1     Gene mutation assays
4.1.1   In vitro
        In one early study, bisphenol A diglycidyl ether was not mutagenic to
        S. typhimurium TA98 and TA100 (Wade et al. (1979)18 cited in IARC1), while in
        a later study, bisphenol A diglycidyl ether was mutagenic to S. typhimurium
        TA100 and TA1535 but not to TA98 and TA1537 (Canter et al. (1986)19 cited in
        IARC1).
             This finding by Canter (see Section 4.1.2) was more recently confirmed by
        Sueiro et al. (2001)1,20 who investigated the mutagenicity of bisphenol A
        diglycidyl ether, its first and second hydrolysis products (the diol epoxide and
        bis-diol of bisphenol A diglycidyl ether, respectively) and the bis-chlorohydrin of
        bisphenol A diglycidyl ether using the Ames Salmonella assay with strains
        TA98, TA100, TA1535 and TA1537. The assays were performed in the absence
        and presence of various concentrations of rat liver S9 fraction. The results
        obtained confirm the mutagenic activity of bisphenol A diglycidyl ether in strains
        TA100 and TA1535 and show a positive response to the diol epoxide of
        bisphenol A diglycidyl ether in these strains, although the latter compound was
        ~10 times less potent than the former. A lack of mutagenic activity of the bis-diol
        of bisphenol A diglycidyl ether and the chlorohydrin under study is also shown.
        Similar results were obtained by the same authors (Sueiro et al. (200621)) using
        Genotoxicity                                                                        29
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<pre>      the E. coli tryptophan reverse mutation test with strains WP2, WP2uvrA and
      IC3327.
          An aqueous emulsion of EPIKOTE 828 was mutagenic to S. typhimurium
      TA100 and TA1535 in the absence of an exogenous metabolic system; in
      TA1535 its mutagenicity was increased when it was tested in the presence of an
      exogenous metabolic system (Andersen et al. (1978)22 cited in IARC1). In line
      with this an abstract reported that EPIKOTE 828 was mutagenic to S.
      typhimurium TA100 but not to TA98 (Nishioka & Ohtani, 1978;23 cited in
      IARC1).
          As reported in an abstract, EPIKOTE 828 (composed mainly of bisphenol A
      diglycidyl ether) induced DNA repair in E. coli (Nishioka & Ohtani, 197823;
      cited in IARC), and was mutagenic to E. coli WP2 uvrA in the absence of an
      exogenous metabolic system (Hemminki et al. (1980)24 cited in IARC1).
          A forward mutation assay in mouse lymphoma cells without exogenous
      metabolic activation system using a single dose of 0.03 µg/ml was positive for
      TK 12386 (specification not available)25 (cited in EFSA3).
          Bisphenol A diglycidyl ether (>98% pure) was tested in a hprt gene mutation
      test with V79 cells. Bisphenol A diglycidyl ether but not its hydrolysis product,
      induced gene mutations at the hprt locus of these cells (see also Paragraph 4.2.1)
      (cited in ECHA4 (gen. tox. vitro 015)).
4.1.2 In vivo
      No in vivo mutagenicity studies of bisphenol A diglycidyl ether were recovered
      from either the IARC monograph or a later date.
4.2   Cytogenetic assays
4.2.1 In vitro
      The effect of bisphenol A diglycidyl ether on the formation of chromosomal
      aberrations in human peripheral lymphocytes was examined. Chromosomal
      preparations of leukocytes cultured from human peripheral blood were treated
      with 5-100 ug/mL bisphenol A diglycidyl ether in DMSO. Bisphenol A
      diglycidyl ether did not cause a significant increase in the number of cells with
      chromosome aberrations over control levels at dose levels as high as 50 µg/ml.
      At 100 ug/ml cytotoxicity was noted as only a few mitotic cells were scored
      (cited in ECHA4 (gen. tox. vitro 021)).
 0    Bisphenol A diglycidyl ether
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<pre>Bisphenol A diglycidyl ether (>98% pure) was tested in a micronucleus assay
with and without S9 activation (aroclor-treated male rats) (cited in ECHA4 (gen.
tox. vitro 015)). Chinese hamster lung fibroblasts (V79 cells) were treated with the
test material in DMSO for 3-6 hours. The cytotoxicity was measured in the hprt
test with V79 cells described in 4.1.1. Bisphenol A diglycidyl ether is very stable
in the absence of metabolizing enzymes (S9-mix) but is rapidly hydrolyzed to a
diglycol by S9-mix. Bisphenol A diglycidyl ether but not the diglycol, induced
an increase in cells with micronuclei and an increase in the hprt mutant
frequency. The induced micronuclei were characterized with CREST
antikinetochore antibodies and consisted of acentric chromosomal fragments and
did not contain whole chromosomes/chromatids. It was concluded that bisphenol
A diglycidyl ether exhibits clastogenic and mutagenic potential, which is lost
after hydrolysis of the epoxide rings and converted to aneuploidogenic potential
after cleavage to bisphenol A.
Rat liver (RL1 or RL4) cells in slide cultures were exposed for 24 h to culture
medium containing EPIKOTE 828 or bisphenol A diglycidyl ether (cited in
ECHA4 (gen. tox. vitro 014)). Upon treatment with EPIKOTE 828 in tested cultures of
RL4 there was a concentration-related increase in cells with chromosome
aberrations in cultures treated with 10 or 20 µg/mL. Consequently, EPIKOTE
828 was considered genotoxic in this chromosome aberration test in vitro.
      Upon treatment with bisphenol A diglycidyl ether in tested cultures of RL1
cells, a substantial increase in cells with chromosomal aberrations (exchange
figures) was seen at the highest dose (15 µg/mL) only. Bisphenol A diglycidyl
ether is considered genotoxic in this chromosome aberration test in vitro.
Suarez et al. (2000)26 examined the epoxy resin bisphenol A diglycidyl ether, its
hydrolysis products and a chlorohydrin of bisphenol A diglycidyl ether
(BADGE.2HCl) for their genotoxicity in the micronucleus test with human
peripheral blood lymphocytes in vitro, in the presence and absence of an
exogenous metabolizing system. The concentrations tested ranged from 12.5 to
62.5 µg/ml of bisphenol A diglycidyl ether, 12.5 to 2.5 µg/ml of first hydrolysis
product (BADGE.H(2)O), 25.0 to 100.0 µg/ml of second hydrolysis product
(BADGE.2H(2)O) and 6.25 to 50.0 µg/ml of BADGE.2HCl. These compounds
are able to induce both cytotoxic and genotoxic effects in cultured human
lymphocytes, as revealed by the increases observed in the cytokinesis block
proliferation index and an increase in cells with micronuclei, respectively.
Genotoxicity                                                                         31
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<pre>4.2.2 In vivo
      The results of a test for nuclear abnormalities including micronuclei and
      polyploidy in Chinese hamster bone marrow was carried out with bisphenol A
      diglycidyl ether (TK 12386: purified Araldite GY250, 80%-85% monomer,
      15%-20% oligomers, epichlorhydrin<1ppm, BPA<5ppm). The substance,
      dissolved in polyethylene glycol, was given by gavage on 2 consecutive days to
      groups of 3 male and 3 female hamsters at 825, 1,650 and 3,300 mg/kg bw/day.
      Animals were sacrificed 24 hours after the last treatment. No nuclear
      abnormalities were detected27 (cited in EFSA3 and ECHA4).
      A test for chromosome aberrations in Chinese hamster bone marrow cells with 2
      consecutive oral daily administrations of 825, 1,650 and 3,300 mg/kg bw/day of
      bisphenol A diglycidyl ether (TK 12386: purified Araldite GY250, 80%-85%
      monomer, 15%-20% oligomers, epichlorhydrin<1 ppm, BPA<5ppm) dissolved
      in polyethylene glycol was performed. Two males and 2 females per dose group
      were sacrificed 6 hours after the second administration. The result was negative.
      However, the small size of the experimental groups is noted28 (cited in EFSA3).
      In a test for structural chromosome aberrations in mouse spermatogonia,
      bisphenol A diglycidyl ether (TK 10490: Araldite GY250, 80%-85% monomer,
      15%-20% oligomers, epichlorhydrin<10 ppm, BPA<5 ppm) dissolved in
      polyethylene glycol was administered at daily doses of 375, 750, 1,500 and 3,000
      mg/kg bw/day to groups of 8 male mice/dose on five consecutive days by
      gavage. The result was considered negative, since only 1 exchange was detected
      at the low dose, 2 chromosome breaks at the middle dose, 1 chromosome
      fragment at the high dose and none in 800 scored control cells29 (cited in EFSA3
      and ECHA4).
      In another chromosomal aberrations test in mouse spermatocytes, bisphenol A
      diglycidyl ether (TK 12386: purified Araldite GY250, 80%-85% monomer,
      15%-20% oligomers, epichlorhydrin<1 ppm, BPA<5 ppm) was administered
      daily for 5 days at doses of 1,000 mg/kg and 3,000 mg/kg bw/day dissolved in
      polyethylene glycol to groups of 8 male mice/dose. Animals were sacrificed 3
      days after the last treatment. From each animal 100 metaphases of primary and
      secondary spermatocytes were examined. Results were considered inconclusive
      because of the inadequate study protocol. The time interval between the last
      DNA synthesis and first meiotic division in mouse male germ cells is 11 days:
 2    Bisphenol A diglycidyl ether
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<pre>      therefore, because most chemical clastogens are S-phase dependant, sampling
      for cytogenetic analysis of spermatocytes should have been done 11 or more days
      after treatment instead of 830 (cited in EFSA3 and ECHA4).
      A dominant lethal test was carried out in mice using a single oral administration
      of bisphenol A diglycidyl ether (TK 12386: purified Araldite GY250, 80%-85%
      monomer, 15%-20% oligomers, epichlorhydrin<1 ppm, BPA<5 ppm) at doses of
      3,333 and 10,000 mg/kg bw. A biological relevant increase in dominant lethals
      was not observed. as the study lacked a positive control group, the historical data
      using TEM at 0.25 mg/kg-0.5 mg/kg bw ip were used31 (cited in EFSA3).
4.3   Miscellaneous
4.3.1 In vivo
      The induction of liver DNA damage in vivo was evaluated in pairs of male and
      female rats by alkaline elution, 6 hours after a single oral treatment with 500
      mg/kg bw of bisphenol A diglycidyl ether (Ciba-Geigy product batch KA 2/LP,
      purity not stated) as a 20% DMSO solution by gavage. MMS (300 mg/kg bw) by
      gavage was the positive control. A biological relevant increase in DNA damage
      was not observed32 (cited in EFSA3 and ECHA4).
      Liver DNA damage was examined in pairs of male and female rats by alkaline
      elution 6 hours after a single oral gavage treatment with 500 mg/kg bw
      EPIKOTE 828 (no specification supplied) as a 20% solution in DSMO. A
      biological relevant increase in DNA damage was not observed33 (cited in
      EFSA3).
      A single, major type DNA adduct has been observed in the skin of C3H mice
      treated subcutaneously with [14C]bisphenol A diglycidyl ether. Initially it was
      proposed that this was a reaction product of glycidaldehyde and deoxyguanosine,
      based upon co-chromatography on an XAD-resin (Bentley et al. (1989)34 cited in
      IARC2). Later studies with higher resolution high-performance liquid
      chromatography on a C-18 column demonstrated that the adducts of bisphenol A
      diglycidyl ether and glycidaldehyde are indeed identical, but that the mouse skin
      adduct found in the mouse skin is probably
      hydroxymethylethenodeoxyadenosine-3’-monophosphate, by comparison with a
      synthetic reference standard. The alkylation frequency was 0.1-0.8 adducts/106
      nucleotides following dosing with 2 mg bisphenol A diglycidyl ether per mouse
      Genotoxicity                                                                        33
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<pre>    and 166 adducts/106 nucleotides after a similar dose of glycidaldehyde (Steiner
    et al. (1992)35 cited in IARC2).
4.4 Summary of the genotoxicity studies
    Under in vitro conditions, bisphenol A diglycidyl ether was repeatedly shown
    mutagenic bacteria and mammalian cell lines. Structural chromosome
    aberrations were also repeatedly shown in mammalian cell lines. The clastogenic
    effect was not confirmed in in vivo tests for chromosome aberrations both in
    somatic and germ cells. However, the positive results found in the in vitro gene
    mutation assays in bacteria and mammalian cells were not confirmed nor ruled
    out in an appropriate in vivo test on the same genotoxic endpoint. Consequently,
    a final conclusion on the genotoxic potential of bisphenol A diglycidyl ether
    cannot be drawn. Next to that, evidence of formation of DNA adducts that appear
    identical to those formed by its metabolite glycidaldehyde, a substance
    demonstrated to be carcinogenic to skin*, has been found after in vivo topical
    application of bisphenol A diglycidyl ether to skin. The level of DNA adducts
    after skin application of bisphenol A diglycidyl ether is, however, orders of
    magnitude lower than that observed after application of glycidaldehyde, which
    renders the biological relevance of this observation questionable, the more so
    since it was administered by subcutaneous injection.
    Glycidaldehyde is classified by IARC as possibly carcinogenic to humans (Group 2B). This is based
    on evidence in experimental animals: the induction of local tumours upon skin application in mice,
    and upon subcutaneous injection in rats.
 4  Bisphenol A diglycidyl ether
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<pre> hapter 5
        Classification
5.1     Evaluation of data on carcinogenicity and genotoxicity
        No human data on the carcinogenicity of bisphenol A diglycidy ether are
        available.
            Oral administration of pure epoxy resin for two years in rats showed no
        oncogenic potential in the gastrointestinal tract or in other tissues.
            In the carcinogenicity studies with the pure epoxy resin in mice and rats no
        epidermal tumours were found after topical application. No increased incidence
        of the only systemic tumours found in one of these studies, thymic lympho-
        sarcomas, was observed in studies with technical grades of this substance.
        Available carcinogenicity studies with technical-grade bisphenol A diglycidyl
        ether do occasionally show increased incidences of various tumours, but the
        incidences are low and appear incidental in nature: i.e. no clear, reproducible
        target organ can be identified. This suggests that there is no clear relationship
        with the actual bisphenol A diglycidyl ether when administered via this route.
        In contrast to the clastogenicity of bisphenol A diglycidyl ether both in somatic
        and germ cells, the positive results found in the in vitro gene mutation assays in
        bacteria and mammalian cells were not confirmed nor ruled out in an appropriate
        in vivo test on the same genotoxic endpoint. Consequently, a final conclusion on
        the genotoxic potential of bisphenol A diglycidyl ether cannot be drawn.
        Classification                                                                     35
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<pre>    Evidence of DNA adduct forming capabilities in vivo have been found but the
    biological relevance is questionable.
    The Committee is aware that the pure (analytical grade) bisphenol A diglycidyl
    ether is negative for any tumours in a number of animal carcinogenicity studies
    after oral and dermal exposure. However, the Committee is also aware that not
    all dermal animal studies completely exclude oncogenicity. In addition, the
    Committee observes a complete absence of any epidemiological studies.
    Therefore, the Committee is of the opinion that the available data on the pure
    substance are insufficient to evaluate the carcinogenic properties (Category 3).
    In addition, the Committee observes that technical grades of bisphenol A
    diglycidyl ether may occasionally induce local and systemic tumours while no
    clear relationship with the actual bisphenol A diglycidyl ether is suggested. The
    Committee is of the opinion that exposure to technical grades of bisphenol A
    diglycidyl ether, e.g. via inhalation, may pose concern for potential carcinogenic
    effects.
5.2 Recommendation for classification
    The Committee concludes that the available data on pure bisphenol A diglycidyl
    ether are insufficient to evaluate the carcinogenic properties (Category 3).*
    According to the classification system of the Health Council (see Annex G).
 6  Bisphenol A diglycidyl ether
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<pre>  References
  Some glycidyl ethers. IARC Monographs on the evaluation of the carcinogenic risk of chemicals to
  humans. 1989: no. 47; pp237-261.
  Bisphenol A diglycidyl ether. IARC Monographs on the evaluation of the carcinogenic risk of
  chemicals to humans. 1999: no. 71; pp1285-1289.
  EFSA. Opinion on Bisphenol A diglycidyl ether (BADGE). The EFSA Journal 2004; 86: 1-40.
  ECHA. REACH Dossier on bisphenol A diglycidyl ether. 2010: (list number 500-033-5) http://
  echa.europa.eu/web/guest/information-on-chemicals/registered-substances (accessed 14-08-2013).
  Hine CH, Guzman RJ, Coursey MM, Wellington JS, Anderson HH. An investigation of the
  oncogenic activity of two representative epoxy resins. Cancer Res 1958; 18: 20-26.
  Stebbins KE, Dryzga MD. Bisphenol A Diglycidyl Ether (BADGE): Two-year gavage chronic
  toxicity/oncogenicity study in Fisher 344 rats. 2003: Study ID: 011134 Dow Chemical Co, Midland,
  Michigan.
  Peristianis GC, Doak SM, Cole PN, Hend RW. Two-year carcinogenicity study on three aromatic
  epoxy resins applied cutaneously to CF1 mice. Food Chem Toxicol 1988; 26(7): 611-624.
  Boogaard PJ, Denneman MA, Van Sittert NJ. Dermal penetration and metabolism of five glycidyl
  ethers in human, rat and mouse skin. Xenobiotica 2000; 30(5): 469-483.
  Stebbins KE, Baker PC. DGEBPA: Two-year dermal chronic toxicity study in male B6C3F1 mice.
  1998: Report no. 960003 (26/8/98) submitted by Dow Chemical Co. to the EU Commission.
0 Crissmann JW, Jeffries TK. DGEBPA: Two-year chronic toxicity/oncogenicity study in female F344
  rats. 1998: Report no. 96005 (22/9/98) submitted by Dow Chemical Co. to the EU Commission.
  References                                                                                       37
</pre>

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<pre>1 Holland JM, Gosslee DG, Williams NJ. Epidermal carcinogenicity of bis(2,3-epoxycyclopentyl)ether,
  2,2-bis(p-glycidyloxyphenyl)propane, and m-phenylenediamine in male and female C3H and
  C57BL/6 mice. Cancer Res 1979; 39(5): 1718-1725.
2 Zakova N, Zak F, Froehlich E, Hess R. Evaluation of skin carcinogenicity of technical 2,2-bis-(p-
  glycidyloxyphenyl)-propane in CF1 mice. Food Chem Toxicol 1985; 23(12): 1081-1089.
3 Weil CS, Condra N, Haun C, Striegel JA. Experimental carcinogenicity and acute toxicity of
  representative epoxides. Am Ind Hyg Assoc J 1963; 24: 305-325.
4 Cadmium, nickel, some epoxides, miscellaneous industrial chemicals and general considerations on
  volatile anaesthetics. IARC Monographs on the evaluation of the carcinogenic risk to humans. 1976:
  no. 11; p175.
5 Overall evaluations of carcinogenicity: An updating of IARC monographs volumes 1 to 42. 1987:
  Supplement no. 7.
6 Werkgroep van Deskundigen (WGD). Rapport inzake grenswaarde epichloorhydrine. The Hague,
  The Netherlands: SDU Servicecentrum Uitgeverijen; 1986: no. RA 1/86.
7 Health Council of the Netherlands. Epichlorohydrin (-chloro-2.3-epoxypropane). The Hague, The
  Netherlands: 2000: publication no. 2000/10OSH.
8 Wade MJ, Moyer JW, Hine CH. Mutagenic action of a series of epoxides. Mutat Res 1979; 66(4):
  367-371.
9 Canter DA, Zeiger E, Haworth S, Lawlor T, Mortelmans K, Speck W. Comparative mutagenicity of
  aliphatic epoxides in Salmonella. Mutat Res 1986; 172(2): 105-138.
0 Sueiro RA, Araujo M, Suarez S, Garrido MJ. Mutagenic potential of bisphenol A diglycidyl ether
  (BADGE) and its hydrolysis-derived products in the Ames Salmonella assay. Mutagenesis 2001;
  16(4): 303-307.
1 Sueiro RA, Suarez S, Araujo M, Garrido MJ. Study on mutagenic effects of bisphenol A diglycidyl
  ether (BADGE) and its derivatives in the Escherichia coli tryptophan reverse mutation assay. Mutat
  Res 2006; 609(1): 11-16.
2 Andersen M, Kiel P, Larsen H, Maxild J. Mutagenic action of aromatic epoxy resins. Nature 1978;
  276(5686): 391-392.
3 Nishioka H, Ohtani H. Mutagenicity of epoxy resins; constituents and commercial adhesives in
  bacterial test systems (abstract no. 21). Mutat Res 1978; 54: 247-248.
4 Hemminki K, Falck K, Vainio H. Comparison of alkylation rates and mutagenicity of directly acting
  industrial and laboratory chemicals: epoxides, glycidyl ethers, methylating and ethylating agents,
  halogenated hydrocarbons, hydrazine derivatives, aldehydes, thiuram and dithiocarbamate
  derivatives. Arch Toxicol 1980; 46(3-4): 277-285.
5 Ciba-Geigy. Point mutation assay with mouse lymphoma cells. 1978: In vitro test with TK 12386
  (04-09-1978) previously submitted to the Commission Febr 1987.
6 Suarez S, Sueiro RA, Garrido J. Genotoxicity of the coating lacquer on food cans, bisphenol A
  diglycidyl ether (BADGE), its hydrolysis products and a chlorohydrin of BADGE. Mutat Res 2000;
  470(2): 221-228.
8 Bisphenol A diglycidyl ether
</pre>

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<pre>7 Langauer M, Muller D. Nucleus anomaly test in somatic interphase nuclei - TK 12386. 1978:
  Unpublished report (16-08-1978) submitted by Ciba Geigy to APME.
8 Hool G, Muller D. Chromosome studies in somatic cells - TK 12386. 1982: Unpublished report (02-
  11-1982) submitted by Ciba Geigy to APME.
9 Hool G, Arni P. Chromosome studies on male germinal epithelium of mouse spermatogonia. 1984:
  Unpublished report (10-01-1984) submitted by Ciba Geigy to APME.
0 Hool G, Muller D. Chromosome studies in male germinal epithelium of the mouse - TK 12386. 1982:
  Unpublished report (20-9-1982) submitted by Ciba Geigy to APME.
1 Hool G, Arni P. Dominant lethal study in mouse TK 12386. 1982: Unpublished report (7-12-1982)
  submitted by Ciba-Geigy to APME.
2 Wooder MF. Studies on the effects of diglycidylether of bisphenol A on the integrity of rat liver DNA
  in vivo. 1981: Unpublished report RLGP 80.152 (December 1981) submitted by Shell Toxicology
  Laboratory to APME.
3 Wooder MF. Studies on the effects of Epikote 828 on the integrity of rat liver DNA in vivo. 1981:
  Unpublished report TLGR 80.105 (December 1981) submitted by Shell Toxicology Laboratory to
  APME.
4 Bentley P, Bieri F, Kuster H, Muakkassah-Kelly S, Sagelsdorff P, Staubli W et al. Hydrolysis of
  bisphenol A diglycidylether by epoxide hydrolases in cytosolic and microsomal fractions of mouse
  liver and skin: inhibition by bis epoxycyclopentylether and the effects upon the covalent binding to
  mouse skin DNA. Carcinogenesis 1989; 10(2): 321-327.
5 Steiner S, Honger G, Sagelsdorff P. Molecular dosimetry of DNA adducts in C3H mice treated with
  bisphenol A diglycidylether. Carcinogenesis 1992; 13(6): 969-972.
6 Health Council of the Netherlands. Guideline to the classification of carcinogenic compounds. The
  Hague, The Netherlands: 2010: publication no. A10/07E.
  References                                                                                            39
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<pre>A Request for advice
B The Committee
C The submission letter
D Comments on the public review draft
E IARC Monograph
F Carcinogenicity studies in animals
G Carcinogenic classification of substances by the Committee
  Annexes
                                                             41
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<pre>2 Bisphenol A diglycidyl ether</pre>

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<pre>nnex A
     Request for advice
     In a letter dated October 11, 1993, ref DGA/G/TOS/93/07732A, to, the State
     Secretary of Welfare, Health and Cultural Affairs, the Minister of Social Affairs
     and Employment wrote:
     Some time ago a policy proposal has been formulated, as part of the simplification of the
     governmental advisory structure, to improve the integration of the development of recommendations
     for health based occupation standards and the development of comparable standards for the general
     population. A consequence of this policy proposal is the initiative to transfer the activities of the
     Dutch Expert Committee on Occupational Standards (DECOS) to the Health Council. DECOS has
     been established by ministerial decree of 2 June 1976. Its primary task is to recommend health based
     occupational exposure limits as the first step in the process of establishing Maximal Accepted
     Concentrations (MAC-values) for substances at the work place.
     In an addendum, the Minister detailed his request to the Health Council as
     follows:
     The Health Council should advice the Minister of Social Affairs and Employment on the hygienic
     aspects of his policy to protect workers against exposure to chemicals. Primarily, the Council should
     report on health based recommended exposure limits as a basis for (regulatory) exposure limits for air
     quality at the work place. This implies:
     •    A scientific evaluation of all relevant data on the health effects of exposure to substances using a
          criteria-document that will be made available to the Health Council as part of a specific request
     Request for advice                                                                                        43
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<pre>      for advice. If possible this evaluation should lead to a health based recommended exposure limit,
      or, in the case of genotoxic carcinogens, a ‘exposure versus tumour incidence range’ and a
      calculated concentration in air corresponding with reference tumour incidences of 10-4 and 10-6
      per year.
  •   The evaluation of documents review the basis of occupational exposure limits that have been
      recently established in other countries.
  •   Recommending classifications for substances as part of the occupational hygiene policy of the
      government. In any case this regards the list of carcinogenic substances, for which the
      classification criteria of the Directive of the European Communities of 27 June 1967 (67/548/
      EEG) are used.
  •   Reporting on other subjects that will be specified at a later date.
  In his letter of 14 December 1993, ref U 6102/WP/MK/459, to the Minister of
  Social Affairs and Employment the President of the Health Council agreed to
  establish DECOS as a Committee of the Health Council. The membership of the
  Committee is given in Annex B.
4 Bisphenol A diglycidyl ether
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<pre>nnex B
     The Committee
     •  R.A. Woutersen, chairman
        Toxicologic Pathologist, TNO Quality of Life, Zeist, and Professor of
        Translational Toxicology, Wageningen University and Research Centre,
        Wageningen
     •  J. van Benthem
        Genetic Toxicologist, National Institute for Public Health and the
        Environment, Bilthoven
     •  P.J. Boogaard
        Toxicologist, SHELL International BV, The Hague
     •  G.J. Mulder
        Emeritus Professor of Toxicology, Leiden University, Leiden
     •  Ms. M.J.M. Nivard
        Molecular Biologist and Genetic Toxicologist, Leiden University Medical
        Center, Leiden
     •  G.M.H. Swaen
        Epidemiologist, Dow Chemical NV, Terneuzen (until April 1, 2013);
        Exponent, Menlo Park, United States (from August 15, 2013)
     •  E.J.J. van Zoelen
        Professor of Cell Biology, Radboud University Nijmegen, Nijmegen
     •  G.B. van der Voet, scientific secretary
        Health Council of the Netherlands, The Hague
     The Committee                                                              45
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<pre>  The Health Council and interests
  Members of Health Council Committees are appointed in a personal capacity
  because of their special expertise in the matters to be addressed. Nonetheless, it
  is precisely because of this expertise that they may also have interests. This in
  itself does not necessarily present an obstacle for membership of a Health
  Council Committee. Transparency regarding possible conflicts of interest is
  nonetheless important, both for the chairperson and members of a Committee
  and for the President of the Health Council. On being invited to join a
  Committee, members are asked to submit a form detailing the functions they
  hold and any other material and immaterial interests which could be relevant for
  the Committee’s work. It is the responsibility of the President of the Health
  Council to assess whether the interests indicated constitute grounds for non-
  appointment. An advisorship will then sometimes make it possible to exploit the
  expertise of the specialist involved. During the inaugural meeting the
  declarations issued are discussed, so that all members of the Committee are
  aware of each other’s possible interests.
6 Bisphenol A diglycidyl ether
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<pre>nnex C
     The submission letter
     Subject            : Submission of the advisory report Bisphenol A diglycidyl ether
     Your Reference     : DGV/MBO/U-932342
     Our reference      : U-7910/BV/fs/246-Y18
     Enclosed           :1
     Date               : October 18, 2013
     Dear Minister,
     I hereby submit the advisory report on the effects of occupational exposure to
     Bisphenol A diglycidyl ether.
     This advisory report is part of an extensive series in which carcinogenic
     substances are classified in accordance with European Union guidelines. This
     involves substances to which people can be exposed while pursuing their
     occupation.
     The advisory report was prepared by the Subcommittee on the Classification of
     Carcinogenic Substances, a permanent subcommittee of the Health Council’s
     Dutch Expert Committee on Occupational Safety (DECOS). The advisory report
     The submission letter                                                               47
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<pre>  has been assessed by the Health Council’s Standing Committee on Health and
  the Environment.
  I have today sent copies of this advisory report to the State Secretary of
  Infrastructure and the Environment and to the Minister of Health, Welfare and
  Sport, for their consideration.
  Yours sincerely,
  (signed)
  Professor W.A. van Gool,
  President
8 Bisphenol A diglycidyl ether
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<pre>nnex D
     Comments on the public review draft
     A draft of the present report was released in May 2013 for public review. The
     following organisations have commented on the draft document:
     •   National Institute for Occupational Safety and Health (NIOSH), Cincinnati,
         USA
     •   Epoxy Resins REACH Consortium (ERRC), c/o Dow MF Produktions
         GmbH & Co. OHG, Rheinmünster, Germany.
     Comments on the public review draft                                            49
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<pre>0 Bisphenol A diglycidyl ether</pre>

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<pre>nnex E
     IARC Monograph
     Volume 47, 1989 (Excerpt from Some glycidyl ethers, pp. 237-261)
     Summary of Data Reported and Evaluation
     1 Exposure data
     Glycidyl ethers are basic components of epoxy resins which have been
     commercially available since the late 1940s. Bisphenol A diglycidyl ether and its
     oligomers are major components of epoxy resins. Epoxy resins based on
     bisphenol A diglycidyl ether are widely used in protective coatings, including
     paints, in reinforced plastic laminates and composites, in tooling, casting and
     moulding resins, in bonding materials and adhesives, and in floorings and
     aggregates. Occupational exposure to bisphenol A diglycidyl ether may occur
     during their production, during the production of epoxy products and during
     various uses of epoxy products, but data on exposure levels are sparse.
     2 Experimental carcinogenicity data
     Bisphenol A diglycidyl ether of various technical grades was tested by skin
     application in mice in five studies. In one of the studies, an increased incidence
     of epidermal tumours was found in one of two strains tested. In another study, a
     small increase in the incidence of epidermal tumours and small increases in the
     IARC Monograph                                                                     51
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<pre>  incidences of kidney tumours in male mice and of lymphoreticular/
  haematopoietic tumours in female mice were observed. No increase in the
  incidence of skin tumours was observed in two further studies, and the other
  study was inadequate for evaluation. Following subcutaneous injection of
  technical-grade bisphenol A diglycidyl ether to rats, a small number of local
  fibrosarcomas was observed. Following application of technical-grade bisphenol
  A diglycidyl ether to the skin of rabbits, no skin tumour was observed.
  Pure bisphenol A diglycidyl ether was tested in one experiment by skin
  application in mice; no epidermal but a few dermal tumours were observed in
  males, and there was a small increase in the incidence of lymphoreticular/
  haematopoietic tumours in females.
  3 Human data
  No data were available to the Working Group.
  4 Other relevant data
  Some glycidyl ethers have been shown to cause allergic contact dermatitis in
  humans. Glycidyl ethers generally cause skin sensitization in experimental
  animals. Necrosis of the mucous membranes of the nasal cavities was induced in
  mice exposed to allyl glycidyl ether.
      Prenatal toxicity was not induced in rats exposed dermally to bisphenol A
  diglycidyl ether.
      One study of workers exposed to bisphenol A diglycidyl ether showed no
  increase in the incidence of chromosomal aberrations in peripheral lymphocytes.
  The glycidyl ethers were generally mutagenic to bacteria.
  5 Evaluation
  There is limited evidence for the carcinogenicity of bisphenol A diglycidyl ether
  in experimental animals.
      No data were available from studies in humans on the carcinogenicity of
  glycidyl ethers.
  Overall evaluation
  Bisphenol A diglycidyl ether is not classifiable as to its carcinogenicity to
  humans (Group 3).
2 Bisphenol A diglycidyl ether
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<pre>   For definition of the italicized terms, see Preamble Evaluation.
Subsequent evaluation: Volume 71 (1999) (Bisphenol A diglycidyl ether)
Synonyms for Bisphenol A diglycidyl ether
• Araldite 6005
• AralditeR GY 250
• AralditeR GY 6010
• Bis(4-glycidyloxyphenyl)dimethylmethane
• 2,2-Bis(4-glycidyloxyphenyl)propane
• 2,2-Bis(4-hydroxyphenyl)propane diglycidyl ether
• 2,2-Bis(para-glycidyloxyphenyl)propane
• 2,2-Bis(para-hydroxyphenyl)propane diglycidyl ether
• 2,2-Bis[4-(2,3-epoxypropoxy)phenyl]propane
• 2,2-Bis[para-(2,3-epoxypropoxy)phenyl]propane
• 4,4’-Bis(2,3-epoxypropoxy)diphenyldimethylmethane
• 4,4’-Dihydroxydiphenyldimethylmethane diglycidyl ether
• 4,4’-Isopropylidenebis[1-(2,3-epoxypropoxy)benzene]
• 4,4’-Isopropylidenediphenol diglycidyl ether
• Bis(4-hydroxyphenyl)dimethylmethane diglycidyl ether
• BPDGE
• D.E.R.R 331
• Dian diglycidyl ether
• Diglycidyl bisphenol A
• Diglycidyl bisphenol A ether
• Diglycidyl diphenylolpropane ether
• Diglycidyl ether of 2,2-bis-(4-hydroxyphenyl)propane
• Diglycidyl ether of 2,2-bis-(para-hydroxyphenyl)propane
• Diglycidyl ether of 4,4’-isopropylidenediphenol
• Diglycidyl ether of bisphenol A
• para,para’-Dihydroxydiphenyldimethylmethane diglycidyl ether
• Diomethane diglycidyl ether
• EPI-REZR 510
• EpikoteR 815
• EpikoteR 828
• EPONR 828
• EPOTUFR 37-140
• Epoxide A
• Oligomer 340
IARC Monograph                                                         53
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<pre>  Volume 71, 1999 (Excerpt from Bisphenol A diglycidyl ether,
  pp. 1285-1289)
  2 Studies of Cancer in Humans
  No data were available to the Working Group.
  3 Studies of Cancer in Experimental Animals
  Bisphenol A diglycidyl ether of various technical grades was tested for
  carcinogenicity by skin application in mice in five studies. In one of the studies,
  an increased incidence of epidermal tumours was found in C57BL/6 mice, but
  not in C3H mice. In a study with CF1 mice, a small increase in the incidence of
  epidermal tumours and small increases in the incidences of kidney tumours in
  male mice and of lymphoreticular/ haematopoietic tumours in female mice were
  observed. No increase in the incidence of skin tumours was observed in two
  further studies, one with CF1 mice, the other with C3H mice and the remaining
  study with C3H mice was inadequate for evaluation. Following subcutaneous
  injection of technical grade bisphenol A diglycidyl ether to male Long-Evans
  rats, a small number of local fibrosarcomas was observed. Following application
  of technical grade bisphenol A diglycidyl ether to the skin of albino rabbits, no
  skin tumour was observed. Pure (‘analytical grade’) bisphenol A diglycidyl ether
  was tested in one experiment by skin application in CF1 mice; no epidermal, but
  a few dermal tumours were observed in males and there was a small increase in
  the incidence of lymphoreticular/haematopoietic tumours in females (IARC,
  1989). No subsequent studies were available to the Working Group. It was noted
  that glycidaldehyde, a metabolite of bisphenol A diglycidyl ether, is carcinogenic
  to experimental animals and classified as possibly carcinogenic to humans
  (Group 2B) (see this volume).
  4 Other Data Relevant to an Evaluation of Carcinogenicity and its
  Mechanisms
  4.1 Absorption, distribution, metabolism and excretion
  4.1.1 Humans
  No data were available to the Working Group.
4 Bisphenol A diglycidyl ether
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<pre>4.1.2 Experimental systems
A dose of approximately 55 mg/kg bw [14C]bisphenol A diglycidyl ether to mice
was well absorbed after administration by either the oral or dermal route. Most of
the orally administered material was excreted within 24 h. After eight days, 79%
was recovered from faeces and 10% from urine following oral dosing. Following
dermal dosing, 67% and 11% of the radioactivity could be recovered from the
application site after 24 h and 8 days, respectively. Bisphenol A diglycidyl ether
is rapidly metabolized in mice, the major route involving hydration to the
corresponding bis-diol, which occurs both enzymatically, through the epoxide
hydrolase, and nonenzymatically. This hydration is followed by mono-
oxygenase-mediated dealkylation to form a phenol and glyceraldehyde. It also
appears that bisphenol A diglycidyl ether may be directly oxidized with the
release of glycidaldehyde (Figure 1). Urinary and faecal metabolites include
glucuronides and sulfates of the bis-diol and corresponding carboxylic acids
(IARC, 1989).
4.4 Genetic and related effects
4.4.1 Humans
One study of workers exposed to bisphenol A diglycidyl ether showed no
increase in chromosomal aberrations in peripheral blood lymphocytes (IARC,
1989).
IARC Monograph                                                                     55
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<pre>igure 1 Two possible routes of oxidative dealkylation of the glycidyl moiety of bisphenol A diglycidyl ether.
          4.4.2 Experimental systems
          The compound is mutagenic to bacteria (IARC, 1989).
               A single major DNA adduct has been observed in the skin of C3H mice
          treated cutaneously with [14C]bisphenol A diglycidyl ether. Initially it was
          proposed that this was a reaction product of glycidaldehyde and deoxyguanosine,
          based upon co-chromatography on an XAD-resin (Bentley et al., 1989). Later
          studies with higher resolution high-performance liquid chromatography on a C-
          18 column demonstrated that the adducts of bisphenol Adiglycidyl ether and
6         Bisphenol A diglycidyl ether
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<pre>glycidaldehyde with DNA are indeed identical, but that the mouse skin adduct is
probably hydroxymethylethenodeoxy-adenosine-3’-monophosphate, by
comparison with a synthetic reference standard. The alkylation frequency was
0.1-0.8 adducts/106 nucleotides following dosing with 2 mg bisphenol
Adiglycidyl ether per mouse and 166 adducts/106 nucleotides after a similar dose
of glycidaldehyde (Steiner et al., 1992a,b).
5 Evaluation
No epidemiological data relevant to the carcinogenicity of bisphenol A
diglycidyl ether were available.
    There is limited evidence in experimental animals for the carcinogenicity of
bisphenol A diglycidyl ether.
Overall evaluation
Bisphenol A diglycidyl ether is not classifiable as to its carcinogenicity to
humans (Group 3).
    For definition of the italicized terms, see Preamble Evaluation.
Previous evaluation: Volume 47 (1989) (Some Glycidyl ethers)
Synonym
2,2’-[(1-Methylethylidene)bis(4,1-phenyleneoxymethylene)]bis(oxirane).
Last updated: 13 April 1999.
IARC Monograph                                                                   57
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<pre>8 Bisphenol A diglycidyl ether</pre>

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<pre>  nnex        F
              Carcinogenicity studies in animals
 able 1 Incidence of tumours of skin and subcutis in CF1 mice treated with pure (analytical grade) bisphenol A diglycidyl ether and with
echnical grades EPON 828, and EPIKOTE 828 (Peristianis et al. 1988).7
                           Males                                                    Females
                           Con- Pure (%)            EPON           Epikote          Con- Pure (%)           EPON            Epikote
                           trol                     828 (%)        828 (%)          trol                    828 (%)         828 (%)
                           0       1       10       1      10      1       10       0        1       10     1       10      1       10
 kin (treated site)
  pidermal tumours
 quamous-cell              0       0       0        0      1       0       0        0        0       0      0       0       0       0
 arcinoma (M)
 quamous-cell              0       0       0        0      0       1       0        0        0       0      0       0       0       0
 apilloma (B)
  asal-cell                0       0       0        0      0       1       1        0        0       0      0       0       0       1
 arcinoma (M)
 ebaceous-gland            0       0       0        0      0       0       1        0        0       0      0       0       0       0
 denoma (B)
Dermal tumours
 ibrosarcoma (M)           1       0       0        0      0       0       0        0        0       0      0       0       0       0
Haemanchio-                0       0       2        0      0       0       0        0        0       0      0       0       0       0
 arcoma (M)
Haemanchio-                0       0       0        0      0       0       0        0        0       0      0       0       1       0
 ndothelioma (B)
 ibroma (B)                0       0       0        0      0       1       0        0        0       0      0       0       0       0
 ubcutis (treated site)
 ibrosarcoma (M)           0       0       1        0      0       0       0        0        0       0      0       1       0       0
Anaplastic sarcoma (M)     0       0       0        0      0       0       0        0        1       0      0       0       0       0
  =benign; M=malignant
 he treatment groups consisted of 50 males and 50 females. In the control groups were 99 males and 100 females.
              Carcinogenicity studies in animals                                                                                     59
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<pre> able 2 Incidence of neoplasms in tissues other than skin in C3H and C57BL/6 mice treated with technical grade bisphenol A
 iglycidyl ether (Holland et al. 1979).11
                              C3H mice Dose (mg)                             C57BL/6 mice Dose (mg)
                              40 animals per sex and dose                    20 animals per sex and dose
                              0               5               25             0               5                25
                              M       F       M       F       M      F       M       F       M        F       M       F
 ite
 ung                            2       1       1      1       3      6        1       0       1       0       1       0
 iver                         20        6     21       5      22      3        1       3       5       1       0       2
  eticulum cell sarcoma         4       6     11       5       3      3        3       6       7       7       8      10
 nd lymphoma
Ovary                                 17              18             15                2               0               1
  reast                               11              10              4                0               0               1
  onnective tissue              1       1       0      9       1      9        0       0       0       0       0       0
Other mesenchymal               1       1       2      5       0      1        0       1       0       1       0       0
 0            Bisphenol A diglycidyl ether
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<pre> nnex        G
             Carcinogenic classification of
             substances by the Committee
             The Committee expresses its conclusions in the form of standard phrases:
 ategory      Judgement of the committee (GRGHS)                                    Comparable with EU Category
                                                                                    67/548/EEC         EC No 1272/2008
                                                                                    (before            (as from
                                                                                    12/16/2008         12/16/2008
A             The compound is known to be carcinogenic to humans.                   1                  1A
              • It acts by a stochastic genotoxic mechanism.
              • It acts by a non-stochastic genotoxic mechanism.
              • It acts by a non-genotoxic mechanism.
              • Its potential genotoxicity has been insufficiently investigated.
                 Therefore, it is unclear whether the compound is genotoxic.
B             The compound is presumed to be as carcinogenic to humans.             2                  1B
              • It acts by a stochastic genotoxic mechanism.
              • It acts by a non-stochastic genotoxic mechanism.
              • It acts by a non-genotoxic mechanism.
              • Its potential genotoxicity has been insufficiently investigated.
                 Therefore, it is unclear whether the compound is genotoxic.
              The compound is suspected to be carcinogenic to man.                  3                  2
3)            The available data are insufficient to evaluate the carcinogenic      Not applicable     Not applicable
              properties of the compound.
4)            The compound is probably not carcinogenic to man.                     Not applicable     Not applicable
ource: Health Council of the Netherlands. Guidelines to the classification of carcinogenic compounds. The Hague: Health
 ouncil of the Netherlands, 2010; publication no. A10/07E.36
             Carcinogenic classification of substances by the Committee                                                 61
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<pre>2 Bisphenol A diglycidyl ether</pre>

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