<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>Bisphenol A and its Diglycidylether

Health based recommended occupational exposure limits

</pre>

====================================================================== Einde pagina 1 =================================================================

<br><br>====================================================================== Pagina 2 ======================================================================

<pre></pre>

====================================================================== Einde pagina 2 =================================================================

<br><br>====================================================================== Pagina 3 ======================================================================

<pre>en GEZONDHEIDSRAAD …....……..……….
Voorzitter

_ Aan de minister van Volksgezondheid, Welzijn en Sport
Sir Winston Churchilllaan 370
2285 SJ RIJSWIJK

- Onderwerp : aanbieding rapport
Uw kenmerk : DGV/BMO-U-932542
Ons kenmerk : U-3474/CH/YvS/459/T-10
Bijlagen : 1
Datum : 12 september 1996

Bij brief van 3 december 1993, nr. DGV/BMO-U-932542, verzocht de
toenmalige staatssecretaris van Welzijn, Volksgezondheid en Cultuur na-
mens de minister van Sociale Zaken en Werkgelegenheid om gezond-
heidskundige advieswaarden af te leiden ten behoeve van de bescher-
ming van beroepsmatig aan stoffen blootgestelde personen.

Per 1 januari 1994 heb ik daartoe een commissie ingesteld die de werk-
zaamheden voortzet van de Werkgroep van Deskundigen (WGD). De
WGD was een door genoemde minister ingestelde adviescommissie.

Hierbij bied ik u - gehoord de Beraadsgroep Toxicologie - een publicatie
van de Commissie WGD aan over 'Bisphenol-A and its Diglycidylether’.

Le

prof dr JJ Sixma

Postadres eenen BB Neen Bezoekadres
Postbus 1236 Bogaard Centre
2280 cE Rijswijk Sir Winston Churchilllaan 366-368

Telefoon (070) 340 75 20 2285 SJ Rijswijk
Telefax (070) 340 75 23

</pre>

====================================================================== Einde pagina 3 =================================================================

<br><br>====================================================================== Pagina 4 ======================================================================

<pre></pre>

====================================================================== Einde pagina 4 =================================================================

<br><br>====================================================================== Pagina 5 ======================================================================

<pre>Bisphenol A and its Diglycidylether

Health based recommended occupational exposure limits

Report of the Dutch Expert Committee on Occupational Standards,
a committee of the Health Council of the Netherlands

to
the Minister of Health, Welfare and Sports

the Minister and State Secretary of Social Affairs and Employment

No. 1996/02WGD, Rijswijk, 12 September 1996

</pre>

====================================================================== Einde pagina 5 =================================================================

<br><br>====================================================================== Pagina 6 ======================================================================

<pre>Preferred citatton:

Health Council of the Netherlands: Dutch Expert Committee on Occupational Stan-
dards (DECOS). Bisphenol A and its Diglycidylether. Rijswijk: Health Council of the
Netherlands, 1996; publication no. 1996/02WGD.

all rights reserved

ISBN: 90-5549-121-7

</pre>

====================================================================== Einde pagina 6 =================================================================

<br><br>====================================================================== Pagina 7 ======================================================================

<pre>Contents

Samenvatting en advieswaarde 9

Executive summary 13

1 Scope 17

1.1 Background 17

1.2 Committee and procedures 17
1.3 Data 18

2 Identity, properties, monitoring 19
2.1 Identity 19

2.2 Analytical methods 20

3 Sources 23

3.1 Natural occurrence 23

3.2 Man-made sources 23

4 Exposure 25

4.1 Environmental levels 25

4.2 Human exposure 26

7 Contents

</pre>

====================================================================== Einde pagina 7 =================================================================

<br><br>====================================================================== Pagina 8 ======================================================================

<pre>5 Guidelines and standards: 29

5.1 General population 29

5.2 Working population 29

5.3 Previous evaluation by national and international bodies 30

6 Kinetics 31

6.1 Absorption 31

6.2 Distribution 33

6.3 Biotransformation 34

6.4 Elimination 37

6.5 Biological monitoring 38

6.6 Summary 38

7 Effects 39

71 Animal experiments 39

7.2 Observations in man 69

7.3 Summary 76

8 Evaluation of human health risk 79

8.1 Groups at extra risk 79

8.2 Assessment of health risk 79

8.3 Recommended occupational exposure limit 81
References 83
Annexes 91

A Reguest for advice 93

B The committee 95

C Comments on the public review draft 97

D Synonyms of bisphenol A 99

E Synonyms of the diglycidylether of bisphenol A 101

F Abbreviations 103

G DECOS-documents 107

8 Bisphenol A and its Diglycidylether

</pre>

====================================================================== Einde pagina 8 =================================================================

<br><br>====================================================================== Pagina 9 ======================================================================

<pre>Samenvatting en advieswaarde

Vraagstelling

Op verzoek van de Minister van Sociale Zaken en Werkgelegenheid beveelt de Ge-
zondheidsraad gezondheidskundige advieswaarden aan voor beroepsmatige bloot-
stelling aan toxische stoffen in de lucht op de werkplek. De aanbevelingen worden
opgesteld door de Commissie WGD van de Raad. Zij vormen de eerste stap in een
drietraps-procedure die moet leiden tot wettelijke grenswaarden (MAC-waarden).

In het voorliggende rapport bespreekt de commissie de gevolgen van blootstelling aan
bisfenol A en bisfenol-A-diglycidylether en beveelt zij gezondheidskundige advies-
waarden voor deze stoffen aan. De conclusies van de commissie zijn gebaseerd op de
wetenschappelijke publikaties die vóór december 1995 zijn verschenen.

Fysische en chemische eigenschappen

Bisfenol A (BPA) komt voor in de vorm van witte kristallen of vlokken, heeft een
zwakke fenol-achtige geur en een lage dampspanning. Verstoven BPA-poeder in lucht
is explosief. BPA is in geringe mate oplosbaar in water, in tetrachloorkoolstof, en in
verscheidene organische oplosmiddelen.

De diglycidylether van bisfenol A (DGEBPA) is in zuivere vorm een witte kristal-
lijne stof en heeft een lage dampspanning. DGEBPA wordt niet als zuiver monomeer
geproduceerd, maar als een mengsel van monomeer, dimeer, trimeer en tetrameer.

Samenvatting en advieswaarde

</pre>

====================================================================== Einde pagina 9 =================================================================

<br><br>====================================================================== Pagina 10 ======================================================================

<pre>Over de fysische en chemische eigenschappen van de stof in zuivere vorm zijn maar
weintg:- gegevens:
Beide verbindingen worden voornamelijk gebruikt bij de productie van harsen.

Monitoring

Het National Institute for Occupational Safety and Health (NIOSH) van de VS heeft
een methode beschreven voor de bepaling van BPA en DGEBPA in lucht. Er is geen
gevalideerde methode voor biologische monitoring beschikbaar.

Grenswaarden

Nederland, Duitsland, het Verenigd Koninkrijk, Zweden en de VS kennen geen grens-
waarden voor beroepsmatige blootstelling aan de hier beschouwde stoffen.

Toxicokinetiek

Over de kinetiek van beide stoffen na inademing is niets bekend.

Bij ratten vindt na orale inname van BPA snel absorptie plaats. Binnen 3 dagen
wordt ongeveer 80% uitgescheiden. Hetzelfde geldt voor DGEBPA bij muizen. Bij
deze diersoort is de absorptie na dermale toediening veel langzamer dan na orale in-
name. Na drie dagen werd 41% van de aangebrachte dosis aangetroffen op de huid, 22
tot 30% op de bodemdeklaag van de kooi en 4,1% in het spoelwater na reiniging van
de kooi. De fecale uitscheiding varieert met de dosis: van 10% bij een hoge tot 36% bij
een lage dosis. De uitscheiding via de urine is veel geringer.

Het metabolisme van BPA is niet onderzocht. Bij muizen zijn de metaboliet-patronen
in urine en feces na toediening via de huid in essentie dezelfde als die na orale toedie-
ning. De belangrijkste metaboliet in de urine is bis-diol-DGEBPA, gevolgd door het
sulfaat-conjugaat gaat hiervan. Het belangrijkste fecale metaboliet is de aan een kant
tot carboxylzuur geoxideerde bis-diol-verbinding.

Effecten
BPA
BPA is licht irriterend voor de huid, maar maakt de huid niet overgevoelig. De acute

toxiciteit is laag. Subchronische blootstelling aan concentraties van 50 en 150 mg/m’,
hetgeen bijna de maximaal haalbare concentratie in lucht is, veroorzaakte bij ratten

10

Bisphenol A and its Diglycidylether

</pre>

====================================================================== Einde pagina 10 =================================================================

<br><br>====================================================================== Pagina 11 ======================================================================

<pre>lichte hyperplasie en chronische ontsteking in de neusholte. Deze effecten verdwenen
binnen 12 weken na beëindiging van de blootstelling. De geen-waargenomen-nadelig-
effect-concentratie bij 90 dagen van blootstelling was 10 mg/m’. Langdurige orale
blootstelling leidde bij ratten tot vermindering van groei en vervolgens tot toxische ef-
fecten in lever en nieren. Er zijn geen aanwijzingen dat BPA carcinogeen is voor ratten
of muizen van beide seksen. Ook is niet gebleken dat BPA bij ratten en muizen geno-
toxiciteit vertoont, evenmin als reproductie- en ontwikkelingstoxiciteit.

Bij de mens veroorzaakt BPA lichte irritatie van de huid, de ogen, de neus en de
keel. Allergische reacties zijn echter, ook bij geselecteerde groepen van industriële
werkers, slechts bij hoge uitzondering waargenomen.

DGEBPA

DGEBPA irriteert de huid en maakt deze sterk overgevoelig. De acute toxiciteit is ge-
ring. Orale toediening van een dosis van 540 mg/kg per dag aan mannelijke ratten
gedurende 10 weken leidde tot vermindering van het lichaamsgewicht, maar niet tot
macroscopische veranderingen, effecten op orgaangewichten of histologische veran-
deringen in de voortplantingsorganen of het spijsverteringskanaal. Bij mannelijke en
vrouwelijke muizen is geen carcinogeniteit gebleken na toediening via de huid of sub-
cutane injecties. De stof heeft enige mutagene activiteit, maar deze is hoofdzakelijk
waargenomen in in vitro-experimenten. Verscheidene in vivo-experimenten hebben,
evenmin als onderzoek met humane cellen in vitro, geen aanwijzingen voor genotoxi-
citeit opgeleverd. Doses die voor het moederdier toxisch waren (540 mg/kg/dag bij rat-
ten, 180 mg/kg/dag bij konijnen), leidden niet tot reproductietoxische effecten of
ontwikkelingsstoornissen. De geen-waargenomen-nadelig-effectniveaus voor de hier
bedoelde maternale toxiciteit waren 180 mg/kg/dag voor ratten en 60 mg/kg/dag voor
konijnen.

De incidentie van huid-overgevoeligheid bij mensen is ongeveer 4%. In enkele ge-
vallen kan DGEBPA astma veroorzaken.

Evaluatie en advieswaarden
BPA

Het kritische effect is de zeer lichte tot lichte nasale hyperplasie en ontsteking, bij 50
en 150 mg/m’, zoals waargenomen bij inhalatie-experimenten met ratten en die volle-
dig verdwenen binnen 12 weken na beëindiging van de blootstelling. Het geen-
waargenomen-nadelig-effectniveau was 10 mg/m’. Voor de extrapolatie van rat naar
mens vindt de commissie het gebruik van een veiligheidsfactor niet nodig. Systemische

11

Samenvatting en advieswaarde
</pre>

====================================================================== Einde pagina 11 =================================================================

<br><br>====================================================================== Pagina 12 ======================================================================

<pre>effecten zijn immers niet waargenomen en bovendien bedraagt de marge tussen het
geen-waargenomenveffectniveau en het: laagst-waargenomen-effectniveau een factor 5.
Wegens de lage dampspanning kan een concentratie van 10 mg BPA per ni lucht
slechts bestaan in de vorm van vaste deeltjes.

DGEBPA

De kritische effecten zijn de vermindering van het lichaamsgewicht na orale toediening
aan mannelijke ratten en maternale toxiciteit bij zwangere konijnen. De commissie
neemt als uitgangspunt het geen-waargenomen-nadelig-effectniveau van 60 mg/kg/dag
in konijnen. Voor extrapolatie van konijn naar mens hanteert de commissie als
veiligheidsfactor 10. De hieruit onder bepaalde aannamen af te leiden gezondheidskun-
dige advieswaarde bedraagt ongeveer 40 mg DGEBPA per nt lucht. Wegens de lage
dampspanning van DGEBPA kan deze concentratie in lucht uitsluitend bestaan in de
vorm van vaste deeltjes.

Beide stoffen komen in de lucht op de werkplek vermoedelijk uitsluitend voor in de
vorm van stofdeeltjes. De hierboven afgeleide gezondheidskundige advieswaarden zijn
in geval van BPA gelijk aan en in geval van DGEBPA hoger dan de in Nederland geld-
ende MAC-waarde voor stofdeeltjes. De commissie stelt daarom voor om, gemiddeld
over een acht-urige werkdag, de concentratie van respirabel respectievelijk inhaleer-
baar BPA en DGEBPA in de lucht op de werkplek te beperken tot 5 respectievelijk 10
mg/m’, gemiddeld over een acht-urige werkdag.

Ter voorkoming van huid-overgevoeligheid dient huidcontact met DGEBPA te
worden vermeden.

Bisphenol A and its Diglycidylether

</pre>

====================================================================== Einde pagina 12 =================================================================

<br><br>====================================================================== Pagina 13 ======================================================================

<pre>Executive summary

Scope

Upon request of the Secretary of State of Social Affairs and Employment the Health
Council of the Netherlands recommends health-based occupational exposure limits for
the concentration of toxic substances in the air of the workplace. These recommenda-
tion are made by the Council’s Dutch Expert Committee on Occupational Standards. It
constitutes the first step in a three-stage procedure that leads to legally binding limit
values. In the present report the Committee discusses the consequences of exposure to
bisphenol A and bisphenol-A-diglycidylether and recommends health-based occupa-
tional exposure limits for these substances. The Committee's conclusions are based on
scientific publications obtained from data retrieval systems from prior to December
1995.

Physical and chemical properties

Bisphenol A (BPA) consists of white crystals or flakes and has a mild phenolic odour.
Finely dispersed powder with air is explosive. The substance is slightly soluble in wa-
ter and CC1,, and soluble in several organic solvents.

The pure diglycidylether of bisphenol A (DGEBPA) is a white crystalline solid.
DGEBPA is not produced as a pure monomer but as a mixture of monomer, dimer,
trimer and tetramer, and, therefore, very few chemical and physical properties are re-
ported for the pure substance. Both BPA and DGEBPA have a low vapour pressure.

13

Executive summary

</pre>

====================================================================== Einde pagina 13 =================================================================

<br><br>====================================================================== Pagina 14 ======================================================================

<pre>Monitoring *

The National Institute for Occupational Safety and Health (NIOSH) of the USA has
described a method for measurement of BPA and DGEBPA in air, based on sampling
of particulates, extraction, and analysis on an HPLC equipped with uv detection. There
is no validated method for biological monitoring.

Limit values

No occupational exposure limits for these substances have been set in the Netherlands,
Germany, UK, Sweden and the USA.

Toxicokinetics

There is no information on the kinetics of both compounds after inhalation exposure.

Absorption of BPA after oral dosing to rats is rapid. Within 3 days approximately
80% is excreted. The same holds for DGEBPA after oral dosing to mice.

Absorption of DGEBPA after dermal application to mice is much slower. After
three days of exposure 41% of the dose is recovered from the skin, 22 - 30% from the
foil covering and 4.1 % from the cage washing. Faecal excretion varies with the dose
and ranges from 10% for a high dose to 36% for a low dose. Urinary excretion is much
less.

The metabolism of BPA has not been studied. In mice the urinary and faecal metabo-
lite profiles of DGEBPA after dermal and oral administration are essentially the same.
The main urinary metabolite is bis-diol-DGEBPA, followed by the sulfate conjugate of
bis-diol-DGEBPA. The main faecal metabolite is the bis-diol-compound oxidized at
one end to a carboxylic acid.

Effects
BPA

BPA is a slight skin irritant, but not a skin sensitizer. It has a low acute toxicity. Sub-
chronic inhalation exposure to 50 mg/m’ and 150 mg/m? which is almost the maximum
attainable concentration in air, induced very slight to slight hyperplasia and chronic in-
flammation in the nasal cavity of rats. The effects were reversible upon cessation of
exposure. The 90-day no-observed-adverse-effect level was 10 mg/nt. Long-term oral

Bisphenol A and its Diglycidylether

</pre>

====================================================================== Einde pagina 14 =================================================================

<br><br>====================================================================== Pagina 15 ======================================================================

<pre>dosing reduces the weight gain, followed by toxicity in liver and kidney. There is no
evidence that BPA is carcinogenic for rats or mice of either sex. BPA has no
mutagenic or genotoxic activity. BPA does not induce reproductive or developmental
toxicity in rats and mice.

In humans BPA induced mild irritation in skin, eyes, nose and throat. Even in se-
lected groups of workers allergic reactions to BPA are only elicited in rare cases.

DGEBPA

DGEBPA is a skin irritant and a strong skin sensitizer. It has low acute toxicity. Ten
weeks of oral dosing of 540 mg/kg per day to male rats reduced the body weight but
did not induce macroscopic changes, organ weights changes or histologic changes in
the reproductive or alimentary tract. DGEBPA was not carcinogenic in male and fe-
male mice after dermal application and sc injections. The substance has some
mutagenic activity, but mainly in in vitro studies. Several in vivo studies and in human
cells in vitro revealed no genotoxicity. DGEBPA did not induce reproductive or devel-
opmental toxicity in rats, rabbits and mice at dosages which induce maternal toxicity
(540 mg/kg per day for rats, 180 mg/kg per day for rabbits). The no-observed-adverse-
effect levels were 180 mg/kg/day for rats and 60 mg/kg/day for rabbits.

DGEBPA is a skin sensitizer for humans. The incidence in occupationally exposed
workers is approximately 4%.

Recommended occupational exposure limits
BPA

The critical effect which was found in an inhalation study with intermittent exposure
with rats was the slight to very slight nasal hyperplasia and inflammation at 50 and 150
mg/m’. This effect was fully reversible within 12 weeks after cessation of exposure.
The NOAEL was 10 mg/m’. To extrapolate from rat to man a safety factor is not con-
sidered necessary because of the absence of systemic effects, and the fact that the mar-
gin of safety between the NOAEL and the LOAEL for local effects is a factor 5. Due
to the low vapour pressure of BPA 10 mg/m can only be present in the air as solid par-
ticles.

DGEBPA

The critical effects were the reduced body weight that was observed in several studies
with oral dosing to male rats and maternal toxicity in pregnant rabbits. The committee

15

Executive summary
</pre>

====================================================================== Einde pagina 15 =================================================================

<br><br>====================================================================== Pagina 16 ======================================================================

<pre>takes the NOAEL of 60 mg/kg/day in rabbits as a starting point for the evaluation. To
extrapolate from rabbit to-man.a-safety factor of 10 is used: The calculated correspond-
ing concentration in air is about 40 mg/m’. Due to the expected low vapour pressure of
DGEBPA this concentration can only be present in air as solid particles.

Both substances are expected to occur only as particulate matter in the occupational
situation. The calculated health-based recommended occupational exposure limits are
equal to (BPA) or exceed (DGEBPA) the Maximum Allowed Condentration for parti-
cle dusts in the Netherlands. DECOS recommends an occupational exposure limit of 5
mg/m? for respirable BPA and DGEBPA and of 10 mg/m for the compounds in in-
halable form, to be averaged over an 8 hour workday (8-h TWA). These limits are
equal to the Maximum Allowed Concentrations for particle dusts in the Netherlands.
In order to prevent sensitization skin contact with DGEBPA should be avoided.

16 Bisphenol A and its Diglycidylether

</pre>

====================================================================== Einde pagina 16 =================================================================

<br><br>====================================================================== Pagina 17 ======================================================================

<pre>Chapter

1

Scope

1.1

Background

In the Netherlands, occupational exposure limits for chemical substances are set using
a three-step procedure. In the first step, a scientific evaluation of the data on the toxic-
ity of the substance is made by the Dutch Expert Committee on Occupational Stan-
dards (DECOS), a committee of the Health Council of the Netherlands, at the request
of the minister of Social Affairs and Employment (annex A). The purpose of the com-
mittee’s evaluation is to set a health-based recommended exposure limit for the atmos-
pheric concentration of the substance. Such an exposure limit cannot be set if
insufficient data is available or if the toxic action of the substance cannot be evaluated
using a threshold model.

In the next phase of the three-step procedure, the Social and Economic Council ad-
vises the minister on the feasibility of using the health-based limit as a regulatory
Maximum Accepted Concentration (MAC) or recommends a different MAC. In the fi-
nal step of the procedure, the Minister of Social Affairs and Employment sets the offi-
cial exposure limit.

1.2

Committee and procedures

The present document contains the assessment of DECOS, hereafter called the com-
mittee, of the health hazard of Bisphenol A and its Diglycidylether. The members of
the committee are listed in annex B. The first draft of this report was prepared by drs

17

Scope

</pre>

====================================================================== Einde pagina 17 =================================================================

<br><br>====================================================================== Pagina 18 ======================================================================

<pre>MA Maclaine Pont, from the Wageningen Agricultural University, by contract with the
Ministry of Social Affairs and Employment.

In 1994/1995 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 C. The committee has taken these comments into account in deciding on the
final version of the report.

1.3 Data
The literature was obtained from data retrieval systems up to December 1995.
18 Bisphenol A and its Diglycidylether

</pre>

====================================================================== Einde pagina 18 =================================================================

<br><br>====================================================================== Pagina 19 ======================================================================

<pre>Chapter

2

Identity, properties, monitoring

2.1

Identity

2.1.1

Structure

Bisphenol A (BPA) consists of white crystals or flakes and has a mild phenolic odour
(Lew92; Win76; NIA92).

2.1.2

Chemical names and synonyms/registry number

The Chemical Abstracts Service registry number (CAS reg. nr.) is 80-05-7. The chemi-
cal substance prime name of BPA used by the Service is
4,4’-(1-methylethylidene)bisphenol, synonyms are listed in annex D.

The pure diglycidylether of bisphenol A (DGEBPA) is a white crystalline solid (De
Jong, personal communication). The typical commercial unmodified resins are viscous
liquids with a viscosity of 11-16 Pas at 25 °C (Kir80). However, older data report that
DGEBPA is a light yellow epoxy resin with a viscosity from 9 to 13 Pa s and an epox-
ide content of ca. 5.1 equivalents/kg (UII75). Furthermore, it is reported that DGEBPA
is a yellowish brown odourless liquid (Ano93).

The CAS reg. nr. is 1675-54-3. The chemical substance prime name of DGEBPA
used by the Service is 2,2’-((1-methylethylidene)bis-
(4,1-phenyleneoxymethylene))bisoxirane, synonyms are listed in annex E.

19

Identity, properties, monitoring

</pre>

====================================================================== Einde pagina 19 =================================================================

<br><br>====================================================================== Pagina 20 ======================================================================

<pre>21.3 _Physicafand:chemicakproperties: (EEC/IPCS; 1991)
Physical and chemical properties of BPA are listed in Table 1 and of DGEBPA in Ta-
ble 2.
DGEBPA is not produced as a pure monomer but as a mixture of monomer, dimer,
trimer and tetramer; therefore very few chemical and physical properties are reported
for the pure substance (IAR89).
2.2 Analytical methods
Environmental monitoring
A method of the National Institute for Occupational Safety and Health (NIOSH) is
available. The method is based on sampling of BPA and DGEBPA as a particulate
from the air on a filter, extraction with acetonitrile and analysis with reversed phase
high performance liquid chromatography (HPLC) and ultraviolet detection at 230 nm.
Table 1 Physical and chemical properties of BPA.
molecular formula CHO,
structural formula CH3
{
t
HO q OH
CH3
molecular weight 228.29
melting point 152-3 °C (Lid92); 153 °C (NIA92); 157 °C (Oom83)
vapour pressure 0.027 kPa at 170 °C (Dor87; BIB89)
flash point 207 °C (NIA92); 227 °C (U1179) [cup?}; 79.4 °C Tag open
cup (Ano67
explosion finely dispersed powder with air is explosive (NIA92)
autoignition temperature 600 °C (NIA92)
density 1.04 g/cm? at 20 °C (U1179)
1.195 (25/25 °C; Ano67)
solubility; in water: at 25 °C: < 100 - 120 mg/100 mg;
in alcohol: at 83 °C: 344 mg/100 g;
in CCL: soluble;
in ether, benzene, acetic slightly soluble;
acid, acetone, methanol: soluble (Ano67; Win76; U1179; Dor87; Lid92; Lew92)
log P,, 2.20 (Dor87); 4.0917 (McC90)
20 Bisphenol A and its Diglycidylether

</pre>

====================================================================== Einde pagina 20 =================================================================

<br><br>====================================================================== Pagina 21 ======================================================================

<pre>Table 2 Physical and chemical properties of DGEBPA.
molecular formula C,,H,,0,
structural formula

. i Hs
O ia)
CH,
molecular weight 340.42
melting point 8-12 °C (Hin81); 43 °C (Kir80)
flash point Epikote 828° > 150 °C (Web93)
density Epikote 828 1160 kg/m’ at 25 °C (Web93)

a A mixture of oligomers, mainly consisting of DGEBPA, with aMW of 350 - 380 (Web93).

The working range is 0.441 - 1.77 mg/m’ BPA and 0.441 - 1.78 mg/m’ DGEBPA based
on a 288 | air sample. Any compound which has the same retention time as either BPA
or DGEBPA, under the operating conditions of this method, may interfere (NIO80).

Oomens and Schuurhuis (Oom83) improved this method. In their method air sam-
ples are concentrated on commercial silica, desorbed with a mixture of methanol and
water (60:40 v/v) and analyzed by HPLC, using UV detection at 275 nm. This method
has been validated for a concentration range of 0.5-50 mg/m’ BPA based on a 10 1 air
sample.

Biological monitoring

No validated method is available. An analytical method for biological monitoring has
been developed by Eadsforth (Ead83), see Chapter 5.5.

21

Identity, properties, monitoring

</pre>

====================================================================== Einde pagina 21 =================================================================

<br><br>====================================================================== Pagina 22 ======================================================================

<pre>22 Bisphenol A and its Diglycidylether

</pre>

====================================================================== Einde pagina 22 =================================================================

<br><br>====================================================================== Pagina 23 ======================================================================

<pre>Chapter

3

Sources

3.1

Natural occurrence

BPA and DGEBPA are not known to occur as natural products.

3.2

Man-made sources

3.2.1

Production

BPA is manufactured by condensation of phenol with acetone under acidic conditions.
In 1978 production of BPA in the United States was approximately 160 000 tons per
year (Kir78). The estimated average annual USA production of BPA for 1980 was 530
million pounds and was projected to increase to meet an estimated annual demand of
770 million pounds (Mor87). In the second half of the seventies in Western Europe the
amount of BPA used in a year is 136 000 tons (U1179). In 1991 the Dutch capacity to
produce BPA was 170 000 tons. Within the EC a quantity of 310 000 tons was pro-
duced in 1989 (ECD93).

DGEBPA is synthesized from BPA and epichlorohydrin. Epoxy resins can be made by
reaction of DGEBPA and BPA (UII75). Epoxy resins usually consist of DGEBPA
(MW 340) (Hol93) and several oligomers of MW 624, 908, 1,192, 1,476 etc. (Tho78).
Low molecular weight resins (average MW <1000) contain up to 95% DGEBPA and
high-molecular weight resins (average MW >1000) contain from traces to 10% DGE-

23

Sources

</pre>

====================================================================== Einde pagina 23 =================================================================

<br><br>====================================================================== Pagina 24 ======================================================================

<pre>BPA (Fre81). Other components, known as hardeners are added to the system to facili-
tate polymerization; Common types of hardeners include amines (diethylenetriamine,
triethylenetetramine and 4,4’-diaminophenylmethane) and acid anhydrides (phthalic
anhydride) (Hol93). When hardened at room temperature 5 - 25% remains unhardend
for months; high temperatures usually give complete hardening (Mor87). Reactive di-
luents may also be added, such as n-butyl glycidyl ether, cresyl glycidyl ether, phenyl
glycidyl ether and Epoxide-8 (Hol93). Epoxy resins are products of considerable com-
mercial significance with a production of 143,000 metric tons (315 million pounds) in
1980 in the USA (Her87).

No European data are available on capacity, production or consumption (EC93).

3.2.2 Uses

The most important application of BPA is the manufacturing of epoxy, polycarbonate
and corrosion resistant unsaturated polyester-styrene resins (U1179; Kir78). BPA is also
used as an antioxidant (U1179), as a fungicide (Win76), and as antimicrobial substance
in cosmetics (Mat83).

In the EC about 50% is used for polycarbonate resins and about 40% for epoxy
resins (ECD93).

About 75 to 90% of the epoxy resins in industrial use are of the diglycidylether
bisphenol-A-type (Tos92).

Approximately 45% of the total production of epoxy resin is used in protective coat-
ings (Her87). Flyvholm (Fly91) mentioned uses of DGEBPA in a broad spectrum of
products. Of 1291 products containing DGEBPA 563 were used as paints and lacquers,
217 as binders, 104 as hardeners, 96 as adhesives, and 94 as fillings. Minor applica-
tions are castings (69), flooring materials (49), printing inks (35), construction material
(31), metal coatings (17), corrosion inhibitors (11), and colouring agents (5). DGEBPA
is widely used in the home environment; unhardened epoxy resin oligomer with a MW
of 340 has been demonstrated in hobby glues, on signboards, capsules of bottles, twist-
off covers, film cassettes, metal packages and brass door knobs (Fre80). Resins, which
still might contain BPA or DGEBPA, have found applications as low pressure mould-
ing mixtures and binding agents for fiber glass products, electrical moulding powders
and decorative or industrial powder coatings. Uncured they are used as plasticizers and
stabilizer for vinyl resins (Hin8 1). Resins are also used in interior coatings of cans and
drums, reinforced pipes, watermain filters, nail polish, food packaging materials
(Mor87) and ski sticks (Suh83).

24 Bisphenol A and its Diglycidylether

</pre>

====================================================================== Einde pagina 24 =================================================================

<br><br>====================================================================== Pagina 25 ======================================================================

<pre>Chapter

4

Exposure

4.1

Environmental levels

4.1.1

Water

The highest concentration of BPA expected in effluent was reported to be 0.08 mg/l by
Shell and no greater than 0.1 mg/l on the average by other companies (Dor87).

DGEBPA is reported to be found in drinking water in the UK, where epoxy resin was
used for lining cast-iron water pipes to inhibit corrosion of existing water distribution
systems. All compounds reported in this study were present at the low micrograms per
litre concentration range or less (Cra84).

Food

Neither compound occurs naturally in food. Nevertheless, migration can occur from
cans or other packaging material, where the compounds are used in coatings.

From cans with preserved food weighing 300 - 450 g 4 - 23 ug BPA/can could be
extracted (Bro95).

Migration of BPA from three different epoxy resins, used as coating material in
wine-butts, to several wine-simulants has been studied (Lar89). The amount of BPA
released from the resins is stimulated by low pH and high alcoholic strength, but never

25

Exposure

</pre>

====================================================================== Einde pagina 25 =================================================================

<br><br>====================================================================== Pagina 26 ======================================================================

<pre>exceeds 97 mg BPA/kg resin. This corresponds with 0.65 mg/l if a wine-butt of 15 hl is
coated with 10'kg'Tesin:

Migration tests have been carried out using cans coated with a commercial heat-cured
lacquer formulation containing less than 0.001 mg DGEBPA per can. Using a food
simulant the detection limit was 0.01 mg/kg, and the half-life of DGEBPA in the food
simulant was less than two days at 40 C. Food containers that were cold-cured con-
tained more monomer residues (DGEBPA) [not quantified], but no DGEBPA was de-
tected in migration tests with the food simulants, using the same test-conditions
(Tic88).

DGEBPA, used in an acrylic/epoxy adhesive, migrates through poly(ethylene tere-
phthalate) film into a food simulating liquid (FSL) and into food under microwave sus-
ceptor cooking conditions. The FSL is a fractionated coconut oil and the food used in
this experiment was a commercial meat-and-vegetable-filled pastry product designed
for microwave susceptor cooking. The average DGEBPA migration values were 1.33
and 8.59 pg/g for food and FSL respectively, corresponding to a migration on a surface
area basis of 1.26 and 5.67 t1g/cm’. This susceptor package does not meet the require-
ments of the United States and European Community regulations (section 4.1). The
company no longer uses the adhesive, containing DGEBPA, in its microwave suscep-
tor packaging anymore (Beg91).

4.1.3

Air (ambient)

No data available.

4.2

Human exposure

4.2.1

General population

No data available.

4.2.2

Occupational population

Most of the human exposure to BPA occurs in industry during the manufacture of res-
ins (Fre8 1).

NIOSH estimated in 1979 that approximately 200,000 individuals were exposed to
BPA during resin manufacturing or formulation (Mor87), and 45,700 and 13,138
workers were potentially exposed to DGEBPA in the USA in 1972-1974 and
1981-1983, respectively (IAR89). During use of a powder spray paint, levels of DGE-

26

Bisphenol A and its Diglycidylether

</pre>

====================================================================== Einde pagina 26 =================================================================

<br><br>====================================================================== Pagina 27 ======================================================================

<pre>BPA ranged from 0.005 to 0.200 mg/m in personal samples and from 0.002 to 0.008
mg/m? in area samples (LAR89).

There were no detectable (detection limit ranges from 0.02 to 0.1 pg/ml) residues
of DGEBPA in urine samples from workers at a plant making epoxy resins, suggesting
minimal exposure, if any, to DGEBPA (Ead83). No data were given on exposure lev-
els.

27

Exposure

</pre>

====================================================================== Einde pagina 27 =================================================================

<br><br>====================================================================== Pagina 28 ======================================================================

<pre>28 Bisphenol A and its Diglycidylether

</pre>

====================================================================== Einde pagina 28 =================================================================

<br><br>====================================================================== Pagina 29 ======================================================================

<pre>Chapter

5

Guidelines and standards

5.1

General population

The USA Food and Drug Administration permits the use of epoxy resins as compo-
nents of coatings that may come into contact with food (IAR89). The current regula-
tions specify the presence of a functional barrier between the adhesive components and
the food (Beg91).

The Tolerable Daily Intake for man of BPA estimated by the EC Scientific Com-
mittee for Food was 0.05 mg/kg bw (BIB89).

The European Community allows up to a maximum of 0.02 ug DGEBPA per gram
food or food simulating liquid (Beg90).

5.2

Working population

5.2.1

Occupational exposure limits

No exposure limits have been set for BPA and DGEBPA in The Netherlands, Ger-
many, UK, Sweden and the USA.

In 1962 5 mg/m’ was recommended by Russian sources as the maximum allowable
concentration in air for manufacturing installations. In 1964 it was again recommended
(Ano67).

29

Guidelines and standards

</pre>

====================================================================== Einde pagina 29 =================================================================

<br><br>====================================================================== Pagina 30 ======================================================================

<pre>The Federal Government of the USA limited worker exposure to BPA to a ceiling
concentration’of 2.8 mg/m? of airin 1974 (cited in Geo85). The Dow Chemical Com-
pany is using an industrial hygiene guideline of 5 mg/m’ 8 h time-weighted average
(TWA) for BPA (respirable or inhalable?) (Oom83).

In Denmark, Norway, and Finland DGEBPA must be labeled with risk phrase R43:
may cause sensitization by skin contact (Fly91).

5.2.2

Biological exposure indices

No exposure limits have been set for BPA and DGEBPA.

5.3

Previous evaluation by national and international bodies

The International Agency for Research on Cancer (IARC) reviewed available data with
emphasis on carcinogenicity and mutagenicity. It concluded that there is limited evi-
dence for the carcinogenicity of DGEBPA in experimental animals, but that DGEBPA
is not classifiable as to its carcinogenicity to humans (group 3) (IAR89).

30

Bisphenol A and its Diglycidylether

</pre>

====================================================================== Einde pagina 30 =================================================================

<br><br>====================================================================== Pagina 31 ======================================================================

<pre>Chapter

6

Kinetics

6.1

Absorption

The metabolism of BPA was studied (Kna66). Groups of four male rats (Carworth
Farms, Elias Stock) were dosed once orally with a mixture of 120 mg of labeled and
non-labeled BPA. The daily urine and faecal samples were pooled and collected for a
period of eight days, whereupon the animals were sacrificed. Over the eight-day period
28% of the °C was excreted in the urine and 56% in the faeces (Figure 1). No “C
could be detected in exhaled CO,, and at the end of eight days no “°C residues could be
detected in the carcass. A crude estimate of the elimination half life time in rats is a lit-
tle bit more than 1 day.

The authors tried to identify metabolites, but their methods of analysis had prob-
lems: the glucuronide was found to be extremely resistent to acid hydrolysis, the mam-
malian 8-glucuronidase preparations varied in their activity and the products extracted
from faeces could not be analyzed under the GLC conditions used. Moreover, a possi-
ble hydroxylated metabolite was found, but the only attempt to confirm the structure
was by means of acetylation of the product, followed by comparison with BPA-
diacetate. Both compounds had the same retention time upon GLC analysis, indicating
that the compounds were probably identical. Based upon the weaknesses in the analyti-
cal procedure, it is concluded that the only valid data in this study are the radioactivity
profiles as presented in the first paragraph (Kna66).

31

Kinetics
</pre>

====================================================================== Einde pagina 31 =================================================================

<br><br>====================================================================== Pagina 32 ======================================================================

<pre>100;-

Oe Oee 00

Cumulative % of Dose Excreted

le) t 2 3 4 5 6 7 8
Time After Adminisiration (Days*

Figure ] Urinary and faecal excretion of “C-BPA metabolites by the rat after a single oral dose. square: %
in urine and faeces; open circles: % in faeces; closed circles: % in urine (Kna66).

When '*C-DGEBPA was given orally to six male CF1 mice (approximately 55 mg/kg
body weight), it was rapidly excreted, 80% of the administered MC was eliminated in
the faeces and 11% in the urine 0-3 days after a single oral dose (Cli8 1a).

When 1.6 mg '*C-DGEBPA/mouse was dermally applied to six male CF] mice
(approximately 56 mg/kg body weight), followed by occlusive exposure for 1, 3 or 8
days, 20% of the dose was eliminated in faeces and 3% in urine, as a mixture of me-
tabolites, over a period of three days. After three days of exposure 41% of the dose
was recovered from the skin, 22 - 30% from the foil covering and 4.1% from the cage
washing. After 8 days of exposure 36% of the dose was excreted via the faeces, 5.4%
via the urine, 11% remained on the skin. The quantity recovered from the foil re-
mained approximately constant throughout the experiment (Cli8 1a).

Radioactivity of topically applied centrally labeled DGEBPA was found in faeces
and urine of C57BL6 mice [sex unknown], whereas DGEBPA labeled in the side-chain
was excreted via faeces, urine and CO, (Table 3). After evaporation of the solvent the
application site was occluded (Ben89).

Conclusion
No information on absorption after inhalation exposure was found.

Absorption of BPA after oral dosing to rats is rapid. Within three days + 80% is
excreted.

32 Bisphenol A and its Diglycidylether

</pre>

====================================================================== Einde pagina 32 =================================================================

<br><br>====================================================================== Pagina 33 ======================================================================

<pre>Table 3 Excretion of radioactivity 48 h after occlusive dermal application of 14C-DGEBPA to C57BL6
mice (Ben89).

DGEBPA F DGEBPAIP percent of dose n
mg/mouse mg/mouse faeces urine CO, application site

0.4 - 35.3+15.3 87426 0.5 + 0.3 154+ 8.8 5
2 - 10.6 + 1.1 2.9 + 0.1 0.2 + 0.02 27.6 + 10 2
- 0.4 36.3 + 5.2 57219 - 99+ 27 5
- 13 16.3 + 0.2 6423.7 - 17.5+ 1.0 2

DGEBPA lis side chain labelled.
» DGEBPA II is centrally labelled.

Absorption of DGEBPA after oral dosing to mice is also rapid. Within three days +
80% is excreted.

Excretion of DGEBPA after occlusive dermal application to mice depends on the
dose and the time period. After 2 days of exposure to 0.4 mg/mouse faecal excretion
amounted to 35 - 36% of the dose, whereas a quantity of 2 mg/mouse was excreted for
+10%. Three days after exposure to 1.6 mg/mouse the total faecal excretion amounted
to +20%. Urinary excretion is much less.

6.2

Distribution

The distribution of the radioactivity of “C-DGEBPA was investigated (Cli81a). The
radioactivity in the tissues of six male CF1 mice after dermal application of
“C-DGEBPA (approximately 56 mg/kg body weight) one, three and eight days after
dosing is shown in Table 4. The mean total recovery was 94.8%. When'*C-DGEBPA
was dosed orally to six male CF1 mice (approximately 55 mg/kg) the tissue radioactiv-
ity rapidly depleted from all the tissues studied during the course of the eight day ex-
periment (Table 5). The mean total recovery was 92.6% (we calculated 92.7%).

There are route-dependent differences in plasma '*C concentration-time profiles,
tissue/plasma “C ratios and urinary excretion following intravenous or oral administra-
tion of “C-DGEBPA to rats. The “C-DGEBPA was labeled at the isopropylidine
methylene carbon. The plasma radioactivity that resulted from the oral administration
of “C-DGEBPA was eliminated more rapidly than the radioactivity resulting from in-
travenous administration (study from 1981, reported by Gar92).

Conclusion
No data on distribution are available after inhalation exposure. In mice the distribution

of DGEBPA after dermal and oral administration is essentially the same. Concentra-
tions of less than 1% are found in all organs, in blood and in the remaining carcass. Af-

33

Kinetics

</pre>

====================================================================== Einde pagina 33 =================================================================

<br><br>====================================================================== Pagina 34 ======================================================================

<pre>Table 4 Total recovery of radioactivity from male CF1 mice after dermal application of 14C-DGEBPA.
Results are expressed as percentage of‘administered radioactivity (Cli81a).

day (mouse nr.) 1 0) 1 (5) 3 (2) 3 (3) 8 (4) 8 (6)
urine 0.9 0.43 3.80 3.02 4.37 5.59
faeces 3.4 2.37 17.9 12.2 40.9 40.9
skin in toto 65.2 68.9 36.9 44.5 9.4 15.4
intestine 2.60 1.70 1.81 4.82 0.23 0.87
liver 0.2 0.23 0.3 0.51 0.05 0.06
kidney 0.03 0.04 0.04 0.07 <0.01 <0.01
blood 0.05 0.07 0.05 0.17 <0.01 0.02
remaining carcass 0.26 0.49 0.34 0.94 0.09 0.15
cage washing 2.2 0.6 4.11 4.42 3.3 5.8
foil covering 22.6 24.1 30.3 21.8 32.5 25.5
total 97.4 98.9 95.5 92.4 90.8 94

ter oral dosing the compound is mainly eliminated via the faeces. Eight days after
dermal application a quantity of 9 - 15% remained on the total skin and 26 - 36% was
found on the foil covering.

6.3 Biotransformation
Climie et al (Cli81a) showed that the urinary and faecal metabolite profiles derived
from dermal application and oral dosage of DGEBPA were essentially similar. In a fur-
ther study (Cli8 1b) the metabolic products of DGEBPA and their routes of formation
are described, as they are found in male CF1 or CD1 mice.

One day after a single oral dose of + 715 mg/kg approximately 0.1% of the dose
was excreted via urine unchanged. At lower doses DGEBPA could not be detected.
The main metabolite excreted in the urine was bis-diol-DGEBPA (4% of the dose), fol-
Table 5 Total recovery of radioactivity from male CF1 mice after oral dosage of 14C-DGEBPA. Results
are expressed as percentage of administered radioactivity (Cli81a).
day (mouse nr.) 1(1) 1 (2) 3 (5) 3 (6) 8 (3) 8 (4)
urine 8.8 12 13.5 9.32 9.46 9.93
faeces 80.4 53.7 67.7 81.2 82.2 78.9

skin in toto 0.2 0.36 0.12 0.11 0.07 0.06
intestine 2.7 28.3 0.14 0.19 0.01 0.01
liver 0.25 0.66 0.06 0.04 0.01 0.01
kidney 0.01 0.05 0.01 0.01 «0.01 «0.01
blood 0.02 0.15 0.01 0.01 0.01 0.02
remaining carcass 0.28 0.75 0.03 0.06 0.02 0.01
cage washing 0.77 0.99 3.06 2.76 3.4 3.49
total 93.4 97 84.6 93.7 95.2 92.4

34 Bisphenol A and its Diglycidylether

</pre>

====================================================================== Einde pagina 34 =================================================================

<br><br>====================================================================== Pagina 35 ======================================================================

<pre>lowed by the sulphate conjugate of bis-diol-DGEBPA (2% of the dose). One percent of
the administered dose was excreted in the urine as phenol-diol-DGEBPA, and 1% as
the glucuronide conjugate of phenol-diol-DGEBPA. No BPA could be detected.

In the faecal fraction a quantity of «0.1% of the dose chromatographed to the same
R, position as BPA. However, since this fraction was present in such small quantities
no further work was performed. The presence of unchanged DGEBPA is not men-
tioned. Bis-diol-DGEBPA oxidized at one side to a carboxylic acid (compound Villa
in Figure 2) was the main metabolite, it comprised 24% of the dose. The compound is
also excreted as its glucuronide conjugate, comprising 3% of the dose. A further decar-
boxylation product (compound Vla) accounted for 14% of the dose. Its glucuronide
conjugate was found in the faeces in a concentration of 1% of the dose. Other major
compounds excreted in the faeces are compound Va (5%) and Vila (4%). Phenol-diol-
DGEBPA (3%) and bis-diol-DGEBPA (2%) are also excreted in the faeces.

A summary of the known and possible metabolic routes is given in figure 2. It can
be concluded that the major metabolic transformation of orally ingested '*C-DGEBPA
is by hydrolytic ring-opening of the two epoxide rings to form diols. This metabolite
(bis-diol-DGEBPA) is excreted in both free and conjugated forms and is further me-
tabolized to various carboxylic acids, including two containing a methylsulphonyl moi-
ety. The product of oxidative dealkylation either of DGEBPA (with concomitant
formation of glycidaldehyde) or bis-diol-DGEBPA (with concomitant formation of
glyceraldehyde) is excreted in both free and conjugated forms representing 5% of the
dose.

In order to confirm that bis-diol-DGEBPA is a substrate for oxidative dealkylating
enzymes it was fed to two mice. After a single oral dose of bis-diol-DGEBPA the total
amount excreted was 9% of the dose via the urine (after one day) and 81% of the dose
via faeces (after two days). The compound was excreted unchanged (5% of the dose in
the urine and 5% in the faeces) or as a sulphate conjugate (2.5% of the dose in the
urine). Another metabolite was also excreted: phenol-diol-DGEBPA (2% of the dose
in the urine and 0.6% in the faeces) or as a glucuronide (0.4% of the dose via the
urine). These two compounds were also excreted after administration of DGEBPA, in
approximately the same amounts, indicating that the metabolic route of DGEBPA is
via the bis-diol metabolite. In both excreta no BPA was detected.

Since epoxide ring opening is such an important metabolic pathway, the total he-
patic DGEBPA epoxide hydratases of rat, mouse and rabbit were compared and found
to be present in the ratio 1:2:3 (Cli81b). Data on human hepatic epoxide hydratases are
not available.

A further dose-excretion study of DGEBPA has been carried out with rabbits, which
have excretion characteristics more similar to those of man. The total amount of bis-

35

Kinetics

</pre>

====================================================================== Einde pagina 35 =================================================================

<br><br>====================================================================== Pagina 36 ======================================================================

<pre>° o
ZN ZN
CH; CH CHJ- O-R—O-—CH, —CH—CH, "en,

1 EN
En "OO
MA ZN s
H=—C--CH—CH, >

[6 OH OH N A
ZN : ' 1 NN N A xa N
CH;— CH~ CH O- R—- OCH CH CH, voce 0 M
M N
XI NN \
gk 9H ot oH Sous \
u: 4% excrete 1 excreted u: 1%
< —CH- CH O—-R-O- —CH— > —— CH- CH= O- R—- we >
1: 24 CHz CH-CH;— O-R-O-CH;—CH- CH, > CHz;— CH CH;— O— R-OH AT 1. 3%
/ m
1
1
A axcreted sulphate N Y
ui 2% conjugate ‘ qr OH on î
° '
‚CH; CH— CH O—R—O-CHz— CH—C~OH glucuronide excreted 1%
i ru:
A N conju gat
éxcreted M Villa MA jugate
1: 3e ' ‘ NA
conjugate ' 1 ~
N A A AN ki
excreted A ' 2
re N ' AN / <
{: 24% « N ‘ pas N 1 KI
4 i Pild DEN ‘ ad
OH OH ’ o Dad MN o OH ' OH O ks)
1 | ti a ll | tou excreted 4
CHz;= CH-CHJ-O-R-O-CHJ-C-OH 7 HC 8 CHg CH= CHz~ O-R O— GHz GH = C OH ee |: 4% ra
Vla Tes o Vila, A
excreted N Ss ; 2
NN - 1 5
1: 1% + excrated glucuronide DN ‘ s
* conjugate CH kN fe) OH Y o «a
1: 14% i? Il | fi <
R = Á Nil HCT S= CHy~ CH CHy~ ORO — CH C—OH ceed „ 1.5% =
(e)
CH, (9) Va 5
u = urinary elimination a
f = faecal elimination 2
{ss}

ry of known and possible metabolic roues to the urinary and faecal metabolites of DGEBPA orally dosed to mice [XI] was isolated in vitro

Figure 2 Summa
| DGEBPA, III bis-diol-DGEBPA; VI phenol-diol-DGEBPA; XII glyceraldehyde; XIII glycidaldehyde

but hot in vivo. —=known routes; ----- possible routes;
(Cli8 Tb).

36

</pre>

====================================================================== Einde pagina 36 =================================================================

<br><br>====================================================================== Pagina 37 ======================================================================

<pre>diol-DGEBPA excreted in the three day period after dosing was on average 10% (2%
free) and 2% (0.4% free) of the administered dose for rabbits given 5 mg/kg and 50
mg/kg DGEBPA, respectively (Ead83).

Climie et al (Cli81b) could find no indication that glycidaldehyde was produced in an
in vitro system. Bentley et al (Ben89) demonstrated formation of a glycidaldehyde
DNA adduct after dermal application of 0.8 and 2 mg DGEBPA per C3H mouse. Ste-
iner et al (Ste92) showed that this was a glycidaldehyde-deoxyguanosine adduct.
Forming of an adduct indicates that DGEBPA may be directly dealkylated by the skin
in vivo. At a lower dose (0.4 mg/mouse) no adduct was seen. These results can be ex-
plained by the presence of two competing reactions. At lower doses the epoxide hy-
dratase can effectively inactivate DGEBPA before dealkylation occurs and no
glycidaldehyde is formed, or in such small amounts that they are inactivated before
they interact with the DNA. As the concentration of DGEBPA in the skin increases the
inactivation via hydration becomes saturated and some epoxide is dealkylated before
hydration occurs. Glycidaldehyde is then produced in increasing amounts and may in-
teract with DNA to produce the adduct. More information about adduct-forming be-
tween DNA and glycidaldehyde is given in section 7.1.5.

Conclusion

No information on biotransformation is available after inhalation exposure. In mice the
urinary and faecal metabolite profiles of DGEBPA after dermal and oral administra-
tion are essentially the same. The main urinary metabolite is bis-diol-DGEBPA, fol-
lowed by the sulphate conjugate of bis-diol-DGEBPA. The main faecal metabolite is
the bis-diol compound oxidized at one side to a carboxylic acid.

6.4 Elimination
See previous paragraphs.

6.5 Biological monitoring
The free and conjugated forms of bis-diol-DGEBPA are determined by HPLC with
UV-detection after solvent extraction from hydrolysed urine and extraction column
clean-up. The limit of detection ranges from 0.02 to 0.1 g/ml, with an overall recov-
ery of the metabolite through the analytical procedure of 71%. Data on relationship be-
tween exposure and excretion in human beings are not available (Ead83).

37 Kinetics

</pre>

====================================================================== Einde pagina 37 =================================================================

<br><br>====================================================================== Pagina 38 ======================================================================

<pre>A group of 13 workers producing glass fibre reinforced resin pipes collected
24-hour urine samples over the five-day work week and a single spot sample voided af-
ter the commencement of the first shift after the weekend. The amount of bis-diol ex-
creted was very low (< 0.01 - 0.17 mg) and in the majority of samples below the
analytical limit of detection, which was not given. No cumulative excretion of the bis-
diol over the working week could be found. The conclusion was that absorption of
DGEBPA was very low, but there were no data on the concentration of DGEBPA in
the air (study from 1984, reported by Web93).

6.6

Summary

There is no information on the kinetics of both compounds after inhalation exposure.

Absorption of BPA after oral dosing to rats is rapid. Within three days + 80% is
excreted. The same holds for DGEBPA after oral dosing to mice.

Excretion of DGEBPA after occlusive dermal application to mice depends on the
dose and the time period. After 2 days of exposure to 0.4 mg/mouse faecal excretion
amounted to 35 - 36% of the dose, whereas a quantity of 2 mg/mouse was excreted for
+10%. Three days after exposure to 1.6 mg/mouse the total faecal excretion amounted
to +20%. Urinary excretion is much less.

In mice the distribution of DGEBPA after dermal and oral administration is essen-
tially the same. Concentrations of less than 1% are found in all organs, in blood and in
the remaining carcass. After oral dosing the compound is mainly found in the faeces.
Eight days after dermal application a quantity of 9 - 15% remained on the whole skin
and 26 - 36% was found on the foil covering.

In mice the urinary and faecal metabolite profiles of DGEBPA after dermal and
oral administration are essentially the same. The main urinary metabolite is bis-diol-
DGEBPA, followed by the sulphate conjugate of bis-diol-DGEBPA. The main faecal
metabolite is the bis-diol compound oxidized at one side to a carboxylic acid.

No biological monitoring method can be indicated for BPA. Biological monitoring
of DGEBPA is preferably performed on the urinary metabolite bis-diol-DGEBPA and
its sulphate conjugate. The limit of detection ranges from 0.02 to 0.1 pg/ml.

38

Bisphenol A and its Diglycidylether

</pre>

====================================================================== Einde pagina 38 =================================================================

<br><br>====================================================================== Pagina 39 ======================================================================

<pre>Chapter

7

Effects

7.1

Animal experiments

7.1.1

Irritation and sensitization
Irritation

BPA is a slight skin irritant. Mild irritation effects were caused by 250 mg BPA openly
applied to the skin of rabbits. Possible severe eye irritations were caused by exposure
to 20 mg BPA for 24 h in rabbits, but the original data cannot be evaluated (Lew92).

After 24-h occlusive exposure to 5% (w/v) BPA in acetone, no irritation was seen
on the skin of guinea pigs (Tho77).

Several unpublished studies on skin irritation are reviewed (Web90). Five studies
used rabbits, two use guinea pigs. It is concluded that BPA is slightly irritating to rab-
bit skin following prolonged and repeated application. Slight to moderate irritation has
been observed in guinea pigs.

Three unpublished studies deal with eye irritation (Web90). Two studies use rab-
bits, in the third study the species in unspecified. It is concluded that BPA may be se-
verely irritating to the rabbit eye at concentrations in excess of 1% in certain solvents.
The dry powder was slightly irritant while a 10% aqueous suspension was essentially
non-irritating.

No topical irritancy was produced by 80% [probably 80% (w/v) in acetone] DGE-
BPA (Tho78).

39

Effects

</pre>

====================================================================== Einde pagina 39 =================================================================

<br><br>====================================================================== Pagina 40 ======================================================================

<pre>On the other hand, it is reported that DGEBPA is a skin irritant. The skin of rabbits
was mildly irritated by 500 mg openly applied DGEBPA.

The only study which reports severe eye irritation is cited by Lewis (Lew92): ex-
posure to 2 mg DGEBPA for 24 h in rabbits caused severe eye irritation. However, the
original study is not available, and therefore, cannot be evaluated. On the other hand it
is reported (Web93) that DGEBPA and all the Epikote grades tested, irrespective of
molecular weight, whether undiluted or formulated in solvent, are non- or at most
slightly irritant to the eyes. Also Gardiner et al (Gar92) report that DGEBPA-based
resins cause only minimal eye irritation.

The incidence of cutaneous irritation caused by DGEBPA (10% (w/v) in acetone,
twice weekly) at the site of application during a two-year carcinogenicity study with
CF1 mice was assessed macroscopically. In the control group exposure to acetone in-
duced irritant lesions in 16% of males and 14% of females. A higher incidence of irri-
tant lesions, characterized mainly by epilation and skin flaking/scabbing, but inducing
ulceration in a few animals, was recorded in the mice of the exposure groups. Forty-
two percent, 32%, and 42% of the males and 21%, 21%, and 27% of the females
showed signs of skin irritation after exposure to EPON 828, Epikote 828, and pure
DGEBPA, respectively. Each group consisted of 50 animals of both sexes (Per88).

After 20 exposure periods of one hour or of seven hours no erythema or oedema
was reported. Since this was tested in a Draize test the species was probably the rabbit.
Two types of Epikote 828 scored in the Draize test as follows (EEC/OECD score): for
erythema after 24 and 72 hr: 1.1 and 1.3; for oedema after 24 and 72 hr: 0.5 and 0.95;
for erythema after seven days: 0.9 and 0.6; for oedema after seven days: 0.4 and 0.5,
respectively. The primary irritation indexes were 1.8 and 2.15, respectively. A 20% so-
lution of EPON 828 in toluene was slightly more irritating whereas a 20% solution of
EPON 828 in acetone was almost non-irritating (studies from 1978, reported by
Web93).

Sensitization

When BPA was applied as a solution in a mixture of acetone, dioxane and guinea pig
fat on guinea pig skin no reactions were observed in any of the test animals (unpub-
lished results, reported by Web90).

Thorgeirsson and Fregert (Tho77) investigated the sensitizing capacity of DGEBPA-
based epoxy resins, using the guinea pig maximization test of Magnusson and Klig-
man. Twenty albino female guinea pigs of the Hartley strain were exposed to epoxy
resins, whereas 15 animals were exposed to BPA or epichlorohydrin. Twenty or 15

40

Bisphenol A and its Diglycidylether

</pre>

====================================================================== Einde pagina 40 =================================================================

<br><br>====================================================================== Pagina 41 ======================================================================

<pre>animals, respectively, served as controls. The induction was performed with: 0.1 ml
Freund’s adjuvant, 0.1 ml of the test substance (5.0% (w/v) DGEBPA in acetone, 5%
(w/v) epoxy resin (average MW 350) in acetone, 5% (w/v) BPA in acetone, or 5 %
(w/v) epichlorohydrin in ethanol), and 0.1 ml of a mixture containing the substance in
the vehicle and an equal amount of complete Freund’s adjuvant. Challenge was per-
formed two weeks after the second stage of the induction as a 24-hour occluded patch
test. The concentrations were a fifth of those used for induction. Simultaneously, a
cross-sensitization test was performed by applying the other test substances on the ani-
mals as patch tests. All the 20 animals exposed to DGEBPA and to epoxy resin with an
average MW of 350 became sensitized. BPA gave no reaction in the 15 animals ex-
posed, and epichlorohydrin sensitized nine of 15 animals. The control animals showed
no reactions. No cross-reactions were observed between BPA, DGEBPA-based epoxy
resins, and epichlorohydrin (Tho77).

In the same study (Tho77), guinea pig maximization tests were conducted with ep-
oxy resins with a higher average MW. Of 20 animals, 17 reacted to the resin having an
average MW of 480, 11 to that of 900, and six to the epoxy resin with an average MW
of 1280. Gel permeation chromatography showed that epoxy resins with an average
MW of 900 and 1280 contain 10% DGEBPA, and epoxy resin with an average MW of
1850 contains 5% DGEBPA, which is probably the cause of positive reactions in this
test (Tho78).

In a further study (Tho78) to investigate the sensitization capacity of epoxy resin
oligomers in the guinea pig, three sensitization techniques were used: the guinea pig
maximization test, topical exposure with and without sodium lauryl sulphate, and sin-
gle intradermal injection.

The guinea pig maximization test was performed as described before. Sixty-one
animals were sensitized with 5% (w/v) DGEBPA in acetone. One additional series of
ten animals were sensitized with 0.5% (w/v) DGEBPA. DGEBPA-based epoxy resins
of a higher MW were tested in equimolar concentrations: 28 animals were sensitized
with 9.2% (w/v) MW 624 oligomer, 30 animals with 13.5% (w/v) MW 908 oligomer,
and 15 animals were sensitized with 17.5% (w/v) MW 1,192 oligomer. DGEBPA pro-
duced positive reactions in 56 of 61 animals (92%) sensitized to 5% (w/v) DGEBPA,
and in ten of 15 animals (67%) sensitized to 0.5% DGEBPA. The oligomer of MW
624 elicited a reaction in 57% (16/28) of the animals, while after induction and chal-
lenge with MW 908 and 1,192 oligomer, the animals showed no positive patch test. In
all animals which received the induction and challenge with DGEBPA, no cross-
reactions to oligomers with a higher MW were observed. Of the animals treated with
the MW 624 oligomer, 29% showed cross-reactions to DGEBPA, but not to the other
oligomers. Animals induced and challenged with oligomers with a higher MW showed
no cross-reactions to DGEBPA.

41

Effects
</pre>

====================================================================== Einde pagina 41 =================================================================

<br><br>====================================================================== Pagina 42 ======================================================================

<pre>Induction and challenge by topical exposure was performed in ten animals. A two
by four cm Whatman 3 MM paper was saturated with approximately 0.2'ml of a 20%
(w/v) solution of DGEBPA, and applied as a 24-hour closed patch test on a clipped
and shaved flank. This procedure was repeated after three days. After two weeks, a
patch test was performed on the opposite flank. In another series of 17 animals the
clipped and shaved flank was rubbed with 10% sodium lauryl sulphate in vaseline, and
a Whatman 3 MM paper was left under occlusion for 48 hours. After two weeks the
animals were challenged. Topical sensitization without sodium lauryl sulphate pro-
duced no reactions, and with sodium lauryl sulphate 18% (3/17) reacted positive.
When the same sensitization procedure was repeated in the same animals 47% (8/17)
reacted. These results are inconsistent with those of other investigators; it is unclear
whether differences in test material may account for these different observations
(Gar92).

Fifteen animals received induction with 0.1 ml of a 20% (w/v) mixture of DGE-
BPA dissolved in acetone and an equal amount of complete Freund’s adjuvant, in-
jected intradermally in the shoulder region. After two weeks, when the animals were
challenged as in the maximization test, 30% (3/10) of the animals responded (Tho78).

Several other studies performed with DGEBPA, EPON 828 and Epikote 828, also re-
veal the skin sensitizing properties of the compound (seven studies performed in
1963-1986, reported by Web93).

Photosensitization

Age-matched female mice were photosensitized to BPA by the application to a clipped
site on the rear flank, followed by radiation of the site with UV-B and UV-A. The im-
munological adjuvantia used were cyclophosphamide, or heat-killed Corynebacterium
parvum (Propionbacterium acnes). Five or more days after their first exposure the
mice were photochallenged by applying 0.01 ml BPA-solution to the left ear, followed
by UV-A to both ears. After this the right ear was challenged with 0.01 mi BPA-
solution without further UV-A. Measurements of ear thickness of both ears were taken
at 24 h and 48 h post-challenge.

In a typical experiment a group of six female ICR mice were photosensitized to 1%
BPA; C. parvum was used as adjuvant. Lack of ear swelling in the toxicity group dem-
onstrates the absence of phototoxicity of BPA under the conditions of the photochal-
lenge. The lack of reactivity of the chemical applied to the right ear after UV-A in the
group of photosensitized mice, demonstrates the absence of classical allergic contact
dermatitis. The left ears were excised from several mice of each group after the 24
hour measurement. In the control group histopathology showed no inflammation. In

Bisphenol A and its Diglycidylether

</pre>

====================================================================== Einde pagina 42 =================================================================

<br><br>====================================================================== Pagina 43 ======================================================================

<pre>contrast, mice of the experimental group showed oedema, and a mononuclear cellular
infiltrate.

In a rechallenge experiment UV-A radiation of previously positive challenge sites
caused these old photoallergy test sites to flare, evidenced by increased ear thickness.
Ears previously challenged by UV-A followed by BPA did not become thickened fol-
lowing UV-A alone challenge.

In four experiments, the author failed to induce any photosensitization of the
guinea pig to BPA, although the maximization methods used were successful with
other photosensitizers (Mag88).

Cyclophosphamide pretreated female BALB/c mice were induced to BPA by topi-
cal treatment of the dorsal skin surface on three consecutive days, and challenged on
the ears five days after the last induction. For each induction and challenge treatment
mice were irradiated with UV-A and UV-B radiation, 30 min. to one hour after test
material application. A 20% solution (w/v) BPA was applied during induction, and
10% (w/v) during the challenge. There were contact allergy, vehicle/radiation, and
phototoxicity control groups. Swelling of the ears was measured 24 h after the chal-
lenge. A statistically significant difference (p0.001) in ear swelling was found, when
photoallergic reactions were compared to control allergy, vehicle/radiation, and photo-
toxicity control groups (Ger90).

The photoallergic capacity of BPA might be explained by the release of free radi-
cals, during the UV-B-range photodecomposition of BPA (Pel86). Maguire (Mag88)
suggested that these radicals may react covalently with nearby macromolecules to form
the antigen that is responsible for photoallergy to BPA.

Conclusion
BPA is a slight skin irritant. DGEBPA is a skin irritant. It is not or is at most a slight

eye irritant. BPA is not a skin sensitizer in guinea pigs. DGEBPA is a strong skin sen-
sitizer. BPA is a photosensitizer in mice, but not in guinea pigs.

7.1.2 Acute toxicity

A summary of acute toxicity data of BPA is given in Table 6 and of DGEBPA in Table
7. The acute toxicity is low for both compounds via the oral and dermal routes of expo-
sure. Signs of intoxication of oral BPA administration include initial excitability, fol-
lowed by depression, ataxia, occasional spasms and hind limb paresis. Others report
atonia, severe diarrhea and diuresis (Web90).

Signs of intoxication after ip injection of BPA include vasiculation, tremors, pros-
tration, loss of consciousness and roughening of the coat (Web90).

43 Effects

</pre>

====================================================================== Einde pagina 43 =================================================================

<br><br>====================================================================== Pagina 44 ======================================================================

<pre>Signs of intoxication of DGEBPA include depression, weight loss and slight difficulty
in breathing (Web93). After dermal application of DGEBPA skin irritation has been
observed (Web93).

Conclusion

According to the EC classification (EC93) BPA and DGEBPA are of a low order of
acute toxicity upon oral and dermal administration. Due to the low vapour pressure of
BPA and DGEBPA, and the lack of data, their inhalation toxicity cannot be assessed.

7.1.3

Short-term toxicity
BPA, sc implant, mice

Groups of eight CD-1 mice of each sex were continuously exposed to BPA via subcu-
taneous Silastic implants, containing 0, 6.25, 12.5, 25, 50, or 100 mg BPA suspended
in corn oil for a period of two weeks. No treatment-related deaths or changes in body
weight gain were observed, but a no statistically significant increase in female repro-
ductive tract weight was seen. Therefore, dose levels of 0, 25, 50, and 100 mg BPA
were selected for reproduction and fertility assessment by continuous breeding (section
7.1.6) (Ree84).

BPA, oral administration, mice

Eight male and eight female CD-1 mice per dose group were given 0, 0.31, 0.62, 1.25,
2.5, or 5% BPA in their feed for 14 days, equivalent to approximately 310, 620, 1250,
2500 or 5000 mg/kg body weight. No clinical signs of toxicity were observed in either
male or female mice in the 0, 0.31, 0.62, and 1.25% BPA dose groups. In the 2.5%
BPA-treated group, both male and female mice exhibited clinical signs of toxicity, in-
cluding dehydration, dyspnoea, lethargy, tremors, and ptosis. In the 5.0% BPA dose
group dehydration, dyspnoea, lethargy, piloerection, diarrhea, ptosis, and moribundity
were observed in both male and female mice. During the 14-day exposure six males
and six females in the 5.0% BPA group died, but no deaths occurred in the other dose
groups. For those animals that survived, the percent combined weight gain was signifi-
cantly depressed (p < 0.01) in the 1.25, 2.5, and 5.0% BPA groups relative to the con-
trols. Based on these results, dietary levels of 0, 0.25, 0.5, and 1.0% BPA were
selected for reproduction and fertility assessment by continuous breeding (section
7.1.6) (Ree85).

44

Bisphenol A and its Diglycidylether

</pre>

====================================================================== Einde pagina 44 =================================================================

<br><br>====================================================================== Pagina 45 ======================================================================

<pre>Table 6 Acute toxicity data of BPA.

species route of entry dose or concentration acute effect reference
rat oral 3250 mg/kg (agar) LD, Lew92
rat oral 5660 mg/kg (DMSO) LD,, Web90
rat oral 4240 mg/kg LD,, Mor87
rat oral > 12,000 mg/kg LD, Web90
rat oral 6500 mg/kg LD, Web90
rat oral + 3200 mg/kg LD,, Web90
Sherman rat oral 4040 mg/kg LD Web90
Fischer 344 rat, male oral 4100 mg/kg LD. NTP82
Fischer 344 rat, female oral 3300 mg/kg LD, NTP82
rat inhalatory 1898 mg/m?* LC, Lew92
rat inhalatory > 170 mg/m? LC, Web90
rat intraperitoneal 400 - 800 mg/kg LD, Web90
mouse oral + 1600 mg/kg LD,, Web90
mouse oral 2400 mg/kg LD, Web90
mouse oral 2500 mg/kg LD, Lew92
B6C3F, mouse, male oral 5200 mg/kg LD, NTP82
B6C3F, mouse, female oral 4100 mg/kg LD, NTP82
mouse intraperitoneal 150 mg/kg LD,, Lew92
mouse intraperitoneal + 200 mg/kg LD,, Web90
rabbit oral 2230 mg/kg LD, Lew92
rabbit oral 4000 mg/kg LD, Web90
rabbit dermal 3000 mg/kg LD, Lew92
rabbit dermal 3600 mg/kg LD, BIB89
rabbit dermal 6400 mg/kg (40% in 1/5 died Web90

DMSO)

2000 mg/kg (10% in pro- 3/15 died

pylene glycol)
guinea pig oral 4000 mg/kg LD. Web90
mammal oral 6500 mg/kg LD,, RTE92

* Number of hours of exposure not reported.

In a preliminary study to establish a MTD for the chronic study, ten male and female
B6C3F, mice were fed with 0, 5000, 10,000, 15,000, 20,000, or 25,000 ppm BPA in
the diet, corresponding to approximately 500, 1000, 1500, 2000, and 2500 mg/kg/day,
for a period of 13 weeks. Two of ten female mice receiving 5000 ppm died, but no
other deaths occurred. Weight gain was depressed by 14% or more in male mice re-
ceiving 15,000 to 25,000 ppm, and by 17% or more in all dose groups of female mice.
The depression in weight gain was not dose related in females. Multinucleated giant
hepatocytes were observed in all dosed groups of male mice with an incidence and se-
verity that were dose related. Multinucleated giant hepatocytes were found in 9/10
males receiving the highest dose, compared with 0/10 female mice receiving this dose.
Doses selected for the chronic study were 1000 and 5000 ppm BPA in feed for male
mice, and 5000 and 10,000 ppm for females (NTP82).

45 Effects
</pre>

====================================================================== Einde pagina 45 =================================================================

<br><br>====================================================================== Pagina 46 ======================================================================

<pre>Table 7 Acute toxicity data of DGEBPA.

species” route of entry’ dose or concentration acute effect - reference
rat oral 11,000 mg/kg LD, Lew92
rat oral 21,600 mg/kg LD, Web93
rat intragastric 11,400 mg/kg LD, Hin81
rat intraperitoneal 2,400 mg/kg LD, Hin81
rat dermal >1,600 mg/kg LD, Web93
rat dermal >1,600 mgkg LD, Gar92
rat subcutaneous 2,580 mg/kg LD, Hin58
rat inhalatory >saturated, 8 hours no deaths observed Hin81
mouse intragastric 15,600 mg/kg LD, Hin81
mouse intraperitoneal 4,000 mg/kg LD, Hin81
mouse dermal >1,200 mgkg LD, Web93
mouse dermal >800 mg/kg LD. Gar92
rabbit intragastric 19,800 mg/kg LD, Hin81
rabbit dermal >22,000 mg/kg LD,, Web93
rabbit dermal 20,000 mg/kg LD,, Hin81

BPA, oral administration, rats

BPA was fed to groups of five male and five female rats for two weeks in a concentra-
tion of 0, 2000, 4000, 8000 and 12,000 ppm in the diet. There were no clinical signs of
intoxication. Dose-related decreases in body weight were seen in males at the three
highest dose levels and in females at 8000 and 12,000 ppm. Food consumption was
slightly decreased for male rats at 8000 and 12,000 ppm. There were no compound-
related gross pathologic lesions. The two-week dietary no-effect levels were: 2000
ppm for male rats and 4000 ppm for female rats (study from 1976, reported by
Web90).

Groups of ten male and ten female Wistar rats were fed 0, 400, 2000 and 10,000
ppm BPA in the diet for four weeks. The general condition, behavior, and survival
were not adversely affected at any dose level. Growth, food intake and food efficiency
were markedly decreased at 10,000 ppm in both sexes. Gross autopsy did not reveal
any treatment-related changes. The four week dietary no-effect level was 400 ppm for
rats (study from 1979, reported by Web90).

In an 8-week study 30 - 40 male and female rats were fed 10,000 ppm BPA in the
diet. Body weight gain was significantly reduced in both sexes but there were no other
ill effects (study from 1959, reported by Web90).

Three studies were performed feeding rats during 90 days with BPA. One study
added 8000 ppm BPA to the diet and found no deleterious effects (study from 1967, re-
ported by Web90). The second study added 0, 100, 500 and 2500 ppm BPA to the diet.
Groups of 15 male and 15 female Wistar rats were used. There were no deaths in any
treatment or control group. Clinical signs were confined to slight alopecia at the top

46

Bisphenol A and its Diglycidylether
</pre>

====================================================================== Einde pagina 46 =================================================================

<br><br>====================================================================== Pagina 47 ======================================================================

<pre>dose level in both sexes. Gross pathological examination revealed enlarged caeca in
both sexes at 2500 ppm and in the 500 ppm group males. Microscopic examination did
not reveal any abnormalities, full examination was confined to top dose animals. The
90-day dietary no-effect level was 500 ppm for rats (study from 1979, reported by
Webb 1990). The third study used a range of 2 - 520 mg/kg/day, added to the diet of
groups of five male and five female Sherman rats. No overt signs of toxicity and no
microscopic changes which could be attributed to the compound at any dose level. The
upper intestine, kidney, liver and spleen were examined. It is concluded that the 90-day
no-effect level for rats is 520 mg/kg/day (study from 1951, reported by Web90).

In a preliminary study to establish a maximum tolerated dose (MTD) for the
chronic study, ten male and female F344 rats were fed with 0, 250, 500, 1000, 2000, or
4000 ppm BPA in the diet, corresponding to approximately 12.5, 25, 50, 100, and 200
mg/kg/day, for a period of 13 weeks. Two of ten male rats receiving 1000 ppm died,
but no other deaths were seen. Weight gain was depressed 18% or more in males re-
ceiving at least 1000 ppm, and by more than 10% in females receiving 1000 ppm or
more. Feed consumption was not affected. Hyaline masses were found in the bladder
lumen of 4/10 male rats receiving 4,000 ppm, 6/10 receiving 2000 ppm, 3/10 receiving
500 ppm, and 5/10 receiving 250 ppm, compared with none in control male rats. Cae-
cal enlargement was noted in 60-100% of the animals of each dose group, with the ex-
ception of females treated with 250 ppm BPA, and was considered to be compound
related. No inflammatory changes of other mucosal abnormalities were detected when
the cell walls were examined histologically. Based on the data for weight gain depres-
sion, doses selected for the chronic study were 1000 and 2000 ppm BPA in feed
(NTP82).

BPA, oral administration, other animals

A group of 13 rabbits were given 500 mg BPA/kg via the oral route during two
months. No significant effect on body weight or condition was observed. The erythro-
cyte count was reduced as were blood phospholipids. At the end of the experiment
spleen/body weight ratios were increased while adrenal/body weights ratios were de-
creased (report from 1968, reported by Web90).

A 2-week range finding study with one male and one female Beagle dog per dose
group used 2000, 4000, 8000, and 12,000 ppm BPA in the diet. Pretreatment measure-
ments served as controls. There were no clinical signs of intoxication, nor treatment-
related changes in body weight or food consumption. There were no gross lesions,
however there were several cases of focal mucosal congestion and haemorrhage of the
gastrointestinal tract (study from 1976, reported by Web90). In the subsequent study
four male and four female Beagle dogs were fed with a diet containing 0, 1000, 3000,

47

Effects

</pre>

====================================================================== Einde pagina 47 =================================================================

<br><br>====================================================================== Pagina 48 ======================================================================

<pre>or 9000 ppm BPA for 90 days. There were no compound-related changes in general
behavior and appearance, body weight, food consumption, ophthalmoscopy, haematol-
ogy, biochemistry or urinalysis. Pathological examination revealed no gross lesions. At
9000 ppm mean liver weights were significantly higher than the control group. It is
concluded that the 90-day no-effect level for dogs is 3000 ppm. The only effect at 9000
ppm was an increase in liver weight (study from 1976, reported by Web90).

BPA, inhalation exposure, rats

In an inhalation study with four male Alderley Park rats five exposures of six h toa
saturated atmosphere induced no signs of intoxication. There are no data on how this
atmosphere was obtained. Upon autopsy the organs were normal (study from 1970, re-
ported by Web90).

Groups of 20 male and 20 female Fischer rats were exposed to 0, 10, 50, or 150 mg
BPA/m (almost maximum attainable concentration), 6 hr/day, 5 d/week for nine expo-
sures. The particle size ranged from 2.6 to 6.2 micron. Necropsies were performed the
day after the last exposure and 29 days later. Full histopathological examination of tis-
sues was confined to top dose and control animals. At 10 and 50 mg/m’ only the respi-
ratory tract was examined and this was also the case with all the recovery groups. It is
concluded that the nine exposure no-effect level for rats is 10 mg/. At higher dose
levels inflammation of the anterior part of the nasal cavity and hyperplasia of the nasal
epithelium have been observed (study from 1985, reported by Web90).

A subchronic study comprises the exposure of 30 male and 30 female Fischer rats
per group to 0, 10, 50 and 150 mg BPA/m, 6 hr/day, 5 d/week for 13 weeks. The high-
est concentration is the almost maximum attainable concentration. Mass median aero-
dynamic diameter of the particles (depending on the method) range from 1.5 to 5.2
micron. Ten males and ten females were necropsied 1, 28 and 84 days after the last ex-
posure. Porphyrin-like reddish staining around nose and perineal soiling in both sexes
were observed at 50 and 150 mg/m’ and in some females at 10 mg/m?. Reddish nasal
staining occurred in some males at 10 mg/m?. These effects were not progressive as ex-
posure continued and regressed within seven days of cessation of exposure to 150
mg/m’. Body weights (mean of up to 30 rats/group) were decreased significantly
throughout the study in the 50 and 150 mg/m’ exposure groups. At 10 mg/m’ body
weights were reduced for most of the exposure period but were comparable to control
values at the end of the exposure period. There were no changes in haematological or
clinical chemical parameters considered biologically significant. The only treatment-
related histopathological changes were observed in the nasal cavity. A dose-related
very slight to slight hyperplasia of the stratified squamous epithelium (ventral meatus)
and respiratory epithelium (adjacent to vomeronasal organ) and very slight to slight

Bisphenol A and its Diglycidylether

</pre>

====================================================================== Einde pagina 48 =================================================================

<br><br>====================================================================== Pagina 49 ======================================================================

<pre>chronic inflammation of the underlying submucosa was observed at 50 and 150 mg/m’
in the anterior part of the nasal cavity. There was also slight to moderate hyperplasia of
the goblet cells on naso- and maxilloturbinates and the lateral nasal wall. Twelve
weeks after cessation of exposure there were no gross or microscopic pathological
changes attributable to treatment. It is concluded that the 90-day no-effect level for rats
was 10 mg/m’. Hyperplasia and inflammatory changes observed in the anterior nasal
cavity at higher dose levels were fully reversible within 12 weeks of cessation of expo-
sure (study from 1988, reported by Web90).

DGEBPA, oral administration, rats

Rats were fed DGEBPA in their diets for three months at concentrations up to 3%.
Rats at the highest dose level rejected the diets and failed to gain weight; these rats
showed effects on gross and histopathologic examination that were consistent with
malnutrition. There was no evidence of systemic toxicity at any level (study from
1958, reported by Gar92).

In another subchronic study, DGEBPA was fed to rats at dietary concentrations of 0.2,
1, and 5% for 26 weeks. All rats at the highest dose died by the end of 20 weeks, but
gross and histopathologic examination did not reveal evidence of systemic toxicity at
any dose (study from 1958, reported by Gar92).

Administration of a low molecular weight DGEBPA-based resin (Araldite GY250)
by gavage to rats for 28 days at doses of 0, 50, 200 and 1000 mg/kg/day did not alter a
large range of parameters, a.o. gross pathology, histopathology, clinical observations,
haematology and blood chemistry (study from 1984, reported by Gar92).

DGEBPA, ip injection, mice

To investigate lung tumours, 30 male mice of the Heston A strain received intraperito-
neal injections of 4.0 g/kg epoxy resin B1, a commercial DGEBPA resin, [type and
quantity of impurities unspecified], 95% in acetone every other day for 16 weeks.
There was an acetone control group of 30 males in which six mice developed a pulmo-
nary adenoma. The incidence in mice injected with epoxy resin B1 was between zero
and seven tumours [not exactly specified]. There was no statistical difference between
the incidence in treated mice and controls (Hin58). Due to imperfections in data pres-
entation no conclusions can be drawn.

49

Effects
</pre>

====================================================================== Einde pagina 49 =================================================================

<br><br>====================================================================== Pagina 50 ======================================================================

<pre>Conclusion

BPA
Subcutaneous implantation of BPA had no effects on mice in dosages up to 100 mg.

Oral dosing via the diet of 5% BPA for two weeks killed six out of eight mice. At
2.5% BPA mice showed dehydration, dyspnoea, lethargy, tremors, and ptosis. Feeding
of 15,000 to 25,000 ppm for 13 weeks depressed weight gain in male mice. In female
mice weight gain was depressed after feeding BPA from 5000 ppm upward, but not
dose-related. Multinucleated giant hepatocytes were observed in male mice after feed-
ing BPA from 5000 ppm with a dose-related increase and severity.

In rats 8000 - 12,000 ppm BPA in the diet reduced body weight gain after two,
four and eight weeks. Feeding rats 2500 ppm BPA for 90 days induced slight alopecia.
Enlarged caeca were observed after feeding from 500 ppm upward in female rats and
from 250 ppm upward in males. No microscopic abnormalities were found. Hyaline
masses were found in the bladder of male rats, there was no dose-related increase.

Feeding dogs for 90 days with 9000 ppm BPA increased the mean liver weight. No
other changes were observed. No effects were observed after feeding 3000 ppm.

The almost maximum attainable concentration in air, 150 mg/m’, and 50 mg/m’,
induced porphyrin-like reddish staining around nose and perineal soiling in rats, de-
creased body weight, and very slight to slight hyperplasia and chronic inflammation in
the nasal cavity. The effects are reversible upon cessation of exposure. The 90-day no-
effect level for rats was 10 mg/m’.

DGEBPA

The feeding of DGEBPA to rats at dietary concentrations up to 30,000 ppm for three
months does not induce systemic toxicity. However, dosages of 50,000 ppm induced
death in 100% of the rats by the end of 20 weeks, mainly due to malnutrition.

7.1.4

Long-term toxicity/carcinogenicity
BPA, oral administration, mice and rats

The following describes a NTP study from 1982.

BPA (containing five unidentified minor impurities, one occurring at 1.8%) was
administered to 50 F344 rats of either sex (1000 or 2000 ppm in the diet), to 50 male
B6C3F, (1000 or 5000 ppm in the diet), and to 50 female B6C3F, mice (5000 or
10,000 ppm in the diet) for a period of 103 weeks. The administered doses corre-
sponded to approximately 74 and 148 mg/kg/day in male rats, 74 and 135 mg/kg/day in
female rats, 100 and 500 mg/kg/day in male mice, and 500 and 1000 mg/kg/day in fe-

50

Bisphenol A and its Diglycidylether

</pre>

====================================================================== Einde pagina 50 =================================================================

<br><br>====================================================================== Pagina 51 ======================================================================

<pre>male mice. Groups of 50 rats and 50 mice of either sex served as controls. The survival
among all groups of animals was comparable in both species and sexes. Two control
male mice and two high-dose female mice were accidently killed and were censored
from statistical analysis. Mean body weights of treated rats of either sex, of low- and
high-dose female mice, and high-dose male mice were lower than those of the controls.
Food consumption of dosed male rats was 90% that of controls. Food consumption of
dosed female rats was only 70 to 80% that of the controls throughout most of this
study and was probably the cause of reduced body weight gain. Food consumption
among all groups of mice appeared to be similar.

Leukaemias of the haematopoietic system occurred in male rats at increased inci-
dences in the high-dose group (13/50 controls, 12/50 low-dose, 23/50 high-dose). This
was a significant trend in the positive direction (p = 0.021). The high-dose group had a
significantly higher incidence (p = 0.030), when compared to the controls, but this is
above the value of p = 0.025 required by the Bonferroni inequality criterion for an
overall significance of p = 0.05, when two dosed groups are compared with a control
group. Neither trend, nor higher incidence were significant after life table analyses,
which adjust for intercurrent mortality. The increased incidences in dosed female rats
were not statistically significant (7/50, 13/50, 12/50). Lymphomas or leukemias of the
haematopoietic system in male mice were observed in increased proportion in the low-
dose group compared with the other two groups (2/49, 9/50, 5/50). The difference be-
tween low-dose and control group was significant (p = 0.028), but this is above the
value of p = 0.025 required by the Bonferroni inequality criterion for an overall signifi-
cance of p = 0.05, when two dosed groups are compared with a common contro! group.
No significant incidence was observed in high-dose males as well as in female mice
(incidence: 13/50, 10/48 and 8/48).

Interstitial-cell tumours of the testis occurred at statistically significant incidences
in low-dose (48/50; p = 0.001), and high-dose (46/49; p = 0.003) rats when compared
with controls (35/49). However, since this lesion normally occurs at high incidence in
aging F344 male rats, the increased incidence observed in this study was not consid-
ered compound related.

A compound related increase of multinucleated giant hepatocytes was observed in
male mice (1/49, 41/49, 41/50), but there was no increase of liver tumours. Extensive
histopathological examination did not reveal any other effect on liver and kidney of
both species and sexes.

Due to a high background incidence and high variation between the treatment
groups there is no convincing evidence that BPA is carcinogenic for F344 rats or
B6C3F, mice of both sexes under the conditions of this bioassay. The lowest dose
tested, 74 mg/kg/day reduced the body weight gain in male and female rats. Female
rats were more sensitive to this effect. Extensive histopathological evaluation of the

51

Effects
</pre>

====================================================================== Einde pagina 51 =================================================================

<br><br>====================================================================== Pagina 52 ======================================================================

<pre>liver and the kidney revealed only multinucleated giant hepatocytes in both dose
groups of‘ male-mice-(100ànd: 500:mg/kg/day) (NTP82).

DGEBPA, dermal application, mice and rabbits

Thirty male C3H mice received skin application of 0.3 % epoxy resin B1, a commer-
cial DGEBPA resin, dissolved in acetone once a week or 5% once or three times
weekly for 24 months [type and quantity of impurities unspecified]. The control mice
received 0.2 ml acetone three times weekly. From a total of 240 mice 104 animals sur-
vived. It is not specified in which treatment group this occurred and what was the
cause of death. No tumours were seen in the control and treated groups (Hin58). Due
to a high death rate and the unknown purity of the compound no conclusions can be
drawn.

In another skin painting study in mice, “one brushful” of undiluted resin was ap-
plied to the skin of C3H mice three times weekly for up to 23 months. A skin papil-
loma was detected in a single mouse after 16 months of treatment, at which time 32 of
the 40 mice started on the study were still alive (Wei63). When the study was repeated,
twice for 24 months and once for 27 months, no skin tumours were found (Wei63).

In a study conducted on C3Hf/Bd mice with specified technical-grade DGEBPA
obtained from three different manufacturers, no treatment related skin neoplasms were
found after skin application of 75 mg/week for two years (cited by Zak85; the original
article was not available in The Netherlands).

A study from 1987 is reported (Gar92): The carcinogenic potential and chronic
dermal toxicity of three commercially available DGEBPA-based resins were investi-
gated. The test materials were dissolved in acetone, and 50 ul was applied topically,
twice a week, for 94 weeks, to the backs of C3H/HeJ male mice, 50 animals per treat-
ment group. The three DGEBPA-based resins tested were 42% DGEBPA, 76% DGE-
BPA, and 27% DGEBPA, and were tested in acetone at concentrations of 50%, 25%,
and undiluted, respectively. Thus, the actual concentrations of DGEBPA applied were
21, 19, and 27%. Two groups of 50 mice each were treated twice weekly with 50 | of
acetone or 0.025% benzofa]pyrene in acetone to serve as negative and positive control
groups, respectively. An additional group of 50 mice received no treatment as a nega-
tive control group. The skin from all animals was examined by light microscopy for
nonneoplastic and neoplastic lesions, and histopathologic examination of internal or-
gans was conducted on half of the mice from each group. Forty-eight of the mice in the
positive control group developed skin tumours, with an average latent period of 32.4
weeks, whereas no skin neoplasms were observed in either of the negative control
groups or in the groups treated with resins in acetone at a final concentration of 19 or
27% DGEBPA. Three of the fifty mice treated with test material containing 21%

Bisphenol A and its Diglycidylether

</pre>

====================================================================== Einde pagina 52 =================================================================

<br><br>====================================================================== Pagina 53 ======================================================================

<pre>DGEBPA in acetone had microscopically detectable skin papillomas, but no malignant
neoplasms of the skin were present in any of the animals in this treatment group. The
incidence of hepatocellular carcinoma observed in the treated and control groups was
within the range of those detected in historical control animals from the same labora-
tory and below values reported by the animal supplier for this strain of mouse.

Fifty male and 50 female CF1 mice were treated with acetone once a week or
twice a week with 1% or 10% (v/v) technical DGEBPA (Araldite GY250, containing
4,3 ppm epichlorohydrin) in 0.2 ml acetone for a period of two years. The 10% con-
centration was determined to be the maximum tolerated dose. There was no effect on
survival and no skin tumour was observed at the site of application. High incidences of
malignant lymphomas in the lymphoreticular tissues and of pulmonary adenomas and
carcinomas were found in both treated and control groups, but there was no statistical
evidence for a treatment related effect (Zak85).

Groups of 50 male and 50 female CF1 mice were treated with pure DGEBPA,
EPON 828 (<29 ppm epichlorohydrin) or EPIKOTE 828 (<3 ppm epichlorohydrin)
dissolved in acetone (1 or 10% w/v) twice weekly (0.2 ml/dose) over a period of two
years. The doses of the epoxy resins were selected on the basis of a preliminary
4-week cutaneous irritancy study. The contro! group consisted of 100 animals of both
sexes and was treated with acetone alone. Survival of the CF1 mice was unaffected by
cutaneous exposure to each epoxy resin and the etiology of death or terminal illness
was not influenced significantly by treatment. The incidence of cutaneous tumours of
the treated site or of the skin at all sites was not statistically significant when compared
with acetone controls. There were no metastases of cutaneous or subcutanuous tu-
mours.

The incidence of renal tumours in males treated with EPON 828 gave rise to a sig-
nificant trend (p = + 0.03), control: 6/99, 1%: 0/50, 10%: 8/50. However, renal neo-
plasms are common in CF1 mice bred in the laboratory of the authors, the absence of
this tumour in the 1% dose group is rather unusual. In the parallel studies with
EPIKOTE 828 and pure DGEBPA none of the treated male groups had renal tumours
at an incidence significantly greater than in the control group. There were significant
trends (0.05 > p > 0.01) for the number of females treated with EPIKOTE 828 with
reticulum-cell sarcoma (16/99, 11/50, 15/50) and lymphoblastic sarcoma (4/99, 2/50,
4/50). A significant trend was also seen for the total number of females with at least
one systemic tumour and also for the number with a tumour of the
lymphoreticular/haematopoietic tissue. The only significant trend (0.05 > p > 0.01) for
treatment with pure DGEBPA was the incidence of thymic lymphosarcomas in females
(7/99, 2/50, 5/50). However, the authors think it is likely that the CF1 mice used are
susceptible to the development of tumours of lymphoreticular/haematopoietic tissues
as a result of the presence of a virus and/or a genetic tendency to viral infection. It is

53

Effects

</pre>

====================================================================== Einde pagina 53 =================================================================

<br><br>====================================================================== Pagina 54 ======================================================================

<pre>possible, therefore, that the increased incidence of reticulum cell-sarcomas or lympho-
sarcomas in female mice after treatment with EPIKOTE 828 or pure DGEBPA is not a
direct or valid indication of any systemic carcinogenic potential of these epoxy resins
(Per88).

Hine et al (Hin58) treated a group of 16 male albino rabbits with acetone, two ep-
oxy resins and 20-methylcholanthrene on a predesignated shaved area. Each animal re-
ceived all three compounds simultaneously on different areas of the body, therefore no
conclusions can be drawn.

DGEBPA, oral administration, mice

Male mice of the Heston A strain were fed with a diet containing 0.2% of epoxy resin
B1 [type and quantity of impurities unspecified]. The daily intake of each mouse was
5-6 mg resin for a period of 11 months. After termination the animals were investi-
gated for lung tumours. In the control group 29/30 survived and 15/29 developed lung
tumours, four of which had multiple tumours (two to five per mouse). Of the 30 treated
mice 23 survived and 12/23 developed lung tumours, one of which was multiple (two
tumours). This difference was not statistically significant (Hin58). Due to a high death
rate and the unknown purity of the compound, no conclusion can be drawn.

DGEBPA, subcutaneous injection, rats

Male rats of the Long-Evans strain were given three injections of epoxy resin B1 [type
and quantity of impurities unspecified] 50% in propylene glycol once a week for 24
months. The total amount injected was equal to the LD,,: 2580 mg/kg body weight.
Controls received propylene glycol alone. Among the controls 17/30 survived and no
tumours were found at the site of injection. Elsewhere five malignant tumours ap-
peared. No details are provided on place or type of the tumours. In the treated group
14/30 survived; in the surviving rats four fibrosarcomas were found at the site of appli-
cation with seven malignant tumours appearing elsewhere. These animals died during
the experimental period. None of the survivors had neoplasms at the injection site, al-
though all of them had foreign body reactions, not further specified. The sarcomas
formed at the injection site are not considered very relevant for human risk evaluation,
because rats are unusually susceptible to subcutanuous implantations (Hin58). Al-
though there is a high death rate, both among the control and the treated animals, it can
be concluded that DGEBPA probably does not induce systemic tumours in rats after
multiple subcutaneous injections.

54

Bisphenol A and its Diglycidylether

</pre>

====================================================================== Einde pagina 54 =================================================================

<br><br>====================================================================== Pagina 55 ======================================================================

<pre>Conclusion

There was no convincing evidence that BPA was carcinogenic for F344 rats of B6C3F
mice of either sex after oral administration.

After dermal application and subcutaneous injections of pure and commercial DGE-
BPA no skin tumours developed in rats and mice. Although lymphoreticular tumours
were increased in some groups of some experiments, the data lacked consistency and
therefore the increase of this spontaneously occurring tumour is not considered indica-
tive of a carcinogenic potential of the compound.

Mutagenicity

A summary of data on mutagenicity of BPA is given in Table 8 and of DGEBPA in
Table 9.

The reaction of DGEBPA with DNA was studied in vivo (Ben89 and Ste92).

Bentley et al (Ben89) applied 0.4, 0.8 or 2 mg radiolabeled DGEBPA to shaved
dorsal skin of C57BL6 and C3H mice. After 48 hours the mice were killed and the skin
of four pooled animals was treated to extract and isolate proteins, RNA and DNA. De-
spite the fact that most of the radioactivity was found to bind to protein and RNA, a
DNA adduct was detected, which co-chromatographed with a glycidaldehyde-
deoxyguanosine adduct. More radioactivity was associated with DNA isolated from
C3H mice than from C57BL6 mice. No formation of an adduct was seen at the lowest
dose tested.

Steiner et al (Ste92) showed that the adduct formed was not a glycidaldehyde-
deoxyguanosine adduct, but that adenine residues are the major target of metabolically
formed glycidaldehyde. Nine male C3H mice were treated with a single topical dose of
2 mg DGEBPA in 100 | acetone and were killed after 48, 96, or 192 hours. Two mice
were treated with 2 mg glycidaldehyde in 100 1 acetone and were killed after 24 hours
of exposure. Control mice received acetone alone and were killed after 192 hours. Epi-
dermal DNA was isolated and aliquots of hydrolysed DNA were separated by HPLC
and analyzed by fluorescence emission. All epidermal DNA hydrolysates from mice
treated with DGEBPA or glycidaldehyde contained hydroxymethylethenodeoxyadeno-
sine-3’- monophosphate (HMEdAp), not hydroxymethylethenodeoxy-
guanosine-3’-monophosphate (HMEdGp). This adduct was not detectable in DNA
samples obtained from animals treated with acetone alone. The amounts of adducts
measured in mice treated with DGEBPA for different exposure times were 0.5
adducts/10° nucleotides after 48 h, 0.1 adducts/10° nucleotides after 96 h and 0.3

55

Effects
</pre>

====================================================================== Einde pagina 55 =================================================================

<br><br>====================================================================== Pagina 56 ======================================================================

<pre>adducts/10° nucleotides after 192 h respectively. In glycidaldehyde-treated mice 166
adducts/10° nucleotides-eould be detected: The limit-of detection using this assay was
~30 fmol in the presence of 1.6 mol natural nucleotides (0.02 adducts/10° nucleotides).
A comparison of the adduct levels after treatment with DGEBPA and glycidaldehyde
allows a calculation of the bioavailability of glycidaldehyde from DGEBPA. The re-
sults show that a dose of 2 mg glycidaldehyde leads to the formation of 166
HMEdAp/10° nucleotides. Treatment with 2 mg DGEBPA resulted, at the most (one
mouse after 48 h of exposure), in formation of 0.8 HMEdAp/ 10° nucleotides. Under
the assumption of a linear dose versus adduct-level relationship, this would be equal to
a dose of 10 pg glycidaldehyde. Since 2 mg DGEBPA contains 0.85 mg glycidalde-
hyde equivalents at the most 1.1% of the glycidaldehyde moiety in DGEBPA was
available for DNA adduct formation.

The weak activity of DGEBPA to form DNA adducts is supported by the weakin
vivo mutagenicity of glycidaldehyde (Bar83, Bar89, Vog90).

Conclusion

BPA does not induce mutations in bacteria, does not induce chromosomal aberrations,
sister chromatid exchanges, or transformations in mammalian cells in vitro.

DGEBPA is mutagenic in some bacterial test systems. It probably causes basepair sub-
stitutions rather than frameshift mutations. In higher dosages (0.8 mg/mouse) DGE-
BPA or a metabolite may react with DNA in mammals in vivo after dermal application.
DGEBPA may induce neoplastic transformations, gene mutations and chromosomal
aberrations in mammalian cells in vitro. It is negative in the host-mediated assay. It
does not induce UDS in human cells in vitro. No induction of micronuclei, dominant
lethality or DNA single strand breaks are observed in mammals in vivo.

7.1.6

Reproduction toxicity
BPA, rats

Young adult female Sprague-Dawley rats (250-300 g) were treated with 85 mg/kg
(four animals) or 125 mg/kg (12 animals) BPA dissolved in corn oil and injected daily
intraperitoneally from the first day of gestation through the 15th day. The highest dose
was the maximum tolerated dose. A control group of 12 rats received ip injections of
corn oil. On day 21 of gestation the females were killed and litters and maternal organs
were collected. The higher dosage significantly (p = 0.0014) impaired the establish-
ment of pregnancy of sperm-positive rats and both doses caused a significant (p <

56

Bisphenol A and its Diglycidylether
</pre>

====================================================================== Einde pagina 56 =================================================================

<br><br>====================================================================== Pagina 57 ======================================================================

<pre>Table 8 Mutagenicity data of BPA.

type of test species concentrations tested remarks results references
Ames Salmonella typhimu- 0.1-1.0 mg/ml in liquid with and without - study from 1978,
rium TA1538 suspension cultures; RLiA* reported by Web90
0.2-500 pg/plate -
Ames Salmonella typhimu- not reported with and without - And78
rium TA100, TA1535 RLiA
Ames Salmonella typhimu- -333 pg/plate with and without - Ten86 and Ten87
rium TA98, TA 100, RLiA
TA1535, TA1537
Ames Salmonella typhimu- 0 - 333.3 pg/plate with and without - Haw83
rium TA98, TA100, RLiA and HLiA®
TA1535, TA1537
reversed mutation Escherichia coli 0.1-1.0 mg/ml in liquid with and without - study from 1978,
WP2 and WP2 uvrÂ suspension cultures; RLiA reported by Web90
0.2-500 pg/plate -
UDS primary rat not reported - Ten86
hepatocytes
mitotic gene conver- Saccharomyces 0.01-0.5 mg/ml with and without - study from 1978,
sion cerevisiae JDI RLiA reported by Web90
chromosomal aberra- RL4 (rat liver) cells 0-30 pg/ml - study from 1978,
tion reported by Web90
chromosomal aberra- chinese hamster -50 pg/ml - Ten86 and Ten87
tion ovary cells
chromosomal aberra- chinese hamster 0 - 50 pg/ml with and without - Ive89
tion ovary cells RLiA
sister chromatid ex- chinese hamster -50 pg/ml + Ten86 and Ten87
change ovary cells
sister chromatid ex- chinese hamster 0 - 25 pg/ml with and without - Ive89
change ovary cells RLiA
thymidine kinase L5178Y mouse -50 pg/ml - Ten86 and Ten87
locus lymphoma ceils
thymidine kinase L5178Y mouse 0 - 60 pg/ml with and without - Myh91
locus lymphoma cells RLiA; 60 g/ml is le-
thal
transformation Syrian hamster 0 - 60 pg/ml - Jon88
assay embryo cells
transformation Balb/c 3T3 cells not reported with and without - Ten86
assay RLiA
sex-linked Drosophila melano- feeding 10 g/kg surviving males - Fou94

recessive lethality
dominant lethality

gaster
male Sprague-
Dawley rats

for 3 days

85 mg/kg/day ip inj. on 5

consecutive days

were mated

study from 1980,
reported by Web90

a

b

Rat liver activation.

Hamster liver activation.

57 Effects

</pre>

====================================================================== Einde pagina 57 =================================================================

<br><br>====================================================================== Pagina 58 ======================================================================

<pre>Table 9 Mutagenicity data of DGEBPA.

type of test species - concentrations tested: remarks: results references
Ames Salmonella typhimu- 0 - 54 umol/plate with and without RLiA* + And78
rium TA100, TA1535
Ames Salmonella typhimu- 0.5 - 2.0 pmol/plate with and without RLiA * study from 1977,
rium TA1535, TA98 with and without RLiA reported by Gar92
Ames Salmonella typhimu- urine of mice after a - study from 1977,
rium TA1535 single oral dose of 1000 reported by Gar92
mg/kg
Ames Salmonella typhimu- not reported with and without RLiA + study from 1979,
rium TA100, TA98 with and without RLIA reported by Gar92
Ames Salmonella typhimu- - 2000 ug/plate with RLIA + study from 1979,
rium TA1535, TA1538 without RLIA - reported by Gar92
with RLiA +
without RLiA -
Ames Salmonella typhimu- not reported with RLiA TA98: - study from 1981,
rium TA98, TA100, TA100: - reported by Gar92
TA1535, TA1537, TA1538: -
TA1538 TA1535: +
TA1537: +
without RLiA all: -
Ames Salmonella typhimu- not reported with and without RLiA + study from 1982,
rium TA100, TA1535 reported by Gar92
Ames Salmonella typhimu- 0.05 mg/plate and with and without RLiA - Wad79
spot test rium TA98, TA100, 10.0 mg/plate
TA1535, TA1537
Ames Salmonella typhimu- 0 - 10 mg/plate; TA 100: with and without RLiA TA98: - Can86
rium TA98, TA100, 0 - 1.0 mg/plate and HLiA® TA1537: -
TA1535, TA1537 TA100: +
TA1535: +
Ames Salmonella typhimu- range not specified with and without RLiA TA98: - Kie86
rium TA98, TA100, TA1537: -
TA1535, TA1537 TA100: +
TA1535: +
Ames Escherichia coli WP2 20 - 10,000 uM + Hem80
uvrÂ
Ames Escherichia coli WP2 not reported - study from 1981,
or WP2 uvrA reported by Gar92
induction Saccharomyces not reported with and without RLiA + study from 1982,
of mitotic cerevisiae IDI reported by Gar92
gene con-
version
* Rat liver activation.
> No dose response.
° — Hamster liver activation.
58 Bisphenol A and its Diglycidylether

</pre>

====================================================================== Einde pagina 58 =================================================================

<br><br>====================================================================== Pagina 59 ======================================================================

<pre>Table 9 Continued.

type of test species concentrations tested remarks results references
induction human mononuclear up to 500 ppm - study from 1977,
of UDS white cells reported by Gar92
induction of mouse lymphoma not reported with - 2 studies from 1982
gene mutation cells without RLiA + and 1986, reported by
Web93
chromosomal ab- rat liver cells 3.75 - 20 pg/ml + study from 1981,
errations reported by Gar92
induction male and female single oral dose test in liver DNA - study from 1981,
of single strand Wistar rats of 500 mg/kg reported by Gar92
breaks in DNA
induction of mi- 10 female 5 gavage doses of 1000 - study from 1977,
cronuclei B6D2F, mice mg/kg reported by Gar92
induction of baby hamster up to twice the LC50 + study from 1981,
neoplastic trans- kidney cells reported by Gar92
formation
host-mediated as- S. typh. inoculated mice pretreated by - study from 1977,
say into the peritoneal gavage for 5 days with reported by Gar92
cavity of mice 1000 mg/kg
dominant 10 male B6D2F, dermal treatment with == males were mated with sev- - study from 1977,
lethal assay mice 3000 mg/kg, three times eral virgin females; test on reported by Gar92
per week, for a mini- pregnancy, total number of
mum of 8 weeks implants and foetal death

0.02) reduction in the number of live foetuses per litter. Foetal toxicity was evident as
statistically significantly (p < 0.001) dose related reductions of foetal body weight and
crown-rump length (Har81). However, in view of the very toxic and for occupational
circumstances irrelevant route of exposure the results will not be used in the risk as-
sessment.

Female CD rats (200-275 g) were dosed by gavage with 0, 160, 320, 640, and 1280
mg/kg/day BPA dissolved in corn oil on gestation days (GD) 6 through 15. On the 20th
day of gestation all rats were sacrificed and examined. Two replicate studies of the de-
velopmental toxicity evaluation were conducted. Approximately egual numbers of
sperm-positive females were assigned to each of five dose groups in each replicate
(>10 per dose per replicate) for a total of at least 20 confirmed-pregnant females per
dose.

Dams in the high-dose group (1280 mg/kg/day) exhibited an unexpectedly high
mortality rate of 26% (7/27 animals), 10% (1/10) in the first and 35% (6/17) in the sec-
ond replicate. A mortality rate of 10% was predicted, based on a preliminary toxicity
study. The authors have not found an explanation for this replicate-dependent increase
of maternal mortality. There was no increase in the incidence or percentage of foetuses

59 Effects

</pre>

====================================================================== Einde pagina 59 =================================================================

<br><br>====================================================================== Pagina 60 ======================================================================

<pre>malformed per litter in this group. Data from the 1280 mg/kg/day dose group are ex-
cluded from datarused to make conclusions regarding the teratogenic potential of BPA.

The primary clinical signs associated with BPA treatment were lethargy, piloerec-
tion, pica, rough coat, wet urogenital area, weight loss, and alopecia. These effects oc-
curred infrequently in control rats. Maternal toxicity of CD rats exposed to BPA is
shown in Table 10. In the 27 to 29 treated rats in each dose group, pregnancy was con-
firmed in 92 to 100% of the treated females. No significant differences were observed
among treatment groups with respect to the total of number of corpora lutea per dam,
the number of implantation sites per dam, or the percentage of preimplantation loss
(data not shown). Maternal weight gains (gestation, treatment and gestational corrected
for gravid uterine weight) were reduced in a dose-related manner. Gravid uterine
weight and absolute and relative maternal liver weight were unaffected by BPA treat-
ment.

There was no significant effect of BPA treatment on any observed measure of de-
velopmental toxicity, including percentage resorptions per litter, percentage litters with
resorptions, number of live foetuses per litter, sex ratio, average foetal body weight per
litter, percentage malformed foetuses per litter, and percentage litters with malformed
foetuses. It is concluded that BPA does not cause extemal, visceral, or skeletal malfor-
mations at dosages which caused significant maternal toxicity (Mor87, Geo85).

In a specific breeding study groups of ten male and ten female Charles River rats
were fed 0, 1000, 3000, and 9000 ppm BPA in the diet for 17 weeks. It is not clear at
what age of the rats the experiment started. At about 100 days of age the F, generation
rats were mated one female with one male of the same dose level. Dietary feeding was
maintained throughout the reproductive phase. After weaning selected offspring, 15
males and 15 females/group, were used for the 90-day feeding study. There were no
compound-related changes in appearance or behavior. One control male and two fe-
males at each of the two top dose levels died in the F, generation. In the F, generation
there were no effects in fertility indices, pups/litter or pup survival. Slight reductions
in body weight gain at 21 days of age were observed at 3000 and 9000 ppm. In the F,
90-day feeding study body weights were decreased in females at all dose levels and in
males at 3000 and 9000 ppm. Haematology, biochemistry, urinalysis and ophthal-
moscopy were all normal. No compound related gross lesions or variations in organ
weights were observed in any rats from the experimental groups. It is concluded that
fertility, the number of pups/litter and pup survival were not affected in rats by dietary
feeding of BPA at levels up to 9000 ppm. Pup weights were reduced at 3000 and 9000
ppm. Parental body weights were also reduced at these dose levels. The only effects
observed in the F, 90-day study were reductions in food consumption and body weight
(study from 1976, reported by Web90).

Bisphenol A and its Diglycidylether

</pre>

====================================================================== Einde pagina 60 =================================================================

<br><br>====================================================================== Pagina 61 ======================================================================

<pre>Table 10 Maternal toxicity in CD rats administered BPA by gavage on gestational days 6 through 15
(Mor87).

BPA (mg/kg/day)

0 160 320 640
subjects (dams)
total treated 27 27 27 29
removed 2 0 1° 0
no. pregnant (%) at sacrifice 23 (92)° 26 (96) 24 (92) 29 (100)
maternal weight gain (g)"
gestation period (GD 0-20) 122.2+4.4° 108.4+3.27 106.2:+3.4” 104.6+2.9°°
treatment period (GD 6-15) 42.0+1.8° 27.242.3" 19.6+2.9" 19.442.4"
corrected weight gain 50.3+2.5° 36.442.6" 37.42.17 33.4+2.57
gravid uterine weight® 71.943.7 72.0+2.5' 68.8+2.6 71.2+2.7
maternal liver weight*
absolute (g) 15.4+0.1 14.5+0.2 15.0+0.3 14.7+0.3
relative (% body weight) 4.3+0.1 4.2+0.1 4.4+0.1 4.3+0.1

4 One dam was removed due to punctured oesophagus; one dam was removed due to preexisting.
Pathological conditions found at sacrifice including large bladder, calculi, and small left kidney.

> One dam received 1/2 the appropriate dose on GD 13, due to a malfunction of the gavage syringe,
and was removed.

* One dam had all resorptions.

¢ Includes all dams pregnant at sacrifice; mean + SE.

° Weight gain during gestation minus gravid uterine weight.

One gravid uterine weight was not recorded.

Linear trend test, p <0.05.

Dunett’s test or William’s test, p <0.05.

The study was repeated using lower dose levels: 0, 100, 250, 500, 750 or 1000
ppm BPA in the diet. Since no effects were expected, based on the above study results,
and were not found, only the final conclusion is given: the dietary feeding of BPA at
levels up to 1000 ppm had no effect on male or female fertility for one generation and
no effect on pup survival and growth. The F, feeding of doses up to 1000 ppm for 90
days had no meaningful toxicological effects (study from 1978, reported by Web90).

BPA, mice

Female CD-1 mice (20-35 g) were dosed by gavage with 0, 500, 750, 1000 and 1250
mg/kg/day BPA dissolved in corn oil on gestation days 6 through 15. On gestation day
17 mice were killed and examined. Like the study conducted on CD rats as described
before two replicates were performed (>10 mice per dose group per replicate). Ap-
proximately equal numbers of mice were pregnant in each treatment group (Table 11).
BPA treated females exhibited clinical signs of toxicity including arched back, leth-
argy, piloerection, rough coat, vaginal bleeding, vocalization, alopecia, weight loss,

61

Effects
</pre>

====================================================================== Einde pagina 61 =================================================================

<br><br>====================================================================== Pagina 62 ======================================================================

<pre>Table 11 Maternal toxicity in CD-1 mice administered BPA by gavage on gestational days 6 through 15
(Mor87)..

BPA (mg/kg/day)

0 500 750 1,000 1,250
subjects (dams)
total treated 29 29 29 34 33
removed 0 1° 1? 2 0
no. pregnant (%) at sacrifice 26 (90) 23 (88) 21 (78) 23 (77) 21 (78)
maternal weight gain (8)
gestation period (GD 0-17) 19.8+0.9° 21.8+1.2 20.7+1.0 18.1+1.6 13.5+2.1"
treatment period (GD 6-15) 11.620.4° 12.2+0.8 12.5+0.7 9.4+1.1 6.6+1.27
corrected weight gain' 4.9+0.4 6.2+0.5 6.0+0.8 4.6+0.8 3.5+0.7
gravid uterine weight 14.7+0.8°° 15.6+0.9 14.8+0.9° 13.4+1.2 10.0£1.57
maternal liver weight
absolute (g) 2.6+0.0 3.0x0.1"* 3.1+0.17 3.0+0.1" 2.8+0.17
relative (% body weight) 5.4+0.1° 5.9+0.17 6.1+0.17 6340.2" 6.8+0.2"°

3 One dam was removed due to punctured oesophagus.

> Two dams were removed due to delivery before scheduled sacrifice.
© Includes all dams pregnant at sacrifice; mean + SE.

Weight gain during gestation minus gravid uterine weight.

©  Gravid uterine weight for one dam was inadvertently not recorded.
One liver weight was incorrectly recorded and was not included.
Linear trend test, p < 0.05.

Dunett’s test or William’s test, p < 0.05.

and wheezing. Maternal deaths occurred in all BPA dose groups, reaching 18% in the
1250 mg/kg/day group. There was a trend towards reduced maternal weight gain dur-
ing both gestation and treatment, with mice in the highest dose group gaining signifi-
cantly less weight (p<0.05) than those in the control group. Corrected weight gain
(weight gain during gestation minus gravid uterine weight) was not significantly differ-
ent among dose groups. There was a trend towards reduced gravid uterine weight with
increasing BPA dose; the mean high-dose weight was significantly less than that of the
control group. The absolute maternal liver weight was significantly increased for the
500, 750, and 1000 mg/kg/day dose groups compared to the control group. The relative
maternal liver weight was significantly increased in all BPA dosed groups.

There was no difference among treatment groups in the number of implantation
sites per litter, but the number of corpora lutea per dam decreased in relation to in-
creasing BPA dose. There was no effect on preimplantation loss. The percentage re-
sorptions per litter increased in the two highest dose groups, with the 1250 mg/kg/day
group significantly different from the control group. There were seven litters in the
high dose groups that were totally resorbed. A dose-dependent decrease in average foe-
tal body weight per litter was observed with increasing BPA dose; the 1250 mg/kg/day
average foetal body weight was significantly less than that of the control group. There

Bisphenol A and its Diglycidylether

</pre>

====================================================================== Einde pagina 62 =================================================================

<br><br>====================================================================== Pagina 63 ======================================================================

<pre>was no significant effect of BPA on the number of live foetuses per litter, on the sex
ratio, on the percentage malformed per litter or on the percentage litters with mal-
formed foetuses. There were no significant treatment-related effects on any measure of
teratogenic response. It is concluded that BPA had no effect on the incidence of exter-
nal, visceral, or skeletal malformations at dosages that cause significant maternal mor-
tality (Mor87).

A continuous breeding study on CD-1 mice treated with BPA was performed
(Ree84). Mice received a suspension of 0, 25, 50 or 100 mg BPA in corn oil via subcu-
taneous Silastic implants. The control group consisted of 40 mice of each sex and
treatment groups of 20 mice of each sex. Eleven-week old male and female CD-1 mice
were exposed to BPA during a 7-day premating period, a 98-day cohabitation group
(one male and one female per cage), and a 21-day segregation period. Newborn litters
are evaluated and discarded. During the 18-week treatment period, BPA released from
the Silastic implants was approximately 11.65 mg for the 25 mg dose group, 20.05 mg
for the 100 mg dose group, and 38.60 mg for the 100 mg dose group. Several animals
in each treatment group expelled their implant through cutaneous lesions that devel-
oped over the implant or through the original site of incision. When this occurred, a
new implant containing the original amount of BPA was inserted. Pregnant females
were allowed to deliver their litter prior to being anaesthetized and reimplanted. Sev-
eral animals received subcutaneous Silastic implants on as many as four occasions. A
total of two females (one in the control group and one in the 50 mg dose group) died
during the study. Exposure to BPA had no effect on body weight, fertility, the number
of litters per fertile pair, and weights of liver, brain, pituitary gland, and male and fe-
male reproductive organs in this study. Although a few reproductive parameters were
significantly different among treatment groups, these differences were random in na-
ture and appeared to be due to chance alone. Because the Silastic implants tended to be
expelled and since they appeared to release too little BPA to cause generalized or re-
productive toxicity this study was terminated and neither a crossover breeding study,
nor a study on reproductive performance in the offspring, as required by the National
Toxicology Program (NTP) protocol, were performed. Under the conditions of this
study, BPA exerted no adverse effects on fertility or reproduction in male and female
CD-1 mice (Ree84).

A complete reproduction and fertility assessment in CD-1 mice was performed
(Ree85). Twenty mice of each sex were fed with 0.25, 0.5, or, 1.0% BPA in their feed,
representing 437.5, 875.0, and 1750.0 mg/kg body weight. A vehicle control group
consisted of 40 mice of each sex. All mice were 11 weeks of age at the outset of the
trial. For the first week animals were housed by sex. Subsequently, mice were ran-
domly paired and cohabited for 98 days, one breeding pair per cage. Thereafter, each
mouse was separated for a period of 21 days. Continuous exposure to BPA during

63

Effects
</pre>

====================================================================== Einde pagina 63 =================================================================

<br><br>====================================================================== Pagina 64 ======================================================================

<pre>these three periods had no effect on the proportion of breeding pairs able to produce at
least one litter. Fhe numberof: litters per pair was significantly reduced (p < 0.05 or
0.01) in the 0.5 and 1.0% dose groups, and these groups had a significantly depressed
(p < 0.01) number of live pups per litter relative to the control group. The proportion
of pups born alive was significantly depressed (p < 0.01) in the 1.0% BPA group rela-
tive to the control group. Live male pup weight (p < 0.05) and live pup weight for
sexes combined was significantly elevated (p < 0.05 or 0.01) for the 0.5 and 1% BPA
groups relative to control pairs, whereas live female pup weight was significantly ele-
vated (p < 0.01) relative to controls only in the 0.5% BPA group. The absence of a live
female pup weight in the 1% BPA group in spite of a mean value that was elevated
above controls was most likely due to the variability of the data for this parameter in
the treated group. When pup weight was adjusted for the number of dead and live per
litter there was no longer any significant difference among dose groups, implying that
the larger absolute live pup weights were due to the smaller litter size in the 0.5 and
1.0% BPA groups. Postpartum body weights of the highest dose females were signifi-
cantly below (p < 0.01) those from the controls, indicating generalized maternal toxic-
ity.

Because of the significant decrease in the number of litters per pair and in the
number of pups per litter at doses of 0.5 and 1.0% BPA, a crossover mating trial was
conducted in order to determine the affected sex. Three combinations of breeding pairs
were evaluated: control male x control female; 1% BPA male x control female; control
male x 1% BPA female. These pairs were cohabitated for seven days, during which no
BPA was administered, and then separated. Then BPA treatment was reinstated. The
production of detected matings and fertility were not significantly different among
these three groups of mating pairs. The number of live pups per litter (sexes combined)
was significantly less (p < 0.05) in pairs with a treated male than in control pairs. The
number of pups, live male pups, and live female pups per litter was significantly less in
pairs with a treated female than in control pairs (p < 0.01) and in pairs with treated
males (p < 0.05). When pup weight was adjusted for the number of live and dead pups
per litter, no statistical differences were apparent. The proportion of pups born alive,
the sex of pups born alive, and postpartum weights of the treated females after the
crossover mating were not statistically different from controls.

By now, F, male and female mice used in the mating trials were weighed and ne-
cropsied. Body weights for treated females (1% BPA) were significantly below (p <
0.05) the control group, and both male and female treated (1% BPA) mice exhibited
significantly increased (p < 0.01) adjusted liver and kidney weight and histopathologi-
cal evidence of treatment-related hepatic and renal toxicity. Hepatic lesions in male
mice included centrilobular hepatocytomegaly, multifocal necrosis, and multinucleated
giant hepatocytes. Female mice exhibited multifocal necrosis, and multinucleated giant

Bisphenol A and its Diglycidylether

</pre>

====================================================================== Einde pagina 64 =================================================================

<br><br>====================================================================== Pagina 65 ======================================================================

<pre>hepatocytes. Renal lesions observed in treated F, male mice included tubular cell nu-
clear variability and amplification of spontaneous tubular and interstitial lesions nor-
mally seen in these mice. In addition to exhibiting renal lesions similar to those
observed in the F, male mice, treated F, female mice had large microcalculi in the cor-
tical tubules, sometimes associated with effaced tubular epithelium, tubular regenera-
tion and/or dilated tubules containing proteinaceous or slightly pigmented tubular
casts. In general, hepatic lesions were more severe in male mice while renal lesions
were more prevalent in female mice. Treated males also had significantly reduced (p <
0.01) adjusted seminal vesicle weight and significantly reduced (p < 0.01) sperm mo-
tility, but no evidence of pathological lesions of the tissue of the reproductive system.

The offspring obtained in the last 21 days of the continuous breeding study, the F,
generation, did not exhibit significant differences in body weights at 21 days of age or
at 74 + 10 days of age between BPA-treated mice and controls, indicating normal
growth of pups surviving to the lactational and postweaning periods. However, con-
tinuous administration to 1.0% BPA of the F, generation mice was lethal to 37.5%
(18/148) compared to 6.3% (8/126), 3.8% (4/105), and 13.9% (11/79) lethality ob-
served in samples of 0, 0.25, and 0.5% BPA-treated mice, respectively.

In order to assess the reproductive effects of BPA on the E generations, litters
were randomly selected at day 21, were housed by sex, and maintained on the same
feed level as their parents. At 74 + 10 days of age a male and a female from different
litters within treatment groups were cohabited for seven days. The pairs were then
separated and the females were allowed to deliver their litters. There were 20 pairs in
the 0, 0.25, and 0.5% BPA group and 11 pairs in the 1% BPA group due to decreased
viability of weanlings in this group. One female died in the 0.25% BPA group during
this trial. F, mice were necropsied three weeks after the cohabitation period. No sig-
nificant difference was observed in the reproductive performance of F, breeding pairs
exposed to BPA as compared to controls. Postpartum weights for F, females after de-
livery of a single litter did not differ significantly among treatment groups. However,
at necropsy, adjusted liver and kidney/adrenal weight of BPA-treated E male and fe-
male mice were significantly higher (p < 0.05 or 0.01) than of control mice. At the
lowest dose tested the relative liver weights were increased 6.7% and 5.9% for males
and females, respectively, and the increase of the relative kidney weights was 15.7 and
12.5%, respectively. Both organs exhibited an increase in treatment-related lesions.
Centrilobular hepatocytomegaly, multifocal hepatocellular necrosis, and multinucle-
ated giant hepatocytes were observed in the livers of male mice of all three treated
groups, but were not observed in control F, males. Hepatic lesions in F, females in-
cluded multinucleated giant hepatocytes, and multifocal necrosis that occurred in a
dose-related manner and with less severity than in treated male F, mice. Multifocal
mineralization of hepatic cells was also observed in the females of the 1% BPA group.

65

Effects

</pre>

====================================================================== Einde pagina 65 =================================================================

<br><br>====================================================================== Pagina 66 ======================================================================

<pre>Kidney lesions including cortical tubular dilatation, tubular casts, microcalculi, and
mineralization-of renal cells occurred ina dose-related:manner in bothrF; male and fe-
male mice. Renal lesions tended to be more prominent in F, female than in F, male
mice. Treated F, males also exhibited significantly reduced (p < 0.05 or 0.01) adjusted
weight of reproductive organs at all three dose levels, indicating BPA toxicity, al-
though there was no histopathological evidence of tissue lesions. Sperm assessment in-
dicated a significant reduction (p < 0.01) in sperm motility in the 0.5% BPA group
relative to controls.

The authors concluded that BPA was a reproductive toxicant that caused a reduc-
tion in the number of live pups born in the F, generation at the two highest doses, and
reduced sperm motility and weight of some male reproductive organs in both the F,
and the F, generations, and reduced postnatal survival of the F, generation. These ef-
fects were accompanied by significant hepatic and renal toxicity in the parental F, and
F, animals. It is possible therefore, that some or all of the adverse effects on reproduc-
tive performance observed in this study may be secondary to the generalized toxicity
of BPA (Ree85). The committee feels that there are insufficient data to make a defini-
tive conclusion on the mode of action of BPA.

DGEBPA, rats and rabbits

A one-generation reproduction study in rats was conducted in which DGEBPA-based
epoxy resin (Araldite GY250 or TK 10490) was administered by gavage at doses of 0,
20, 60, 180 and 540 mg/kg. Oral administration of this resin to males for ten weeks and
to females for two weeks prior to mating produced a lower mean body weight in males
at 540 mg/kg/day, but did not affect mating performance, gestation period, or the abil-
ity of females to successfully rear their offspring to weaning. No treatment-related
macroscopic changes, differences in mean organ weights or histologic changes in the
reproductive or alimentary tracts (highest dose only) in either sex of the F, generation
were observed (study from 1989, reported by Gar92).

The same compound, TK 10490, was administered to rats and rabbits throughout
gestation. The purity of the compound is not given, but the density varies between
0.998 and 1.009 g/ml. The nominal dosages for rats were 60, 180 and 540 mg/kg/day,
for rabbits 20, 60 and 180 mg/kg/day. The achieved dosages were for rats 5 - 16% be-
low those intended, for rabbits they were 4 - 23% below those intended. The com-
pound was administered by oral gavage, on GD 6 - 15 to rats, and on GD 7 - 19 to
rabbits. The group size was 22 - 24 rats, and 15 - 17 rabbits.

Bisphenol A and its Diglycidylether

</pre>

====================================================================== Einde pagina 66 =================================================================

<br><br>====================================================================== Pagina 67 ======================================================================

<pre>Results of the rat study

Treatment with the high dose was associated with:
= — post-dosing salivation in all animals generally for five days
* retarded weight gain during the dosing period.

Treatment with the mid dose was associated with:
= post-dosing salivation in occasional animals for one to four days.

At 60 mg/kg no adverse effects were detected in the parent female.

Litter parameters as assessed by mean values for litter size, pre- and post-
implantation losses, litter and mean foetal weight were not adversely affected by treat-
ment.

Treatment with TK 10490 had no adverse effect on the incidence of malforma-
tions, visceral and skeletal anomalities or skeletal variants (Smi88a).

Results of the rabbit study

Treatment with the high dose was associated with:

"anorexia and cold ears in approximately half of the animals during the dosing pe-
riod

* reduced food consumption resulting in initial weight loss during the dosing period.

Treatment at 60 and 20 mg/kg/day did not produce any clear or consistent adverse ef-
fects on the parent female. Mean litter parameters at 180, 60 and 20 mg/kg/day were
essentially similar to the controls, none of the differences from controls attained statis-
tical significance (p > 0.05).

Treatment with TK 10490 showed no obvious adverse effect on embryonic and
foetal development as assessed by overall incidences and types of malformations, vis-
ceral and skeletal anomalies (Smi88b).

It can be concluded that 180 mg/kg/day is a NOAEL for rats and that 60 mg/kg/day
is a NOAEL for rabbits.

DGEBPA was applied daily to the clipped skin of pregnant New Zealand White
rabbits for approximately six hours a day at dose levels of 30, 100, or 300 mg/kg/day,
dissolved in polyethylene glycol 400 on days 6 through 18 of gestation. Control rabbits
received polyethylene glycol alone. Each treatment group consisted of 26 animals. All
rabbits were killed on day 28 of gestation. Dermal application produced a dose-related
increase in erythema, exfoliation/fissuring, haemorrhage, and oedema at the site of ap-
plication. No treatment-related effects on body weights, body weight gains, or liver
weights of pregnant rabbits were observed. A summary of the reproductive parameters

67

Effects

</pre>

====================================================================== Einde pagina 67 =================================================================

<br><br>====================================================================== Pagina 68 ======================================================================

<pre>and foetal observations made at the time of Cesarean section are presented in Table 12.
External; visceral,:and: skeletal. observations-were performed on the foetuses; but no
statistically significant increases in malformations or variations were observed in any
treatment group when compared with the control group. A total of eight foetuses, scat-
tered throughout the dose levels, exhibited malformations. Most of these malforma-
tions have also been observed at these low frequencies in historical control data of
New Zealand White rabbits. Therefore, it can be concluded that no evidence of embryo
or foetal toxicity or teratogenicity was observed at any dose level used in this study.
Thus, the embryo/foetal no-observed effect level for dermally applied DGEBPA was
300 mg/kg/day, the maximum tolerated dose (Bre88).

Conclusion

After oral administration of BPA to rats and mice during gestation there was no sig-
nificant effect on any observed measure of developmental toxicity, or on the incidence
of external, visceral, or skeletal malformations at dosages which cause significant ma-
ternal toxicity (rats) or mortality (mice). In a complete reproduction and fertility as-
sessment by continuous breeding in mice treated with 0.25, 0.5 or 1% BPA significant
hepatic and renal toxicity of BPA is the primary cause of the reproductive effects.

Continuous oral administration of a low molecular weight DGEBPA-based resin to
male and female rats did not induce teratogenic or embryotoxic effects in the offspring.
After oral administration of a low molecular weight DGEBPA-based resin during ges-
tation there was no significant effect on any observed measure of developmental toxic-
ity, or on the incidence of teratogenic or embryotoxic effects in rats and rabbits at
dosages which induce maternal toxicity (540 mg/kg/day for rats, 180 mg/kg/day for
rabbits).

Dermal application of the maximum tolerated dose of DGEBPA (300 mg/kg/day, 6
hr/day) on days 6 through 18 of gestation had no effect on the reproductive perform-
ance of rabbits. No embryo or foetal toxicity or teratogenicity was observed.

7.1.7

Other studies

BPA has a weak oestrogenic activity; when compared to the human hormone
oestradiol-17B, the oestrogenic activity of BPA is approximately 1 : 2000 that of oes-
tradiol for rat oestrogen receptors and approximately 1 : 5000 that of oestradiol for hu-
man progesterone receptors (Kri93).

In another study the oestrogenic activity of BPA was 1000-fold lower than that of
oestradiol (Bro95).

68

Bisphenol A and its Diglycidylether

</pre>

====================================================================== Einde pagina 68 =================================================================

<br><br>====================================================================== Pagina 69 ======================================================================

<pre>Table 12 The effect of dermal application of DGEBPA on reproductive parameters in rabbits (Bres88).

DGEBPA (mg/kg/day)

0 30 100 300
no. deaths/no. of females 1/26 0/26 0/26 0/26
pregnancies detected by stain 0/0 0/6 0/5 1/4
% pregnant 100 77 81 86
no. of litters 23° 20 21 23°
corpora lutea per dam* 9+2 10 +1 10 + 2 10 +2
implantations per dam’ 123 7+3 723 7+2
live foetuses per litter? 623 743 723 6+3
% implantations resorbed 14 (23/164) 4 (6/142) 6 (8/144) 14 (20/148)
foetal body weight (g)° 36.7 + 5.3 35.7 + 5.3 36.7 2 5.5 36.9 + 5.6
foetal sex ratio, M:F 50:50 40:60" 45:55 49:51

4 Statistically different from control or a binomial distribution (a = 0.05).
t — Two females aborted their litters.

© — Two litters completely resorbed.

4 x+SD.

* x of litter means + SD.

A single sc injection of 0.25 mg (5.2 - 6.9 mg/kg) into immature rats increased the
glycogen production of the uterus 18 h later (Bit70).
The committee feels that these data are too few to evaluate their meaning properly.

7.2

Observations in man

7.2.1

Irritation and sensitization

Irritation

Complaints about eye, nose, and throat irritation have been received from workers ex-
posed to BPA dust at average (8-h TWA) atmospheric levels of 5 mg/m (EPA85).
However, no information is available on the clinical aspects of the complaints, the
number of persons exposed, the number with and without complaints or the size distri-
bution of the particles. However, available monitoring data from other sources indicate
that BPA dust is readily available because of its respirable size. In two samples col-
lected during packaging of flaked BPA less than respectively 30 and 14% of the BPA
dust by weight was less than 10 pin size. Plant area monitoring studies showed daily
levels between 0.4 and 6.8 mg/m’. It can be concluded that at least a part of the BPA
dust is inhalable, and possibly also respirable.

On the other hand, another report states that eye and nose irritation was generally
not seen until concentrations approached 15 mg/m? (it is not given whether this con-
centration was an 8 h TWA) (Row62). Also here, data are lacking on clinical spects

69

Effects

</pre>

====================================================================== Einde pagina 69 =================================================================

<br><br>====================================================================== Pagina 70 ======================================================================

<pre>and numbers of persons. The irritation is described as nuisance irritation, and, there-
fore, has to be ascribed‘to inert dust, rather than-to BPA toxicity.

Generated dusts of BPA, if inhaled, may produce irritation of the upper respiratory
passages. Skin contact may also cause some mild irritation (Oom83).

Sensitization

Several case studies of allergies to BPA and DGEBPA are listed in Table 13. All cases
reacted positively to the patch tests.

Allergic reactions to BPA and DGEBPA were investigated by patch testing workers,
patients, or volunteers on many different occasions. Results are listed in Table 14.

The studies where the number of workers that are occupationally exposed to DGE-
BPA is given, are taken together; they comprise of (Jol87, Hol93, Pre86, Bru89,
Suh83). Of a total of 3331 workers there were 274 persons with skin disorders. Upon
patch testing of these persons 137 reacted positively to DGEBPA. That means that the
frequency in which sensitization occurs is in the order of 4%. This is in line with other
incidences of allergy.

Cross-sensitization

When tested in a group of six patients with a confirmed allergic contact dermatitis to
epichlorohydrin no cross sensitization was found with BPA. In all cases the patch with
1% BPA scored negative after 48 and 72 h (Joo88a).

When tested in a group of 71 patients with occupational contact allergy for DGEBPA,
no cross sensitization occurred with BPA. Patch tests were performed with 1% BPA
and approximately 0.55% DGEBPA (J0187).

On the other hand, two of eight patients with contact allergy to bisphenol F (isomer of
dihydroxydiphenylmethane) were also allergic for BPA (Bru85).

Four non-atopic females with hypersensitivity to BPA, confirmed by a positive
patch test (1% in ethanol), showed positive reactions to dimethyldi-
(4-hydroxyphenyl)silane (1% in acetone) (Fre61).

Eighteen patients hypersensitive to diethylstilbestrol are also allergic to BPA
(Fre60 and Fre62a).

Three patients with allergic contact dermatitis for bis-GMA (an epoxyacrylate)
were also allergic to DGEBPA (Jol90).

70

Bisphenol A and its Diglycidylether
</pre>

====================================================================== Einde pagina 70 =================================================================

<br><br>====================================================================== Pagina 71 ======================================================================

<pre>Conclusion

BPA induces mild irritation in skin, eyes, nose and throat.

Even in selected groups of workers allergic reactions to BPA are only elicited in
rare cases.

Cross sensitization has been described between BPA and bisphenol F,
dimethyldi-(4-hydroxypheny])silane, and diethylstilbestrol.

DGEBPA is a skin sensitizer, the incidence in occupationally exposed workers is
approximately 4%. In a few workers it can cause asthma.

Three patients with allergic contact dermatitis for bis-GMA were also allergic to
DGEBPA.

7.2.2

Acute toxicity (incidents)

No data available.

7.2.3

Short-/long-term exposure (accidental, controlled)

No data available.

7.2.4

Epidemiological studies

A chromosome aberration test on peripheral lymphocytes of human beings was con-
ducted on nine individuals (aged 30-66 years, median 45.4 years) occupationally ex-
posed to epoxy resins for 5-16 years (median 6.5 years; Mit80). The average MW of
the epoxy resin was < 900, the main oligomer was DGEBPA, the hardener used was of
the aliphatic amine type. There was a well-developed protective program but intermit-
tent contamination of the skin could not be prevented. A control group consisted of
nine workers matched for sex and age who carried out metal-work in the same factory,
but had not been occupationally exposed to epoxy compounds. However, the smoking
habits of both groups were not recorded.

The frequency of chromosomal aberrations was analyzed in peripheral lympho-
cytes cultured for 72 h. From each individual 200 metaphases were analyzed. The fre-
quency of sister-chromatid exchanges in PHA-stimulated lymphocytes was studied
after 72.5 h incubation; 20 cells with 46 chromosomes were examined in each individ-
ual.

There was no difference between the controls and the group exposed to epoxy
resin. This was true for all types of aberrations recorded, including the sister-chromatid
exchanges. The results, however, should be interpreted with caution. It is generally

71

Effects
</pre>

====================================================================== Einde pagina 71 =================================================================

<br><br>====================================================================== Pagina 72 ======================================================================

<pre>Table 13 Case studies of allergic reactions to BPA and DGEBPA.

exposure* sex: - age symptoms: patch test > reference
epoxy resin (1 week) man 18 yr irritation on the wrist and forearms, 1% BPA Gau60
dermatitis on the face and neck, oedema
of the eyelids and external nares
wax containing 15 or man 53 yr acute dermatitis of the right hand, a 1% BPA Fre84
30% BPA (5 yr) less florid dermatitis of his nose and
nasolabial folds
plastic footwear woman 17 yr dermatitis over the dorsa of 1% BPA Sri89
both feet
plastic footwear man 25 yr dermatitis over the dorsa of 1% BPA Sri89
both feet
epoxy resin (> 1 yr) man 56 yr contact dermatitis on the face, 1% BPA Joo90
in the inguinal region, and on
the lower legs
probably glue used for re- woman 65 yr burning mouth, burning tongue, slight BPA [?%] Joo88a,
pair of dental plates erythema .ICDRG-epoxy resin’ [?%] Joo88b
wool mixed with syntheticman 55 yr petechial and purpuric lesions on the 1% BPA Rom8l
fibres (15 yr) face and the dorsum of the fingers epoxy resin [?]*
door handles woman 42 yr dermatitis of the volar side of her hand ICDRG-epoxy resin [7%]  Fre80
screwdrivers man not reported hand eczema ICDRG-epoxy resin [27%]  Fis87
metal under watch strap woman not reported dermatitis under her watch strap ICDRG-epoxy resin [27%] — Fre80
epoxy resin man 53 yr dermatitis on face, hands, arms ICDRG-epoxy resin [2%]; Bok82
and chest 0.1% DGEBPA
epoxy resin woman 27 yr dermatitis on hands and face 5.8% epoxy resin; ICDRG- Bok82
epoxy resin [?%]
epoxy resin based woman 26 yr dry fissured and itchy lesions on BPA [2%] Rom86

green glue (four weeks)

the finger tips of both hands and
left palm

epoxy resin [7]

a

b

tional Contact Dermatitis Research Group.
* Positive patch tests to colophy, formaldehyde, neomycin, 1% BPA, 5% urea-formaldehyde resin, 5% melamine formaldehyde,
delayed response to epoxy resin.

Duration before beginning of the symptoms is presented in parentheses.
ICDRG-epoxy resin is a commercial grade DGEBPA epoxy resin and has an average MW of 385 (Pre86). ICDRG = Interna-

green glue (1% and 0.1%) was positive in the patient and negative in 25 healthy controls.

Standard patch tests were positive to epoxy resin, BPA, formaldehyde, paratertiarybutylphenol and formaldehyde resin. The

72 Bisphenol A and its Diglycidylether
</pre>

====================================================================== Einde pagina 72 =================================================================

<br><br>====================================================================== Pagina 73 ======================================================================

<pre>Table 14 Patch tests performed on workers, patients, or volunteers.

group patch test result reference

8 persons with dermatitis following occu- 1% BPA no allergic reactions Fre62b

pational exposure to uncured epoxy resin,

6 positive patch tests to epoxy hardeners

50 control persons 1% BPA no allergic reactions Fre84

5 patients sensitive to epichlorohydrin 1% BPA no allergic reactions Joo90

100 patch-tested patients 1% BPA no allergic reactions Bru85

20 volunteers 1% and 2% BPA no allergic reactions Pre86
1% DGEBPA

236 workers with ACD’ not caused by 1% BPA 1 allergic reaction Jol90

DGEBPA epoxy resins and 28 workers

with current or past ACD caused by epoxy

resins

13 persons with no occupational exposure 1% BPA 7 allergic reactions Fre62b

to epoxy resins, but with a positive patch

test to epoxy resin

16 patients with contact dermatitis 1% BPA 6 allergic reactions, 1 photo- Gri81

allergic reaction
50 control subjects 1% BPA no allergic reactions

48 persons sensitive to Epidian 5° of 422 2% BPA
working at 8 factories

8 workers (of 130 employees) with derma- 1% BPA;1% DGEBPA
titis, handling fibreglass coated with un-
cured epoxy resin (6/8 were tested)

71 workers with ACD caused by DGEBPA 1% BPA

epoxy resins out of 1082 cases of occupa- 1% epoxy resin (European stan-

tional skin diseases among 2484 patients  dard) containing + 0.55% DGE-
BPA

167 individuals with a history suggestive 1% DGEBPA
of DGEBPA-based epoxy resin contact 1% BPA
dermatitis, in this group 70 individuals

with ACD
8 workers exposed to dense fumes of 1% epoxy resin (88.5% BPA);
heated epoxy resin, consisting of 88.5%  0.001-1% epoxy resin and 0.01-1%
BPA BPA followed by
UV-A (6 Jfent)
8 healthy volunteers 1% epoxy resin (88.5% BPA) and
1% BPA followed by UV-A (20
J/cm’)

13 allergic reactions Kra76

all 6 had allergic reactions to DGE- Hol89
BPA;
no allergic reaction to BPA

68 allergic reactions to DGEBPA;no 30187
allergic reactions to BPA

30 allergic reactions to DGEBPA;no —_Ho193
allergic reactions to BPA; 19 allergic
reactions to different types of hardeners

3 allergic and 4 photoallergic reactions All79
to epoxy resin;
8 photoallergic reactions to BPA

no photoallergic reactions All79

73 Effects

</pre>

====================================================================== Einde pagina 73 =================================================================

<br><br>====================================================================== Pagina 74 ======================================================================

<pre>Table 14 Continued.

group”

patch test

result:

reference

19 of 26 workers with work-related erup-
tions in an epoxy resin manufacturing plant
with 228 workers

1559 patients

5 spinners in a fibre glass industry in con-
tact with non-hardened epoxy resin, 1
worker in contact with dry glass fibre some
of which epoxy coated

1008 workers with ACD or other skin dis-
eases not caused by DGEBPA epoxy resins
out of 2484 patients

6 workers with ACD caused by DGEBPA
epoxy resins with a MW>700 out of 2484

patients

dustry

34 patients suspected for occupational con-
tact dermatitis

8 patients suspected for occupational der-
matitis to a commercial epoxy resin with
average MWs of 1280 and 1850

23 workers with ACD caused by DGEBPA
epoxy resins

5 workers with a past relevant ACD caused
by DGEBPA epoxy resins

7 workers with ACD and 1 worker with
contact urticaria mainly caused by the
hardeners or the diluents present in DGE-
BPA epoxy resins

66 spinners working in the glassfibre in-

79 workers (of a total of 159 employees)
making printed circuit boards with a.0.
DGEBPA, with current or previous allergic
or irritant skin disorders

79 age and sex matched controls

1% ICDRG epoxy resin‘ (average
MW 385); 1% liquid epoxy resin
(average MW 370)

1% solid epoxy resin (average MW
980, containing 10-15% DGE-
BPA); 1% epichlorohydrin 1% and
2% BPA

1% DGEBPA
DGEBPA [7%]

1% epoxy resin (European stan-
dard) containing + 0.55% DGE-
BPA

1% epoxy resin (European stan-
dard) [DGEBPA concentration not
reported, probably + 0.55%]

1% DGEBPA

3.7% average MW 1280
5.3% average MW 1850

1% DGEBPA

1% DGEBPA

1% DGEBPA

1% DGEBPA-based epoxy resin
[average MW not reported]

dust extract?
DGEBPA [concentration not re-
ported]

DGEBPA [concentration not re-
ported]

10 allergic reactions to ICDRG epoxy
resin, 8 to liguid epoxy resin, 7 to solid
epoxy resin, and 7 to all 3 types; 8 al-
lergic reactions to epichlorohydrin; 4
concomitant sensitizations to epoxy
resin; no allergic reactions to BPA

58 allergic reactions

6 allergic reactions

15 allergic reactions

6 allergic reactions

34 allergic reactions

8 allergic reactions caused by DGE-
BPA present in the resin

23 allergic reactions?

5 allergic reactions

1 allergic reaction

16 allergic reactions

6 allergic reactions to dust extract and
DGEBPA

3 allergic reactions

Pre86

Hol93
Dah79

J0187

J0187

Fre77

Fre77

Jol90

Jol90

Jol90

Cuy75

Bru89

Bru39

74

Bisphenol A and its Diglycidylether

</pre>

====================================================================== Einde pagina 74 =================================================================

<br><br>====================================================================== Pagina 75 ======================================================================

<pre>Table 14 Continued.

group patch test result reference
135 workers handling uncured epoxy resin 1% epoxy resin (European stan- 25 allergic reactions Put84
employed by 10 companies in the con- dard) [concentration DGEBPA or
struction industry average MW not reported]
871 patients suspected for ACD 1% ICDRG-epoxy resin‘ (average 3 allergic reactions Pre86
MW 385)
35 workers in a ski-stick factory with 293 1%ICDRG-epoxy resin‘ (average 15 allergic reactions” Suh83
employees MW 385)
20 unexposed controls and 5 exposed pa- _prick test with epoxy resin contain- no allergic reactions Kan91
tients ing 89% DGEBPA
23 workers making DGEBPA epoxy resins 1% Epidian 5° S allergic and 9 photoallergic reactions Bac88
with allergic and irritant skin disorders of a 1% Epidian 3° to Epidian 5;
total of 74 employees 2 allergic and 6 photoallergic reactions
to Epidian 3
22 control persons 1% Epidian 3 no allergic or photoallergic reac- Bac88
1% Epidian 5 tions
99 persons in contact with epoxy res- 1% Epidian 5° 48 allergic reactions Kra76

ins and with dermatitis

* ACD: allergic contact dermatitis.

> CAS reg. nr. 25068-38-6, a polymer from BPA and epichlorohydrin.

° — ICDRG = International Contact Dermatitis Research Group

Kd
tion of 1%.

€ One of them had an immediate urticarial reaction, he had both dermatitis and rhinitis.

CAS reg. nr. not known, probably the same polymer as Epidian 5 with a different average MW.

Dust collected from the area around the impregnation machines, extracted with ethanol and adjusted to a DGEBPA concentra-

2 twoofthese patients (further described by Kan91) had occupational immediate allergy (asthma) and delayed allergy (allergic
contact dermatitis). Both reacted to the intracutaneous prick test and the specific IgE determinations. A provocation test was

not performed.

agreed that 48-52 h cultures will issue first-division cells, 72 h will give first, second
and third divisions. The use of a 72-h-fixation time for the assay of chromosomal aber-
rations may therefore result in a loss of cells with aberrations. It should also be men-
tioned that only G, cells are assayed in peripheral blood investigation, cells in other
stages of the cycle may be more sensitive. Another important factor may be the type of
exposure. The people in this study were exposed by skin contact, but probably not by
inhalation as the epoxy resin has a low vapour pressure (Mit80). However, dermal ab-
sorption in mice is slow (section 5.1) and it may be expected that this is the same for
humans. It was stated that it cannot be excluded that if individuals are exposed by in-
halation they will receive higher doses, which may raise the level of chromosomal ab-
errations above normal. But due to the expected low vapour pressure of DGEBPA,

75 Effects

</pre>

====================================================================== Einde pagina 75 =================================================================

<br><br>====================================================================== Pagina 76 ======================================================================

<pre>workers can only be exposed to high concentrations of DGEBPA after aerosol forma-
tion or if the material-is heated:

A health-hazard evaluation was performed at a manufacturing site using DGEBPA-
based epoxy resin (study from 1975, reported by Gar92). Based on the results of envi-
ronmental air measurements, medical questionnaires, pulmonary function tests, and
skin patch tests, it was concluded that the resin used did not represent a health hazard
at the concentrations measured during normal operating conditions. The concentrations
were not given.

Conclusion

No chromosomal aberrations, including sister-chromatid exchanges were seen in work-
ers occupationally exposed to DGEBPA.

7.3

Summary

7.3.1

Bisphenol A
Animal data

BPA is a slight skin irritant.

BPA is not a skin sensitizer in guinea pigs. BPA is a photosensitizer in mice, but
not in guinea pigs.

According to EC classification based on LD,, data, BPA is of a low order of toxic-
ity after oral and dermal administration. Due to the low vapour pressure of BPA, and
the lack of data, the inhalation toxicity cannot be assessed.

Subcutaneous implantation of BPA had no effects on mice in dosages up to 100
mg.

Oral dosing via the diet of 5% BPA for two weeks killed six out of eight mice. At
2.5% BPA mice showed dehydration, dyspnoea, lethargy, tremors, and ptosis. Feeding
of 15,000 to 25,000 ppm for 13 weeks depressed weight gain in male mice. In female
mice weight gain was depressed after feeding BPA from 5000 ppm upward, but the de-
crease was not dose-related. Multinucleated giant hepatocytes were observed in male
mice after feeding BPA from 5000 ppm with a dose-related increase in incidence and
severity.

In rats 8000 - 12,000 ppm BPA in the diet reduced body weight gain after two,
four and eight weeks. Feeding rats 2500 ppm BPA for 90 days induced slight alopecia.
Enlarged caeca were observed after feeding from 500 ppm upward in female rats and

76

Bisphenol A and its Diglycidylether

</pre>

====================================================================== Einde pagina 76 =================================================================

<br><br>====================================================================== Pagina 77 ======================================================================

<pre>from 250 ppm upward in males. No microscopic abnormalities were found. Hyaline
masses were found in the bladder of male rats, there was no dose-related increase.

Feeding dogs for 90 days with 9000 ppm BPA increased the mean liver weight. No
other changes were observed. No effects were observed after feeding 3000 ppm.

The almost maximum attainable concentration in air, 150 mg/m’, and 50 mg/m’,
induced porphyrin-like reddish staining around the nose, and perineal soiling in rats,
decreased body weight, and very slight to slight hyperplasia and chronic inflammation
in the nasal cavity. The effects were reversible upon cessation of exposure. The 90-day
no-effect level for rats was 10 mg/m’.

There is no convincing evidence that BPA is carcinogenic for rats or mice of either
sex. The lowest dose tested, 74 mg/kg/day, reduced the body weight gain in male and
female rats. The latter were more sensitive to this effect.

BPA does not induce mutations in bacteria, does not induce chromosomal aberra-
tions, sister chromatid exchanges, or transformation in mammalian cells in vitro.

After oral administration of BPA to rats and mice during gestation there is no sig-
nificant effect on any observed measure of developmental toxicity, or on the incidence
of external, visceral, or skeletal malformations at dosages which cause significant ma-
ternal toxicity (rats) or mortality (mice).

In a complete reproduction and fertility assessment by continuous breeding in mice
treated with 0.25, 0.5, or 1% BPA, significant hepatic and renal toxicity of BPA occurs
simultaneously with reproductive effects.

Human data

BPA induces mild irritation in skin, eyes, nose and throat.

Even in selected groups of workers allergic reactions to BPA are only elicited in
rare cases. Cross sensitization has been described between BPA and bisphenol F,
dimethyldi-(4-hydroxyphenyl)silane, and diethyistilbestrol.

7.3.2

Diglycidyl ether of bisphenol A
Animal data

DGEBPA is a skin irritant. It is either not or at most only a slight eye irritant. DGE-
BPA is a strong skin sensitizer.

According to EC classification based on LD,, data, DGEBPA is of a low order of
acute toxicity upon oral and dermal administration. Due to the low vapour pressure of
DGEBPA and the lack of data, the acute inhalation toxicity cannot be assessed.

77

Effects

</pre>

====================================================================== Einde pagina 77 =================================================================

<br><br>====================================================================== Pagina 78 ======================================================================

<pre>The feeding of DGEBPA to rats at dietary concentrations up to 30,000 ppm for
three months does not‘induce-systemic toxicity: Dosages of 50,000 ‘ppm induce death
in 100% of the rats by the end of 20 weeks, mainly due to malnutrition.

After dermal application and subcutaneous injections of pure and commercial
DGEBPA no skin tumours developed in rats and mice. Although lymphoreticular tu-
mours were increased in some groups of some experiments, the data lacked consis-
tency and therefore the increase of this spontaneously occurring tumour is not
considered indicative of a carcinogenic potential of the compound.

DGEBPA is mutagenic in bacterial test systems. It probably causes basepair substi-
tutions rather than frameshift mutations. In higher concentrations (0.8 mg/mouse)
DGEBPA or a metabolite (glycidaldehyde) may react with DNA in mammals in vivo
after dermal application.

DGEBPA may induce neoplastic transformations, gene mutations and chromoso-
mal aberrations in mammalian cells in vitro. It is negative in the host-mediated assay.
It does not induce UDS in human cells in vitro. No induction of micronuclei, dominant
lethality or DNA single strand breaks are observed in mammals in vivo.

Continuous oral administration of commercial DGEBPA to male and female rats
did not induce teratogenic or embryotoxic effects in the offspring. After oral admini-
stration of commercial DGEBPA during gestation, there is no significant effect on any
observed measure of developmental toxicity, or on the incidence of teratogenic or em-
bryotoxic effects in rats and rabbits at dosages which induce maternal toxicity (540
mg/kg/day for rats, 180 mg/kg/day for rabbits). Dermal application of the maximum
tolerated dose of DGEBPA (300 mg/kg/day, 6 h/day) on days 6 through 18 of gestation
had no effect on the reproductive performance of rabbits. No embryo or foetal toxicity
or teratogenicity was observed.

Human data

DGEBPA is a skin sensitizer, the incidence in occupationally exposed workers is ap-
proximately 4%. In a few workers it can cause asthma.

Three patients with allergic contact dermatitis for bis-GMA were also allergic to
DGEBPA.

No chromosomal aberrations, including sister-chromatid exchanges were seen in
workers occupationally exposed to DGEBPA.

78

Bisphenol A and its Diglycidylether

</pre>

====================================================================== Einde pagina 78 =================================================================

<br><br>====================================================================== Pagina 79 ======================================================================

<pre>Chapter

8

Evaluation of human health risk

8.1

Groups at extra risk

Because of the sensitizing properties of DGEBPA workers who have developed a
DGEBPA allergy are at extra risk.

8.2

Assessment of health risk

8.2.1

Bisphenol A
Systemic effects

There are insufficient human data upon which to base the risk assessment. The point of
departure is therefore the animal data.

In a long-term oral study BPA was found not to be carcinogenic in male and fe-
male rats and mice. Neither were reproductive effects found in several studies with rats
and mice. The critical effect of BPA is considered to be the reduced body weight gain
followed by toxicity in liver and kidneys. The evidence can be found in several studies
(NTP82, Ree85, Mor87).

Point of departure is the 13-week inhalation study with intermittent exposure to
rats (study from 1988, reported by Web90). The critical effect was the slight to very
slight nasal hyperplasia and inflammation at 50 and 150 mg/m’, which was fully re-
versible within 12 weeks after cessation of exposure. The NOAEL was 10 mg/nt. In

79

Evaluation of human health risk
</pre>

====================================================================== Einde pagina 79 =================================================================

<br><br>====================================================================== Pagina 80 ======================================================================

<pre>view of the absence of systemic effects, and the fact that the margin of safety for local
effects between the NOAEE and the LOAEL is a factor 5, and the fact that rats are
obligatory nose-breathers and man is not, the committee concludes that for extrapola-
tion to humans a safety factor is not necessary. In view of the low vapour pressure of
BPA this concentration can only be present in the air as solid particles. Furthermore,
the particle size can be smaller than 10 p (see section 7.2.1), which implies that BPA
dust is inhalable, and partly respirable. For inhalable and respirable dust the present
Maximum Allowed Concentration-values are 10 mg/m and 5 mg/m’, respectively. The
committee recommends to use these values as occupational exposure limits for BPA.

Local effects

BPA is a slight skin irritant in animals. In humans it is a mild skin, eye, nose and throat
irritant. It is not a skin sensitizer.

8.2.2

Diglycidyl ether of bisphenol A
Systemic effects

There are insufficient human data upon which to base the risk assessment. The point of
departure is therefore the animal data.

DGEBPA is not carcinogenic in male and female mice after dermal application and
subcutaneous injections in several long-term studies. In rats it induced sarcomas at the
injection site but there was no systemic carcinogenicity. After oral administration to
rats and rabbits and after dermal application to rabbits no embryo or foetal toxicity or
teratogenicity was observed.

The critical effect of DGEBPA is considered to be the reduced body weight gain
found in male rats after oral administration of 540 mg/kg/day for ten weeks; maternal
toxicity was observed in pregnant rats after oral administration of 540 mg/kg/day dur-
ing gestation and in pregnant rabbits after oral administration of 180 mg/kg/day during
gestation. In all three cases a commercial DGEBPA-based epoxy resin was used (Ar-
aldite GY250 or TK 10490). The maternal toxicity is limited to post-dosing salivation
and retarded weight gain during the dosing period in rats, and anorexia, cold ears and
reduced food consumption during the dosing period in rabbits. The treatment was not
associated with adverse embryonic or foetal effects. The dose of 180 mg/kg/day ap-
pears to be a NOAEL for rats. The dose of 60 mg/kg/day is a NOAEL for rabbits
(Smi88a, Smi88b).

To extrapolate from animals to man a safety factor of 10 is used. Using the lowest
NOAEL found and assuming the weight of a human to be 70 kg, this results in (70 x

80

Bisphenol A and its Diglycidylether

</pre>

====================================================================== Einde pagina 80 =================================================================

<br><br>====================================================================== Pagina 81 ======================================================================

<pre>60) : 10 mg/day = 420 mg/day. Assuming that this amount is absorbed during an 8
hours working day, that 10 m* of air is inhaled during an 8 h shift, and that absorption
is 100%, then aconcentration of 42 mg/m’ can be recommended as a health based oc-
cupational exposure limit. In view of the expected low vapour pressure of DGEBPA
this concentration can only be present in the air as solid particles. In the Netherlands
the Maximum Allowed Concentration for respirable dust is 5 mg/nr and for inhalable
dust 10 mg/m’. The committee recommends to use these values as occupational expo-
sure limits for DGEBPA.

Local effects
DGEBPA is a skin irritant and a skin sensitizer. The incidence of sensitization for oc-

cupationally exposed workers is approximately 4%. It is not or at most a slight eye irri-
tant.

8.3

Recommended occupational exposure limit

The Dutch Expert Committee on Occupational Standards recommends an occupational
exposure limit of 10 mg/m’ for bisphenol A and for bisphenol A diglycidylether in the
form of inhalable dust and of 5 mg/m’ for these compunds in the form of respirable
dust as an 8 h Time-Weighted Average Concentration.

In order to prevent sensitization skin contact with bisphenol A-diglycidylether
should be avoided.

Rijswijk, 12 September 1996,
On behalf of the committee

—
poe

mrs ir C Hoeksema, Dr VJ Feron,
scientific secretary chairman

81

Evaluation of human health risk

</pre>

====================================================================== Einde pagina 81 =================================================================

<br><br>====================================================================== Pagina 82 ======================================================================

<pre>82 Bisphenol A and its Diglycidylether

</pre>

====================================================================== Einde pagina 82 =================================================================

<br><br>====================================================================== Pagina 83 ======================================================================

<pre>References

Ano67

Ano93
All79

And 78
Bac88

Beg91

Ben89

BIB89

Bit70

Bla87

Bok82

Anonymous. Bisphenol A (4,4’-Isopropylidenediphenol; 2,2-bis(4-Hydroxyphenyl)propane). Am Ind Hyg
Assoc J 1976; 28: 301-4.

Anonymous. Bisphenol A diglycidyl ether. Micromendex,1993: 19, Chris. 3 pp.

Allen H, Kaidbey K. Persistent photosensitivity following occupational exposure to epoxy resin. Arch
Dermatol 1979; 115: 1307-10.

Andersen M, Kiel P, Larsen H, e.a. Mutagenic action of aromatic epoxy resins. Nature 1978; 276: 391-2.
Bachurzewska B, Borucka I, Ogonowski E. Beruflich bedingte allergische und photoallergische Reak-
tionen auf Epoxidharze bei Eisenbahnbeschaftigten. Dermat Beruf Umwelt 1988; 36: 125-7.

Begley TH, Biles JE, Hollifield HC. Migration of an epoxy adhesive compound into a food-simulating liq-
uid and food from microwave susceptor packaging. J Agric Food Chem 1991; 39: 1944-5.

Bentley P, Bieri F, Kuster H, e.a. Hydrolysis of bisphenol A diglycidylether by epoxide hydrolases in cy-
tosolic 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: 321-7.

British Industrial Biological Research Association (BIBRA). Bisphenol A. Toxicity profile. Carshalton
Surrey, Great Britain: BIBRA Toxicology International. 8 pp.

Bitman J, Cecil HC. Estrogenic activity of DDT analogs and polychlorinated biphenyls. J Agric Food
Chem 1970; 18: 1108-12.

Blanken R, Nater JP, Veenhoff E. Protection against epoxy resins with glove materials. Contact Dermatitis
1987; 16: 46-7.

Bokelund F, Fregert S, Trulsson L. Sensitization from epoxy resin powder of high molecular weight. Con-
tact Dermatitis 1982; 6: 144.

83

References

</pre>

====================================================================== Einde pagina 83 =================================================================

<br><br>====================================================================== Pagina 84 ======================================================================

<pre>Bre88

Bro95

Bru85

Bru89

Can86

Cli8 la

Cli81b

Cra84

Cuy75

Dah79

Dor87
Ead83

EC93

ECD93

EPA85

Fis87

Fly91
Fou94

Breslin WJ, Kirk HD, Johnson KA. Teratogenic evaluation of diglycidyl ether of bisphenol A (DGEBPA)
in New Zealand white rabbits following dermal exposure: Fundam Appi Toxicol 1988, 10: 736-43.
Brotons JA, Olea-Serrano MF, Villalobos M, e.a. Xenoestrogens released from lacquer coatings in food
cans. Environ Health Perspect 1995; 103: 608-12.

Bruze M, Zimerson E. Contact allergy to dihydroxydiphenyl methanes (bisphenol F). Dermat Beruf Um-
welt 1985; 33: 216-20.

Bruze M, Almgren G. Occupational dermatoses in workers exposed to epoxy-impregnated fiberglass fab-
ric. Dermat Beruf Umwelt 1989; 37: 171-6.

Canter DA, Zeiger E, Haworth S, e.a. Comparative mutagenicity of aliphatic epoxides in Salmonella. Mu-
tat Res 1986; 172: 105-38.

Climie IJ, Hutson DH, Stoydin G. Metabolism of the epoxy resin component
2,2-bis[4-(2,3-epoxypropoxy)phenyl]propane, the diglycidyl ether of bisphenol A (DGEBPA) in the
mouse. Part 1. A comparision of the fate of a single dermal applicationa and of a single oral dose of
14C-DGEBPA. Xenobiotica 1981; 11: 391-9.

Climie IJ, Hutson DH, Stoydin G. Metabolism of the epoxy resin component
2,2-bis[4-(2,3-epoxypropoxy)phenyl }propane, the diglycidy! ether of bisphenol A (DGEBPA) in the
mouse. Part II. Identification of metabolites in urine and faeces following a single oral dose of
14C-DGEBPA. Xenobiotica 1981; 11: 401-24.

Crathorne B, Fleiding M, Steel CP, e.a. Organic compounds in water: Analysis using coupled column high
performance liquid chromatography and soft-ionization mass spectrometry. Environ Sci Technol 1984; 18:
797-802.

Cuypers JMC, Bleumink E, Nater JP. Dermatologische Aspekte der Glasfaserfabrikation. Berufsdermato-
sen 1975; 23: 143-54.

Dahlquist J, Fregert S, Trulsson L. Allergic contact dermatitis from epoxy resin finished glass fiber. Con-
tact Dermatitis 1979; 5: 190.

Dorn PB, Chou CS, Gentempo JJ. Degradation of BPA in natural waters. Chemosphere 1987; 16: 1501-7.
Eadsforth CV. Diglycidylether of bisphenol A (DGEBPA): development of a method to determine a uri-
nary metabolite. Sittingbourne: Shell research. 1983; SBGR.83.170. 24 pp.

European Commission (EC). Guide to the classification and labelling of dangerous substances and prepa-
rations: criteria for the choice of phrases indicating special risk (R phrases) and safety advice (S phrases).
Off J Eur Commun, Annex IV, Annex VI, part 3, no. L110, p A/52-A/60.

European Chemical Data and Information Network (ECDIN). Computer printout. 1993.

Environmental Protection Agency (EPA). Bisphenol A; a proposed test rule. Fed Reg 1985; 50:
20691-703.

Fischer T, Fregert S, Thulin I, e.a. Unhardened epoxy resin in tool handles. Contact Dermatitis 1987; 16:
45.

Flyvholm MA. Contact allergens in registered chemical products. Contact Dermatitis 1991; 25: 49-56.
Foureman P, Mason JM, Valencia R, e.a. Chemical mutagenesis testing in Drosophila. X. Results of 70

coded chemicals tested for the National Toxicology Program. Environ Mol Mutagen 1994; 23: 208-27.

84

Bisphenol A and its Diglycidylether
</pre>

====================================================================== Einde pagina 84 =================================================================

<br><br>====================================================================== Pagina 85 ======================================================================

<pre>Fre60 Fregert S, Rorsman H. Hypersensitivity to diethylstilbestrol. Acta Derma Venereol 1960; 40: 206-19.

Fre61 Fregert S, Rorsman H. Allergy to a carbon-functional organic silicon compound,
dimethyldi-(4-hydroxypheny])-silane. Nature 1961; 192: 989-90.

Fre62a Fregert S, Rorsman H. Cross-sensitisation pattern observed in patients hypersensitive to diethyistilbestrol.
Proc XII Intern Congr Dermatol, Exerpta Medica Inter Congr Ser 1962; 55: 1231-3.

Fre62b Fregert S, Rorsman H. Hypersensitivity to epoxy resins with reference to the role played by bisphenol A. J
Investig Dermatol 1962; 39: 471-2.

Fre77 Fregert S, Thorgeirsson A. Patch testing with low molecular oligomers of epoxy resins in humans. Contact
Dermatitis 1977; 3: 301-3.

Fre80 Fregert S, Persson K, Trulsson L. Hidden sources of unhardened epoxy resin of bisphenol A type. Contact
Dermatitis 1980; 6: 446-7.

Fre81 Fregert S. Epoxy dermatitis from the non-working environment. Br J Dermatol 1981; 105 (Suppl 21):
63-4.

Fre84 Freeman K, Warin AP. Contact dermatitis due to bisphenol A in semi-synthetic waxes. Contact Dermatitis
1984; 11: 259-60.

Gar92 Gardiner TH, Waechter JM, Wiedow MA, e.a. Glycidyloxy compounds used in epoxy resin systems: a
toxicology review. Regul Toxicol Pharmacol 1992; 15: S1-S77.

Gau60 Gaul LE. Sensitivity to bisphenol A. Arch Dermatol 1960; 82: 1003.

Geo85 George JD, Price CJ, Wolkowski-Tyl R, e.a. Teratologic evaluation of bisphenol A (CAS no. 80-05-7) ad-
ministered to CD(R) rats on gestational days 6 through 15. Report NTP-85-089, Order No. PB85-205110.
Research Triangle Park, North Carolina: National Toxicology Program, National Institute of Environ-
mental! Health Sciences. 1985; 349 pp.

Ger90 Gerberick GF, Ryan CA. A predictive mouse ear-swelling model for investigating topical photoallergy.
Food Chem Toxicol 1990; 28: 361-8.

GR85 Gezondheidsraad. Advies inzake uitgangspunten voor normstelling. De inzichtelijke opbouw van advies-
waarden voor niet-mutagene, niet-carcinogene en niet-immunotoxische stoffen. Rapport nr. 31. 1985; 127
pp.

Gri81 Grimalt F, Romaguera C. Contact dermatitis caused by polyamide trouser pockets. Dermatosen 1981; 29:
35-9.

Har81 Hardin BD, Bond GP, Sikov MR, e.a. Testing of selected workplace chemicals for teratogenic potential.
Scand J Work Environ Health 1981; 7 (Suppl 4): 66-75.

Haw93 Haworth S, Lawlot T, Mortelmans K, e.a. Salmonella mutagenicity test results for 250 chemicals. Environ
Mutagen 1993; 5 (Suppl 1): 3-142.

Hem80 Hemminki K, Falck K, Vainio H. Comparison of alkylation rates and mutagenicity of directly acting in-
dustrial chemicals. Arch Toxicol 1980; 46: 277-85.

Her87 Herrick RF, Smith TJ. Development of a Sampling and Analytical Method for Measuring the Epoxy Con-
tent of Aerosols: I. Development of the Analytical Method. Am Ind Hyg Assoc J 1987; 48: 766-72.

Hin58 Hine CH, Guzman RJ, Coursey NM, e.a. An investigation of the oncogenic activity of two representative
epoxy resins. Cancer Res 1958; 18: 20-6.

85 References
</pre>

====================================================================== Einde pagina 85 =================================================================

<br><br>====================================================================== Pagina 86 ======================================================================

<pre>Hin91

Hol89

Hol93

JAR89

Ive89

Jol87

Jol90

Jon88

Joo88a

Joo88b

Joo90

Kan91

Kie86

Kir78

Kir80

Kna66

Kra76

Kri93

Lar89

Lew92

Hine CH, Rowe VK, White ER, e.a. Epoxy Compounds. In: Patty’s industrial hygiene and toxicology.
Eds.: Cläyton'GD; Clayton-FE. 3rd ed. New York: J. Wiley & Sons. 1991; HAs 2217-32. i

Holness DL, Nethercott JR. Occupational contact dermatitis due to epoxy resin ona fiberglass binder. J
Occup Med 1989; 31: 87-9.

Holness DL, Nethercott JR. The performance of specialized collections of bisphenol A epoxy resin system
components in the evaluation of workers in an occupational health clinic population. Contact Dermatitis
1993; 28: 216-9.

International Agency for Research on Cancer (IARC). IARC monographs on the evaluation of carcino-
genic risks to humans: Some organic solvents, resin monomers and related compounds, pigments and oc-
cupational exposures in paint manufacture and painting. Lyon 1989; 47: 237-61.

Ivett JL, Brown BM, Rodgers C, e.a. Chromosomal aberrations and sister chromatid exchange tests in Chi-
nese hamster ovary cells in vitro. IV. Results with 15 chemicals. Environ Mol Mutagen 1989; 14: 165-87.
Jolanki R, Estlander T, Kanerva L. Occupational contact dermatitis and contact urticaria caused by epoxy
resins. Acta Derm Venereol 1987; 134 (Suppl) 90-4.

Jolanki R, Kanerva L, Estlander T, e.a. Occupational dermatoses from epoxy resin compounds. Contact
Dermatitis 1990; 23: 172-83.

Jones CA, Huberman E, Callaham MF, e.a. An interlaboratory evaluation of the Syrian hamster embryo
cell transformation assay using eighteen coded chemicals. Toxicol In Vitro 1988; 2: 103-16.

Van Joost T. Occupational sensitization to epichlorohydrin and epoxy resin. Contact Dermatitis 1988; 19:
278-80.

Van Joost T, Van Ulsen J, Van Loon LAJ. Contact allergy to denture materials in the burning mouth syn-
drome. Contact Dermatitis 1988; 18: 97-9.

Van Joost T, Roesyanto ID, Satyawan I. Occupational sensitization to epichlorohydrin (ECH) and
bisphenol-A during the manufacture of epoxy resin. Contact Dermatitis 1990; 22: 125-6.

Kanerva L, Jolanki R, Tupasela O, e.a. Immediate and delayed allergy from epoxy resins based on digly-
cidyl ether of bisphenol A. Scand J Work Environ Health 1991; 17: 208-15.

Kier LE, Brusick DJ, Auletta AE, e.a. The Salmonella typhimurium/mammalian micosomal assay. A report
of the US Environmental Protection Agency Gene-Tox Program. Mutat Res 1986; 168: 69-204.
Kirk-Othmer. Encyclopedia of chemical technology, 3rd ed. New York: Intersciences.1978; 2: 90.
Kirk-Othmer. Encyclopedia of chemical technology, 3rd ed. New York: Intersciences. 1980; 9: 275.
Knaak J, Sullivan L. Metabolism of bisphenol A in the rat. Toxicol Appl Pharmacol 1966; 8: 175-84.
Krajewska D, Rudzki E. Sensitivity to epoxy resins and triethylenetetramine. Contact Dermatitis 1976; 2:
135-38.

Krishnan AV, Stathis P, Permuth SF, e.a. Bisphenol-A: an estrogenic substance is released from polycar-
bonate flasks during autoclaving. Endocrinology 1993; 132: 2279-86.

Larroque M, Brun S, Blaise A. Migration of constitutive monomers from epoxy resins used as coating ma-
terials for wine vats. Sci Aliments 1989; 9: 517-31.

Lewis sr RJ. Sax’s dangerous properties of industrial materials. 8th ed. New York: Van Nostrand Rein-
hold. 1992; IT: 511-2.

86

Bisphenol A and its Diglycidylether

</pre>

====================================================================== Einde pagina 86 =================================================================

<br><br>====================================================================== Pagina 87 ======================================================================

<pre>Lid92
Mag88

Mat83

McC90

Mit80

Mor87

Myh91

NIA92

NIO80

NTP82

Oom83

Pel86

Per88

Pre86

Put84

Ree84

Lide DR, ed. CRC Handbook of chemistry and physics. 73rd ed. Boca Raton: CRC Press, 1992; 3: 411.
Maguire jr HC. Experimental photoallergic contact dermatitis to bisphenol A. Acta Derm Venereol 1988;
68: 408-12.

Matissek R. Analysis of antimicrobial agents in non-emulsified cosmetics containing surfactants. Z Le-
bensm Unters Forsch 1983; 176: 95-101.

McCoy GD, Rosenkranz HS, Klopman G. Nonmutagenic carcinogens are primarily hydrophobic. Carcino-
genesis 1990; 11: 1111-7.

Mitelman F, Fregert S, Hedner K, e.a. Occupational exposure to epoxy resins has no cytogenetic effect.
Mutat Res 1980; 77: 345-8.

Morrissey RE, George JD, Price CJ, e.a. The developmental toxicity of bisphenol A in rats and mice. Fun-
dam Appl Toxicol 1987; 8: 571-82.

Myhr BC, Caspary WJ. Chemical mutagenesis at the thymidine kinase locus in L5178Y mouse lymphoma
cells: Results for 31 coded compounds in the National Toxicology Program. Environ Mol Mutagen 1991;
18: 51-83.

Nederlands Instituut voor Arbeidsomstandigheden and Vereniging van de Nederlandse Chemische Indus-
trie (NIA and VNCI). Chemiekaarten, gegevens voor veilig werken met chemicalién, 8th ed. Alphen aan
den Rijn: Samson HD Tjeenk Willink. 1992; 337.

National Institute for Occupational Safety and Health (NIOSH). Analytical method P&CAM no. 333.
NIOSH manual of analytical methods, Cincinnati, Ohio. 1980; 6.

National Toxicology Program (NTP). Carcinogenesis bioassay of bisphenol A (CAS No. 80-05-7) in F344
rats and B6C3F1 mice (feed study) Report NTP-80-35, Order No. PB82-184060. Research Triangle Park,
North Carolina: US Department of Health and Human Services, Public Health Service, National Institute
of Health. 1982; 117 pp.

Oomens AC, Schuurhuis FG. A method for the collection and determination of phenol and bisphenol A in
air. Intern Arch Occup Environ Health 1983; 52: 43-8.

Peltonen K, Zitting A, Koskinen H, e.a. Free radicals from photodecomposition of bisphenol A. Photo-
chem Photobiol 1986; 43: 481-4.

Peristianis GC, Doak SM, Cole PN, e.a. Two-year carcinogenicity study on three aromatic epoxy resins
applied cutaneously to CF1 mice. Food Chem Toxicol 1988; 26: 611-24.

Prens EP, De Jong G, Van Joost T. Sensitization to epichlorohydrin and epoxy system components. Con-
tact Dermatitis 1986; 15: 85-90.

Van Putten PB, Coenraads PJ, Nater JP. Hand dermatoses and contact allergic reactions in construction
workers exposed to epoxy resins. Contact Dermatitis 1984; 10: 146-50.

Reel JR, Wolkowski-Tyl R, Lawton AD, e.a. Bisphenol A: reproduction and fertility assessment in CD-1
mice when administered via subcutaneous silastic implants. Report NTP-84-015, Order No. PB84-155308.
Research Triangle Park, North Carolina: National Toxicology Program, National Institute of Environ-
mental Health Sciences. 1984; 188 pp.

87

References

</pre>

====================================================================== Einde pagina 87 =================================================================

<br><br>====================================================================== Pagina 88 ======================================================================

<pre>Ree85 Reel JR, George JD, Lawton AD, e.a. Bisphenol A: reproduction and fertility assessment in CD-1 mice
when administered"in therfeed:Report-NTP-85-192, Order No: PB86-103207. Research Triangle Park,
North Carolina: National Toxicology Program, National Institute of Environmental Health Sciences. 1985;
350 pp.

Rom81 Romaguera C, Grimalt F, Lecha M. Occupational purpuric textile dermatitis from formaldehyde resins.
Contact Dermatitis 1981; 7: 152-3.

Rom86 Romaguera C, Grimalt F, Vilaplana J. Occupational dermatitis from epoxy resins. Contact Dermatitis
1986; 174: 187.

Row62 Rowe VK. Letter to Du Pont de Nemours, dated February 5, 1962. Dow Chemical Company, Michigan.

RTE92 Register of Toxic Effects of Chemical Substances (RTECS). Computer printout.

Smi88a Smith JA, John DM, Dawe IS. A study of the effect of TK 10490 on pregnancy of the rat. Report to Ciba-
Geigy Limited. Huntingdon Research Centre Ltd. 1988. CBG442/87641.

Smi88b Smith JA, Masters RE, Dawe IS. A study of the effect of TK 10490 on pregnancy of the rabbit. Report to
Ciba-Geigy Limited. Huntingdon Research Centre Ltd. 1988. CBG440/871639.

Sri89 Srinivas CR, Devadiga R, Aroor AR. Footwear dermatitis due to bisphenol A. Contact Dermatitis 1989;
20: 150-1.

Ste92 Steiner S, Hönger G, Sagelsdorff P. Molecular dosimetry of DNA adducts in C3H mice treated with
bisphenol A diglycidylether. Carcinogenesis 1992; 13: 969-72.

Suh83 Suhonen R. Epoxy-dermatitis in a ski-stick factory. Contact Dermatitis 1983; 9: 131-3.

Ten86 Tennant RW, Stasiewicz S, Spalding JW. Comparison of multiple parameters of rodent carcinogenicity
and on vitro genetic toxicity. Environ Mutagen 1986; 8: 205-27.

Ten87 Tennant RW, Margolin BH, Shelby MD, e.a. Prediction of chemical carcinogenicity in rodents from in vi-
tro genetic toxicity assays. Science 1987; 236: 933-41.

Tho77 Thorgeirsson A, Fregert S. Allergenicity of epoxy resins in the guinea pig. Acta Derm Venereol 1977; 57:

| 253-6.

Tho78 Thorgeirsson A, Fregert S, Ramnas O. Sensitization capacity of epoxy resin oligomers in the guinea pig.
Acta Derm Venereol 1978; 58: 17-21.

Tic88 Tice PA. Pira-project on migration of monomers and overall migration. Food Addit Contam 1988; 5
(Suppl 1): 373-80.

Tos92 Tosti A, Guerra L, Bardazzi F. Occupational contact dermatitis from exposure to epoxy resins and acry-
lates. Clin Dermatol 1992; 10: 133-40.

U1175 Ullmann. Encyklopädie der technischen Chemie. Weinheim: Verlag Chemie. 1975; 10: 572-3.

U1179 Ullmann. Encyklopädie der technischen Chemie. Weinheim: Verlag Chemie. 1979; 18: 215-7.

Wad79 Wade MJ, Moyer JW, Hine CH. Mutagenic action of a series of epoxides. Mutat Res 1979 66: 367-71.
Web90 Webb CMC. HSE toxicology data base on diphenylol propane. Report D0190. Shell Internationale Petro-
leum Maatschappij BV, The Hague, Health, Safety and Environment Division. 1990; 39 pp.

Web93 Webb CMC, Bremmer JN. Review of mammalian and human toxicology. Epoxy resins based on bisphenol
A. Report HSE93.010. Shell International Petroleum Maatschappij BV, The Hague, Health, Safety and
Environment Division. 1993; 32 pp.

88 Bisphenol A and its Diglycidylether

</pre>

====================================================================== Einde pagina 88 =================================================================

<br><br>====================================================================== Pagina 89 ======================================================================

<pre>Wei63 Weil CS, Condra N, Haun C, e.a. Experimental carcinogenicity and acute toxicity of representative epox-
ides. Am Ind Hyg Assoc J 1963; 24: 305-25.

Win76 Windholz M, Budavari S, Stroumtsos LY, e.a. The Merck Index. An encyclopedia of chemicals and drugs.
8th ed. Rahway, USA: Merck & Co. 1976; 590.

Zak85 Zakova N, Zak F, Froehlich E, e.a. Evaluation of skin carcinogenicity of technical
2,2-bis-(p-glycidyloxyphenyl)-propane in CF] mice. Food Chem Toxicol 1985; 23: 1081-9.

89 References
</pre>

====================================================================== Einde pagina 89 =================================================================

<br><br>====================================================================== Pagina 90 ======================================================================

<pre>90 Bisphenol A and its Diglycidylether

</pre>

====================================================================== Einde pagina 90 =================================================================

<br><br>====================================================================== Pagina 91 ======================================================================

<pre>Request for advice

The committee

Comments on the public review draft

Synonyms of bisphenol A

Synonyms of the diglycidylether of bisphenol A

Abbreviations

DECOS-documents

91

Annexes

</pre>

====================================================================== Einde pagina 91 =================================================================

<br><br>====================================================================== Pagina 92 ======================================================================

<pre>92 Bisphenol A and its Diglycidylether

</pre>

====================================================================== Einde pagina 92 =================================================================

<br><br>====================================================================== Pagina 93 ======================================================================

<pre>Annex

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 Employ-
ment wrote:

Some time ago a policy proposal has been formulated, as part of the simplification of the governmental ad-
visory structure, to improve the integration of the development of recommendations for health based occu-
pation 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 Occupa-
tional 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:

*  Ascientific 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 for

advice. If possible this evaluation should lead to a health based recommended exposure limit, or, in

93

Request for advice

</pre>

====================================================================== Einde pagina 93 =================================================================

<br><br>====================================================================== Pagina 94 ======================================================================

<pre>the case of genotoxic carcinogens, a ‘exposure versus tumour incidence range’ and a calculated
4

concentration irr air-‘corresponding with reference-tumour incidences of 10% and 10° 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.

94

Bisphenol A and its Diglycidylether

</pre>

====================================================================== Einde pagina 94 =================================================================

<br><br>====================================================================== Pagina 95 ======================================================================

<pre>Annex
The committee
# VJ Feron, chairman
professor of toxicology; TNO Nutrition and Food Research Institute, Zeist
» RB Beems
toxicologic pathologist; National Institute of Public Health and Environmental Pro-
tection, Bilthoven
= DJJ Heederik
epidemiologist; Wageningen Agricultural University
» JJAM Brokamp, advisor
Social and Economic Council, The Hague
= PTh Henderson
professor of toxicology; University Limburg, Maastricht
=" Gde Jong
occupational physician; Shell International Petroleum Maatschappij, The Hague
" Gde Mik
toxicologist; National Institute of Public Health and Environmental Protection,
Bilthoven
= J Molier-Bloot
occupational physician; Academic Medical Centre (AMC), Amsterdam
" PC Noordam, advisor
Ministry of Social Affairs and Employment, The Hague
» H Roelfzema, advisor
Ministry of Health, Welfare and Sports, Rijswijk
95 The committee

</pre>

====================================================================== Einde pagina 95 =================================================================

<br><br>====================================================================== Pagina 96 ======================================================================

<pre>» T Smid
occupational-hygienists KLM Health‘Safety: & Environment, Schiphol
= GMH Swaen
epidemiologist; University Limburg, Maastricht
= HG Verschuuren
toxicologist; DOW Europe, Horgen (Switzerland)
= AAE Wibowo
toxicologist; Coronel Laboratory, Amsterdam
" Fde Wit
occupational physician; Labour Inspectorate, Deventer
= C Hoeksema, secretary
Health Council of the Netherlands, Rijswijk
= CA Bouwman, secretary
Health Council of the Netherlands, Rijswijk

The first draft of the present advisory report was prepared by drs MA Maclaine Pont,
from the Wageningen Agricultural University, by contract with the Netherlands Minis-
try of Social Affairs and Employment.

Secretarial assistance was provided by mrs Y Meems-von Schmidt.
Lay-out: J van Kan.

96

Bisphenol A and its Diglycidylether

</pre>

====================================================================== Einde pagina 96 =================================================================

<br><br>====================================================================== Pagina 97 ======================================================================

<pre>Annex. C
Comments on the public review draft

A draft of the present report was released in 1994/1995 for public review. The follow-
ing organisations and persons have commented on the draft document:
* dr JI Delic

Toxicology unit, Health and Safety Executive, England

“= dr WF Tordoir
Shell International Petroleum Maatschappij BV, The Netherlands

97 Comments on the public review draft

</pre>

====================================================================== Einde pagina 97 =================================================================

<br><br>====================================================================== Pagina 98 ======================================================================

<pre>98 Bisphenol A and its Diglycidylether

</pre>

====================================================================== Einde pagina 98 =================================================================

<br><br>====================================================================== Pagina 99 ======================================================================

<pre>Annex D

Synonyms of bisphenol A

2,2-(4,4’-dihydroxydiphenyl)propane
2,2-bis(4-hydroxyphenyl)propane
2,2-bis(p-hydroxyphenyl)propane
2,2-bis-4’-hydroxyfenylpropan
2,2-di(4-hydroxyphenyl)propane
2,2-di(4-phenylol)propane

4,4’ -(1-methylethylidene)bisphenol
4,4’ -bisphenol A
4,4’-dihydroxy-2,2-diphenylpropane
4,4’-dihydroxydipheny]-2,2-propane
4,4’-dihydroxydiphenyldimethylmethane
4,4’-dihydroxydiphenylpropane

4,4’ -dimethylidenediphenol

4,4 -isopropylidenebisphenol

4,4’ -isopropylidenediphenol
bis(4-hydroxyphenyl)propane
bis(4-hydroxyphenyl)dimethylmethane
bis(p-hydroxyphenyl)propane
bisphenol

bispherol A

dian
dimethyl-bis(p-hydroxyphenyl)methane

99 Synonyms of bisphenol A
</pre>

====================================================================== Einde pagina 99 =================================================================

<br><br>====================================================================== Pagina 100 ======================================================================

<pre>dimethylmethylene-p,p’-diphenol
diphenylolpropane”

DPP

NCI-C50635

Ipognox 88
isopropylidene-bis(4-hydroxybenzene)
Parabis A

Plucarol 245
p.p’-dihydroxydiphenyldimethylmethane
p.p'-dihydroxydiphenylpropane
p.p’-isopropylidenebisphenol
p.p’-isopropylidenediphenol
Rikabanol
B-di-p-hydroxyphenylpropane
B,B’-bis(p-hydroxyphenyl)propane

100

Bisphenol A and its Diglycidylether

</pre>

====================================================================== Einde pagina 100 =================================================================

<br><br>====================================================================== Pagina 101 ======================================================================

<pre>Annex E

Synonyms of the diglycidylether of
bisphenol A

2,2-bis[4-(2,3-epoxypropoxy)phenyl]propane
2,2-bis(4-hydroxyphenyl)propane diglycidyl ether
2,2-bis[p-(2,3-epoxypropoxy )pheny]]-propane
2,2-bis(p-glycidyloxyphenyl)propane
2,2-bis(4-glycidyloxypheny])propane
2,2-bis(p-glycidyloxyphenyl)dimethylmethane
2,2-bis(p-hydroxyphenyl)propane diglycidyl ether
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

4,4’ -isopropylidenediphenol-epichlorohydrin resin
Araldite GY250

Araldite GY6010

Araldite 6005
bis(4-glycidyloxyphenyl)dimethylmethane
bis(4-hydroxyphenyl)dimethylmethane diglycidyl ether
bisphenol A diglycidyl ether

bisphenol A-epichlorohydrin condensate

BPADGE

BPDGE

D.E.R. 331 epoxy resin

101 Synonyms of the diglycidylether of bisphenol A

</pre>

====================================================================== Einde pagina 101 =================================================================

<br><br>====================================================================== Pagina 102 ======================================================================

<pre>dian diglycidyl ether

dian-bis-glycidylether-

diglycidyl bisphenol A

diglycidyl bisphenol A ether

diglycidyl diphenylpropane ether

diglycidyl ether of 2,2-bis(4-hydroxy pheny])propane
diglycidyl ether of 4,4’-isopropylidenediphenol
diglycidyl ether of 2,2-bis(p-hydroxyphenyl)propane
diomethane diglycidyl ether

Epikote 828

EPI-REZ 508

EPI-REZ 510

EPON 828

EPON resin 828

EPOTUF 37-140

epoxide A

epoxy resin B1

ERL-2774

GY 6010

OHSO3222

oligomer 340
p,p’-dihydroxydiphenyldimethylmethane diglycidyl ether

102

Bisphenol A and its Diglycidylether

</pre>

====================================================================== Einde pagina 102 =================================================================

<br><br>====================================================================== Pagina 103 ======================================================================

<pre>Annex

FE

Abbreviations

103

bp
EC,,

HBR-OEL

boiling point

concentration at which a described effect is found in 50% of the exposed animals or at
which the effect is decreased up to 50% of the control value

health based recommended occupational exposure limit

hour

concentration at which inhibition of a certain function is found up to 50% of the control
value

lethal concentration for 50% of the exposed animals

lowest lethal concentration

lethal dose for 50% of the exposed animals

lowest lethal dose

lowest observed adverse effect level

maximaal aanvaarde concentratie (maximal accepted concentration)
minimal adverse effect level

Maximale Arbeitsplatz Konzentration

minimal observed adverse effect level

maximum tolerated dose

no adverse effect level

no effect level

no observed adverse effect level

occupational exposure limit

permissible exposure limit

parts per billion (v/v)10°

parts per million (v/v)10°

dose at which a 50% decrease of respiratory rate is observed
recommended exposure limit

short term exposure limit

Abbreviations

</pre>

====================================================================== Einde pagina 103 =================================================================

<br><br>====================================================================== Pagina 104 ======================================================================

<pre>teg tijd gewogen gemiddelde

TEV threshold:himit-value.

TWA time weighted average

Var maximal reaction velocity of an enzyme

Organisations

ACGIH American Conference of Governmental and Industrial Hygienists
CEC Commission of the European Communities

DECOS Dutch Expert Committee on Occupational Standards

DFG Deutsche Forschungsgemeinschaft

EPA Environmental Protection Agency (USA)

FDA Food and Drug Administration (USA)

HSE Health and Safety Executive (UK)

IARC International Agency for Research on Cancer (WHO)
INRS Institut National de Recherche et de Sécurité (France)
NIOSH National Institute for Occupational Safety and Health (USA)
NTP National Toxicology Programme (USA)

OECD Organisation for Economic Cooperation and Development
OSHA Occupational Safety and Health Association (USA)
RTECS Registry of Toxic Effects of Chemical Substances

SER Social and Economic Council (Sociaal-Economische Raad NL)
WATCH Working Group on the Assessment of Toxic Chemicals (UK)
WHO World Health Organisation

Toxicological terms

bid bis in diem (twice per day)

bw body weight .

CARA chronic non-specific respiratory diseases

CHD coronary heart disease

CNS central nervous system

ECG electrocardiogram

EEG electro encephalogram

FCA Freunds Complete Adjuvans

FEV forced expiratory volume

FSH follicle stimulating hormone

GD gestation day(s)

GPMT guinea pig maximisation test

GSH glutathione

HLiA hamster liver activated

IHD ischaemic heart disease

im intramuscular

ip intraperitoneal

ipl intrapleural

it intratracheal

iv intravenous

LH lutheinising hormone

MAIC minimal alveolar concentration

MFO mixed function oxidase

104 Bisphenol A and its Diglycidylether

</pre>

====================================================================== Einde pagina 104 =================================================================

<br><br>====================================================================== Pagina 105 ======================================================================

<pre>NA not activated

PNS peripheral nervous system
po per os (= oral)

RBC ted blood cells

RLiA rat liver activated

SCE sister chromatid exchange
SC subcutaneous

UDS unscheduled DNA-synthesis
Statistical terms

GM geometric mean

OR Odds Ratio

RR relative risk

SD standard deviation

SEM standard error of mean

SMR standard mortality ratio
Analytical methods

AAS atomic absorption spectroscopy
BEEL biological eguivalent exposure limit
BEI biological exposure index
BEM biological effect monitoring
BM biological monitoring

ECD electron capture detector
EM environmental monitoring
FID flame ionisation detector
GC gas chromatography

GLC gas liguid chromatography
GSC gas solid chromatography
HPLC high performance liguid chromatography
IR infrared

MS mass spectrometry

NMR nuclear magnetic resonance
PAS personal air sampling

TLC thin layer chromatography
UV ultraviolet

Additional abbreviations in the present report

BPA

DGEBPA
MOAEL

bisphenol A
diglycidylether of bisphenol A

minimal observed adverse effects level

105

Abbreviations

</pre>

====================================================================== Einde pagina 105 =================================================================

<br><br>====================================================================== Pagina 106 ======================================================================

<pre>106 Bisphenol A and its Diglycidylether

</pre>

====================================================================== Einde pagina 106 =================================================================

<br><br>====================================================================== Pagina 107 ======================================================================

<pre>G

Annex
DECOS-documents
DECOS has produced documents on the following substances.
To be ordered from the Health Council of the Netherlands:

Acetone cyanohydrin 1995/05WGD
Butanol (1,2- and t-) 1994/10
Cadmium and inorganic cadmium compounds 1995/04WGD
Calculating cancer risk 1995/06WGD
Carbon disulphide 1994/08
Chlorine dioxide 1995/07WGD
Ethylene glycol ethers 1996/01 WGD
Formamide and dimethylformamide 1995/08WGD
Man made mineral fibers 1995/02WGD
Methy! Methacrylate 1994/09
Methacrylates. Ethyl methacrylate, n-butyl methacrylate and isobutyl methacrylate 1994/11
Methyl-t-butylether 1994/23
Methyl chloride 1995/01WGD
Propanol (1- and 2-) 1994/24
Thrichloroethane (-1,1,1) 1995/03WGD
Trichloropropane (1,2,3-) 1994/25
The following documents, that were published before 1994, can be ordered from the
Sdu Uitgeverij Den Haag.

Acetaldehyde RA 6/92
Acrylaten RA 13/87

107 DECOS-documents

</pre>

====================================================================== Einde pagina 107 =================================================================

<br><br>====================================================================== Pagina 108 ======================================================================

<pre>Aflatoxine Bl, B2, G1 en G2
Allyiglycidylether::

Amyl acetate

Aniline

Anorganisch Lood

Anorganische Kwikzouten

Arc welding fume particles not containing chromium and nikkel
Arseenverbindingen (anorganische)
Asbest

Asbest, Evaluatie van risico op kanker bij beroepshalve blootstelling aan
(aanvullend op RA 1/84)

Benzeen

Beryllium and beryllium compounds
Blootstelling, Gezondheidskundige aspecten van het begrip en van het
meten/schatten ervan

Butadiene (1,3-)

Cadmium

Caprolactam

Carbon monoxide

Carbonylfluoride and PTFE pyrolysis products
Carcinogene stoffen

Chloor

Chloroform

B-Chloroprene

Chroom en chroomverbindingen
Cyclohexane

Cyclohexanol

Cyclohexanone

Dibroomethaan

Dichloorethaan (1,1-)

Diisocyanates

Dimethyl- en diethylsulfaat
Dimethylamine

Dimethylbutane (2,2- & 2,3-)
Dimethylhydrazine
Dinitro-ortho-cresol (4,6-)

Dioxaan (1,4-)

Epichloorhydrine

Ethylacrylate

Ethylacetate

Ethyl Methanesulphonate (EMS)
Ethylamine

Ethylbenzene

Ethyleenoxide

Fenylhydrazine

Fluorcarbons (except FC11)
Fluorine compounds (inorganic)
Fluorine

RA 6/87
RA 1/92
RA 4/90
RA 2/89
RA 2/80
RA 3/82
RA 1/93
RA 2/84
RA 1/84

RA 9/89
RA 5/89
RA 4/88

RA 8/90
RA 5/90
RA 5/80
RA 4/84
RA 7/92
RA 3/88
RA 3/80
RA 6/80
RA 7/87
RA 4/93
RA 6/85
RA 15/90
RA 3/90
RA 9/93
RA 5/87
RA 8/87
RA 3/91
RA 12/90
RA 10/90
RA 7/93
RA 2/87
RA 4/87
RA 1/87
RA 1/86
RA 6/90
RA 10/91
RA 4/89
RA 7/90
RA 9/91
RA 6/89
RA 2/87
RA 15/87
RA 1/89
RA 1/89

108

Bisphenol A and its Diglycidylether

</pre>

====================================================================== Einde pagina 108 =================================================================

<br><br>====================================================================== Pagina 109 ======================================================================

<pre>Formaldehyde
Fosfine

Fijn hinderlijk stof; gezondheidskundige aspecten van bijlage 3 bij de Nationale

MAC-lijst 1989

Gasoline

Heptaan (n-)

Heptane (n-)

Hexaan (n-)

Hexachlorobenzene

Hexanone (2-)

Hydrazine

Hydrogenfluoride
Hydroxyethylhydrazine
Isopropyiglycidylether
Isopropoxyethanol (2-)
Koolmonoxide (Carbon monoxide)
Kwikalkylverbindingen - Korte keten
Kwikverbindingen (Organische)
Lachgas (Nitrous oxide)

Lasrook (Arc welding fume......... nickel)
Mangaan

Metallisch Kwik

1-Methox ypropanol-2

2-Methox ypropanol-1

1-Methox ypropylacetate-2
2-Methox ypropylacetate-1
Methylacrylate

Methyleenchloride (Methylene chloride)
Methyl ethyl ketone

Methyl isobutyl ketone

Methyl Methanesulphonate (MMS)
Methylbromide

Methylpentane (2- & 3-)
Monochloorethaan

Monoketones (7/8 carbon chain aliphatic)
Nikkel en nikkelverbindingen
Nitropropaan (2-)

Nitrous oxide

Ozone

para-Dichloorbenzeen

Pentaan

Phthalate esters

Phthalic anhydride

Piperazine

Polyvinyl chloride (PVC) dust
Propoxyethanol (2-)

Propox yethylacetate (2-)

Pyridine

RA 3/87
RA 1/80

RA 9/90
RA 3/92
RA 1/81
RA 6/93
RA 11/87
RA 2/88
RA 2/90
RA 2/87
RA 1/89
RA 12/87
RA 1/92
RA 2/87
RA 2/79 (7/92)
RA 5/82
RA 4/82
RA 2/85 (2/92)
RA 1/93
RA 1/82
RA 5/81
RA 5/93
RA 5/93
RA 5/93
RA 5/93
RA 1/90
RA 1/83 (8/92)
RA 16/90
RA 4/91
RA 4/89
RA 13/90
RA 7/93
RA 2/82
RA 14/90
RA 3/85
RA 1/85
RA 2/92
RA 4/92
RA 1/88
RA 2/81
RA 8/93
RA 3/89
RA 7/91
RA 2/93
RA 12/87
RA 12/87
RA 3/93

109

DECOS-documents

</pre>

====================================================================== Einde pagina 109 =================================================================

<br><br>====================================================================== Pagina 110 ======================================================================

<pre>Selenium en -verbindingen RA 7/89

Silicon-dioxide; crystalline forms: of: RA 5/92
Stikstofdioxide (Nitrogen dioxide) RA 5/85
Styreen RA 8/89
Talc dusts RA 6/91
Tetrahydrofuran RA 1/91
Thiourea RA 11/90
Tolueen diisocyanaat RA 4/80
Tolueen RA 2/91
Trichloorethaan (1, 1, 1-) RA 3/81
Trichloorethyleen RA 3/83
Trichlorofluoromethane RA 14/87
Triethylamine RA 2/83
Trimethylamine RA 9/87
Vadiummetaal en anorganische verbindingen RA 10/87
Wood dust RA 8/91
Xylene RA 5/91
Zwaveldioxide (sulphur dioxide) RA 4/85
110 Bisphenol A and its Diglycidylether

ee
</pre>

====================================================================== Einde pagina 110 =================================================================

<br><br>