<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>Ethyl acrylate
    Evaluation of the carcinogenicity and genotoxicity
</pre>

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<pre></pre>

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<pre>Aan de staatssecretaris van Sociale Zaken en Werkgelegenheid
Onderwerp              : aanbieding advies Ethyl acrylate
Uw kenmerk             : DGV/MBO/U-932342
Ons kenmerk            : U-7413/BvdV/fs/246-D17
Bijlagen               :1
Datum                  : 13 november 2012
Geachte staatssecretaris,
Graag bied ik u hierbij het advies aan over de gevolgen van beroepsmatige blootstelling aan
ethylacrylaat.
Dit advies maakt deel uit van een uitgebreide reeks waarin kankerverwekkende stoffen
worden geclassificeerd volgens richtlijnen van de Europese Unie. Het gaat om stoffen
waaraan mensen tijdens de beroepsmatige uitoefening kunnen worden blootgesteld.
      Dit advies is opgesteld door een vaste subcommissie van de Commissie Gezondheid en
beroepsmatige blootstelling aan stoffen (GBBS), de Subcommissie Classificatie van
carcinogene stoffen. Het advies is getoetst door de Beraadsgroep Gezondheid en omgeving
van de Gezondheidsraad.
Ik heb het advies vandaag ter kennisname toegezonden aan de staatssecretaris van
Infrastructuur en Milieu en aan de minister van Volksgezondheid, Welzijn en Sport.
Met vriendelijke groet,
prof. dr. W.A. van Gool,
voorzitter
Bezoekadres                                                      Postadres
Parnassusplein 5                                                 Postbus 16052
2 5 11 V X D e n          Haag                                   2500 BB Den     Haag
E - m a i l : b . v. d . v o e t @ g r. n l                      w w w. g r. n l
Te l e f o o n ( 0 7 0 ) 3 4 0 7 4 4 7
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<pre></pre>

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<pre>Ethyl acrylate
Evaluation of the carcinogenicity and genotoxicity
Subcommittee on the Classification of Carcinogenic Substances of
the Dutch Expert Committee on Occupational Safety,
a Committee of the Health Council of the Netherlands
to:
the State Secretary of Social Affairs and Employment
No. 2012/19, The Hague, November 13, 2012
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<pre>The Health Council of the Netherlands, established in 1902, is an independent
scientific advisory body. Its remit is “to advise the government and Parliament on
the current level of knowledge with respect to public health issues and health
(services) research...” (Section 22, Health Act).
     The Health Council receives most requests for advice from the Ministers of
Health, Welfare & Sport, Infrastructure & the Environment, Social Affairs &
Employment, Economic Affairs, Agriculture & Innovation, and Education,
Culture & Science. The Council can publish advisory reports on its own
initiative. It usually does this in order to ask attention for developments or trends
that are thought to be relevant to government policy.
     Most Health Council reports are prepared by multidisciplinary committees of
Dutch or, sometimes, foreign experts, appointed in a personal capacity. The
reports are available to the public.
                  The Health Council of the Netherlands is a member of the European
                  Science Advisory Network for Health (EuSANH), a network of science
                  advisory bodies in Europe.
                  The Health Council of the Netherlands is a member of the International Network
                  of Agencies for Health Technology Assessment (INAHTA), an international
                  collaboration of organisations engaged with health technology assessment.
 I NA HTA
This report can be downloaded from www.healthcouncil.nl.
Preferred citation:
Health Council of the Netherlands. Ethyl acrylate. Evaluation of the
carcinogenicity and genotoxicity. The Hague: Health Council of the Netherlands,
2012; publication no. 2012/19.
all rights reserved
ISBN: 978-90-5549-917-5
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<pre>   Contents
   Samenvatting 9
   Executive summary 11
   Scope 13
.1 Background 13
.2 Committee and procedures 13
.3 Data 14
   General information 15
.1 Identity and physicochemical properties 15
.2 IARC classification 16
.3 EU classification 16
   Carcinogenicity 17
.1 Observations in humans 17
.2 Carcinogenicity studies in animals 18
   Mode of action 23
.1 Genotoxic mode of action 23
.2 Non-genotoxic mode of action 26
   Contents                                   7
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<pre>    Classification 29
 .1 Evaluation of data on carcinogenicity and genotoxicity 29
 .2 Recommendation for classification 30
    References 31
    Annexes 35
A   Request for advice 37
B   The Committee 39
C   The submission letter 41
D   Comments on the public review draft 43
E   IARC Monograph 45
F   Human data 51
G   Animal data 53
H   Genotoxicity data 57
    Carcinogenic classification of substances by the Committee 59
    Ethyl acrylate
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<pre>Samenvatting
Op verzoek van de minister van Sociale Zaken en Werkgelegenheid evalueert en
beoordeelt de Gezondheidsraad de kankerverwekkende eigenschappen van stof-
fen waaraan mensen tijdens het uitoefenen van hun beroep kunnen worden bloot-
gesteld. De evaluatie en beoordeling worden verricht door de subcommissie
Classificatie van Carcinogene Stoffen van de Commissie Gezondheid en
Beroepsmatige Blootstelling aan Stoffen van de raad, hierna kortweg aangeduid
als de commissie. In het voorliggende rapport neemt de commissie ethylacrylaat
onder de loep. Ethylacrylaat wordt gebruikt als monomeer in acryl harsen.
Ethylacrylaat kan tijdens de productie en gebruik via lekkage, schoorsteen emis-
sie of afvalwater in het milieu terecht komen. Het is in lage concentraties aange-
toond in afvalwater monsters. Daarnaast is het een vluchtige component in
ananas en Beaufort kaas en wordt het gebruikt als chemische smaakstof in voe-
ding.
    Op basis van de beschikbare gegevens is de commissie van mening dat de
gegevens over ethylacrylaat niet voldoende zijn om de kankerverwekkende
eigenschappen te evalueren (categorie 3).*
Volgens het classificatiesysteem van de Gezondheidsraad (zie bijlage I).
Samenvatting                                                                       9
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<pre>0 Ethyl acrylate</pre>

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<pre>Executive summary
At request of the Minister of Social Affairs and Employment, the Health Council
of the Netherlands evaluates and judges the carcinogenic properties of
substances to which workers are occupationally exposed. The evaluation is
performed by the Subcommittee on the Classification of Carcinogenic
Substances of the Dutch Expert Committee on Occupational Safety of the Health
Council, hereafter called the Committee. In this report the Committee evaluated
ethyl acrylate. Ethyl acrylate is used as a monomer in acrylic resins. Ethyl
acrylate may be released into the environment in escape or stack emissions or in
wastewater during its production and use. It has been detected at low levels in
wastewater samples. It is also a volatile component of pineapple and Beaufort
cheese and used as a chemically defined food flavouring substance.
    The Committee is of the opinion that the available data are insufficient to
evaluate the carcinogenic properties of ethyl acrylate (category 3).*
According to the classification system of the Health Council (see Annex I).
Executive summary                                                                11
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<pre>2 Ethyl acrylate</pre>

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<pre> hapter 1
        Scope
1.1     Background
        In the Netherlands a special policy is in force with respect to occupational use
        and exposure to carcinogenic substances. Regarding this policy, the Minister of
        Social Affairs and Employment has asked the Health Council of the Netherlands
        to evaluate the carcinogenic properties of substances and to propose a
        classification (see Annex A). In addition to classifying substances, the Health
        Council also assesses the genotoxic properties of the substance in question. The
        assessment and the proposal for classification are expressed in the form of
        standard sentences (see Annex I).
        This report contains the evaluation of the carcinogenicity of ethyl acrylate.
1.2     Committee and procedures
        The evaluation is performed by the Subcommittee on the Classification of
        Carcinogenic Substances of the Dutch Expert Committee on Occupational Safety
        of the Health Council, hereafter called the Committee. The members of the
        Committee are listed in Annex B. The submission letter (in English) to the State
        Secretary can be found in Annex C.
            In June 2012, the President of the Health Council released a draft of the
        report for public review. The individuals and organisations that commented on
        Scope                                                                            13
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<pre>    the draft are listed in Annex D. The Committee has taken these comments into
    account in deciding on the final version of the report.
1.3 Data
    The evaluation and recommendation of the Committee is standardly based on
    scientific data, which are publicly available. The starting points of the
    Committees’ reports are, if possible, the monographs of the International Agency
    for Research on Cancer (IARC). This means that the original sources of the
    studies, which are mentioned in the IARC-monograph, are reviewed only by the
    Committee when these are considered most relevant in assessing the
    carcinogenicity and genotoxicity of the substance in question. In the case of ethyl
    acrylate, such an IARC-monograph is available, of which the summary and
    conclusion of IARC are inserted in Annex E.
    More recently published data were retrieved from the online databases Toxline,
    Medline and Chemical Abstracts, covering the period 1990 to 2012. The last
    updated online search was in September 2012, using ethyl acrylate and CAS no
    140-88-5 as key words in combination with key words representative for
    carcinogenesis and mutagenesis. The new relevant data were included in this
    report.
 4  Ethyl acrylate
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<pre> hapter 2
        General information
2.1     Identity and physicochemical properties
        Ethyl acrylate is used as a monomer in acrylic resins. In 1993, the production of
        ethyl acrylate in the United States was reported to be 160 345 tonnes.1 In Europe
        producers and importers have been identified in France, Germany, the
        Netherlands and Belgium.2 The production of ethyl acrylate in Europe is
        estimated to be between 100,000 and 500,000 tonnes per year.3 Ethyl acrylate
        may be released into the environment in escape or stack emissions or in
        wastewater during its production and use. It has been detected at low levels in
        wastewater samples.1 It is also a volatile component of pineapple and Beaufort
        cheese (a type manufactured in a small area of the French Alps).1 It is also a food
        flavouring substance.4,5
            Below is given the identity and some of its physical and chemical properties.
        Chemical name         :  Ethyl acrylate
        CAS registry number   :  140-88-5
        EINECS number.        :  205-438-82
        Synonyms              :  2-propenoic acid ethyl ester, acrylic acid ethyl ester, ethyl propenoate,
                                 ethoxycarbonylethylene, ethyl 2-propenoate1,6
        Appearance            :  clear liquid with an acrid, penetrating odour6
        Chemical formula      :  C5 H 8 O 2 1
        General information                                                                                15
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<pre>    Structure               :                                   2
    Molecular weight        : 100.12 g/mol6
    Boiling point           : 99.4 °C6
    Melting point           : -71.2 °C1,6
    Vapour pressure         : 3.9 kPa at 20 °C, 38.6 mm Hg at 25 °C
    Relative vapour density : 3.456 (air = 1)
    Solubility              : slightly soluble in water; soluble in chloroform; miscible with dietyl
                              ether and ethanol1
    Conversion factor       : 1 mg/m3
    EU Classification       : Flam. Liq. 2: H225 (Highly flammable liquid and vapour)2
    (100% solution)           Acute Tox. 4: H332 (Harmful if inhaled)
                              Acute Tox. 4: H312 (Harmful in contact with skin)
                              Acute Tox. 4: H302 (Harmful if swallowed)
                              Eye Irrit. 2: H319 (Causes serious eye irratation)
                              STOT SE 3: H335 (May cause respiratory irritation)
                              Skin Irrit. 2: H315 (Causes skin irritation)
                              Skin Sens. 1: H317 (May cause an allergic skin reaction)
2.2 IARC classification
    In 1999, IARC concluded that no epidemiological data relevant to the
    carcinogenicity of ethyl acrylate were available. They concluded that there was
    sufficient evidence in experimental animals for the carcinogenicity of ethyl
    acrylate. The overall conclusion of IARC was that ethyl acrylate is possibly
    carcinogenic to humans (Group 2B).1
2.3 EU classification
    Although ethyl acrylate was characterised as “possibly carcinogenic to humans”
    (2B) by IARC1,7, the substance was not classified for carcinogenicity in the
    Annex I to Directive 67/548/EEC in the 19th ATP in 1993. This classification
    was based on the available data up till approximately 1991 or 1992. Since 1991
    few additional studies with respect to the carcinogenicity of ethyl acrylate have
    been published.
 6  Ethyl acrylate
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<pre> hapter 3
        Carcinogenicity
        In addition to the IARC report, a recent review of the available human, animal,
        and mechanistic studies was available to the Committee (Williams and
        Iatropoulos, 2009).8 To conclude on the carcinogenic classification of ethyl
        acrylate the Committee summarized and evaluated the original human and
        animal studies.
3.1     Observations in humans
        In a cohort study, Walker et al. (1991)9 evaluated the mortality from cancer of the
        colon or rectum among workers exposed to ethyl acrylate and methyl
        methacrylate. Three cohorts were assembled consisting of white male workers
        employed at two plants manufacturing and polymerizing acrylate monomers in
        the United States. In the earliest cohort, excess colon cancer seemed restricted to
        men employed extensively in the early 1940s in jobs entailing the highest
        exposures to vapour-phase ethyl acrylate and methyl methacrylate monomer, and
        volatile by-products of the ethyl acrylate/methyl methacrylate polymerization
        process. The excess mortality appeared some 20 years after the equivalent of
        three years work in jobs with the most intense exposures. A smaller elevation in
        colon cancer mortality appeared in a low-exposure group of this cohort. Rectal
        cancer mortality was elevated in the same categories that showed excess rates of
        colon cancer death; however, due to lower rates, the rectal cancer results are less
        precise.
        Carcinogenicity                                                                     17
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<pre>        The ethyl acrylate/methyl methacrylate exposures of members of the three
    cohorts were estimated on the basis of job histories and job-specific exposure
    rating scales. Monitoring data for ethyl acrylate/methyl methacrylate were
    available only from one of the plants beginning in 1972; earlier levels of exposure
    to ethyl acrylate/methyl methacrylate were reconstructed from production records
    and interviews with plant personnel. The resulting exposure scales were semi-
    quantitative, pertained to vapour exposure only, did not distinguish between ethyl
    acrylate and methyl methacrylate, relied on the recollection of long-term
    employees, were not verifiable, were not mutually comparable across all three
    cohorts, and did not take into account the presence of other substances in the
    workplace. These other substances included some which have subsequently been
    considered as either probable or possible carcinogens by the IARC (e.g. lead,
    ethylene dichloride, methylene chloride, and acrylonitrile).9-11
3.2 Carcinogenicity studies in animals
    Oral administration
    Groups of 25 male and 25 female albino Wistar rats were administered 0, 6-7,
    60-70 or 2,000 mg/L ethyl acrylate [purity unspecified] in the drinking-water for
    two years.12 From tests for losses of ethyl acrylate in the water near the end of the
    tube of the drinking bottles it was apparent that there was essentially no loss of
    ethyl acrylate due to volatilisation. Based upon average body weight and water
    consumption, the highest dose (2,000 ppm in drinking water) corresponded to
    approximately 170 or 120 mg ethyl acrylate per kilogram body weight per day
    for males or females, respectively.5 Decreased body weights were reported in
    male and female rats receiving ethyl acrylate in the highest dose group.
    Haematological evaluations (i.e. erythrocyte volume fraction, haemoglobin, total
    white and differential white cell counts) and urine analysis (i.e. protein)
    conducted at 3-month intervals showed normal ranges for the parameters studied
    in all treated animals throughout the study.5 At termination, histopathology (of
    the heart, lung, liver, kidney, urinary bladder, spleen, gastrointestinal tract,
    skeletal muscle, bone marrow, skin, brain, thyroid, adrenal, pancras, pituitary and
    gonads) revealed no compound-related neoplastic or non-neoplastic lesions in
    treated animals of either sex.12 After two years of treatment, survival was: males
    52%, 48%, 60% and 72%; females, 64%, 72%, 36% and 60% in the control, low-
    mid- and high-dose groups, respectively.
        Groups of 50 male and 50 female Fischer 344/N rats, seven weeks of age,
    received 100 or 200 mg/kg bw ethyl acrylate (purity, 99-99.5% stabilized with 15
 8  Ethyl acrylate
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<pre>mg/kg bw of the monomethyl ether of hydroquinone) in 5 ml/kg bw corn oil by
gavage five times per week for 103 weeks. Similar groups of rats received corn
oil only and served as vehicle controls. The experiment was terminated 104-105
weeks after the beginning of the treatment. Survival in the control, low-dose and
high-dose groups was: males, 82%, 64%, and 68% females, 72%, 72% and 84%,
respectively. Histopathology was performed on all organ systems; neoplastic
activity was seen in pancreas (acinar cell tumors), hematopoietic system
(mononuclear cell leukemia) and especially in the forestomach. The incidence of
squamous-cell papillomas and carcinomas of the forestomach are shown in Table
1. Dose related increases were observed in the incidence of non-neoplastic
lesions (hyperkeratosis, hyperplasia and inflammation) in the forestomach in
animals of each sex.13
Table 1 Incidence of forestomach tumours in rats after oral exposure to ethyl acrylate.10
           squamous cell papilloma     squamous cell carcinoma          squamous cell papilloma &
                                                                        carcinoma
dose       control low       high      control low           high       control low       high
males      1/50     15/50    29/50     0/50       5/50       12/50      1/50      18/50   36/50
females    1/50     6/50     9/50      0/50       0/50       2/50       1/50      6/50    11/50
Three groups of 25 male Fischer 344 rats, two months of age, were treated with
200 mg/kg bw ethyl acrylate (purity 99%) by gavage in corn oil on five days per
week for six or 12 months. Control rats received 5 mL corn oil/kg bw per day on
five days per week for 12 months. Five rats from each treatment group were
killed 24 h after the last dose. The remaining rats were killed at 24 months of age.
All animals were examined for gross lesions and the stomachs were collected
and fixed in formalin. Microscopic examination was restricted to three or four
sections of the stomach. No treatment-related neoplastic lesions were observed in
the forestomach of rats exposed to ethyl acrylate for six months and autopsied at
24 months of age. After 12 months of ethyl acrylate administration, all rats
showed hyperplastic lesions but no neoplastic lesions were detected. However,
when rats received ethyl acrylate for 12 months and were killed after nine
months of recovery, they developed squamous-cell carcinomas (3/13) and
papillomas (1/13).14 [The IARC Working Group noted that histopathological
evaluation was limited to the stomach].
     Groups of 50 male and 50 female B6C3F1 mice, seven weeks of age,
received 100 or 200 mg/kg bw ethyl acrylate (purity, 99-99.5% stabilised with 15
mg/kg of the monomethyl ether of hydroquinone) in 10 ml/kg bw corn oil by
gavage five times per week for 103 weeks. Similar groups of mice received corn
oil only and served as vehicle controls. The experiment was terminated 104-106
Carcinogenicity                                                                                   19
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<pre>  weeks after the beginning of the treatment. Survival in the control, low-dose and
  high-dose groups was: males, 56%, 72%, and 60% females, 54%, 70% and 52%,
  respectively. Histopathology was performed on all organ systems; no increased
  neoplastic activity was seen except in the forestomach. The incidence of
  squamous-cell papillomas and carcinomas of the forestomach are shown in
  Table 2. Dose related increases were observed in the incidence of non-neoplastic
  lesions (hyperkeratosis, hyperplasia and inflammation) in the forestomach in
  animals of each sex.13
  Table 2 Incidence of forestomach tumours in mice after oral exposure of ethyl acrylate.10
             squamous cell papilloma     squamous cell carcinoma        squamous cell papilloma &
                                                                        carcinoma
  dose       control low       high      control low          high      control low         high
  males      1/48     4/47     9/50      0/48      2/47       5/50      0/48       5/47     12/50
  females    1/50     4/49     5/48      0/50      1/49       2/48      1/50       5/49     7/48
  Groups of two male and two female pure-bred beagle dogs were given corn oil
  gelatin capsules containing ethyl acrylate at a ‘dietary equivalent’ concentration
  of 0, 10, 100 or 1,000 mg/kg for 2 years.12 This corresponds to average daily
  intakes of 0.75, 7.5 and 75 mg/kg bw, respectively.5 Preliminary tests indicated
  that the amount of ethyl acrylate disappearing from the corn oil at room
  temperature over a 5 day period was no more that 5%. Dogs receiving the highest
  dose on the first day all vomited. After the dose was lowered to 300 mg/kg and
  gradually raised to 1,000 mg/kg bw over the first 16 weeks, no further difficulty
  was encountered. Reduced body-weight gains reported in dogs receiving ethyl
  acrylate at a dose of 75 mg/kg bw per day were correlated with decreased food
  consumption. Haematological evaluations (i.e. erythrocyte volume fraction,
  haemoglobin, total and differential leukocyte counts) and urine analysis (i.e.
  protein) conducted at 3-month intervals showed normal ranges for the
  parameters studied in all treated animals throughout the study. At termination,
  histopathology (of the heart, lung, liver, kidney, urinary bladder, spleen,
  gastrointestinal tract, skeletal muscle, bone marrow, skin, brain, thyroid, adrenal,
  pancreas, pituitary and gonads) revealed no compound-related neoplastic or non-
  neoplastic lesions in either sex of treated animals.
  Skin application
  A group of 40 male C3H/HeJ mice, 74-79 days of age, received thrice-weekly
  skin applications of 25 µl undiluted ethyl acrylate (purity, >99%) on the skin for
  life (approximately 23 mg per application; total dose, approximately 770 mg/kg
0 Ethyl acrylate
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<pre>bw). Control groups were treated either with acetone (negative control) or with
0.1% 3-methylcholanthrene in acetone (positive control). The mean survival
time of animals in the ethyl acrylate-treated group (408 days) did not differ
significantly from that in the acetone controls (484 days). Complete necropsies
were performed, the animals were examined for gross lesions and dorsal skin
was examined histopathologically. No treatment-related tumours were observed
in either ethyl acrylate- or acetone-treated mice. Skin tumours (mainly
squamous-cell carcinomas) were observed in 39/40 mice treated with
3-methylcholanthrene.15 [The IARC Working Group noted that no mention was
made of control for possible losses of the parent compound by volatilization or
polymerization].
Ethyl acrylate was tested in a transgenic mouse model. When applied to the
shaved dorsal skin of female Tg.AC mice (three times per week for 20 weeks),
ethyl acrylate did not cause the development of papillomatous lesions. The
Tg.AC mouse is believed to respond to dermal applications of either genotoxic or
non-genotoxic carcinogens with a rapid production of papillomas in the site of
repeated applications.16,17
    In another study, the dermal application of 60, 300, and 600 µmoles ethyl
acrylate per mouse to the shaved dorsal skin of female Tg.AC mice (three times
per week for 20 weeks) did not cause the development of papillomatous
lesions.18
Inhalation exposure
Groups of 105 female and 105 male B6C3F1 mice, seven to nine weeks of age,
were exposed to vapours of ethyl acrylate (purity, >99.5%) at concentrations of
100, 310 or 920 mg/m3 [25, 75 or 225 ppm] for 6 h per day on five days per
week. The treatment with the low and medium doses lasted 27 months, whereas
high-dose treatment was discontinued after six months due to a significant
decrease in body-weight gain. These animals were followed without further
treatment for up to 27 months. Two concurrent control groups, each of 84 female
and 84 male untreated mice, were used. Interim sacrifices of small groups of
exposed and control animals were made at six, 12 and 18 months, such that
groups of approximately 75 animals per sex in the exposed group and 60 animals
per sex in the control groups were available for the full study. The mean body
weight gains of both male and female mice in the mid- and high-dose groups
were significantly lower than for the control groups throughout the study.
Survival in all groups was adequate for evaluation of late-appearing tumours. No
Carcinogenicity                                                                  21
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<pre>  treatment-related increase in the incidence of tumours was observed, with the
  exception of thyroid follicular adenomas, which were increased in high-dose
  male mice when compared to concurrent but not when compared to historical
  controls (2/121 in concurrent controls; 16% in historical controls; and 7/69 in
  high-dose males). Dose-related increases were observed in the incidence of non-
  neoplastic lesions of the olfactory mucosa (glandular hyperplasia and
  metaplasia) in animals of each sex.19
       Groups of 115 female and 115 male Fisher 344 rats, seven to nine weeks of
  age, were exposed to vapours of ethyl acrylate (purity, >99.5%) at concentrations
  of 100, 310 or 920 mg/m3 [25, 75 or 225 ppm] for 6 h per day on five days per
  week. The treatment with the low and medium doses lasted 27 months, whereas
  high-dose treatment was discontinued after six months due to a significant
  decrease in body-weight gain. The high-dosed animals were followed without
  further treatment for up to 27 months. Two concurrent control groups, each of 92
  female and 92 male untreated rats, were used. Interim sacrifices of small groups
  of exposed and control animals were made at three, six, 12 and 18 months, such
  that groups of approximately 75 animals per sex in the exposed groups and 60
  animals per sex in the control groups were available for the full study. The mean
  body weight gains of both male and female mice in the mid- and high-dose
  groups were significantly lower than for the control groups throughout the study.
  Survival in all groups was adequate for evaluation of late-appearing tumours. No
  treatment-related increase in the incidence of tumours was observed at any dose
  level. Dose-related increases were observed in the incidence of non-neoplastic
  lesions of the olfactory mucosa (glandular and basal-cell hyperplasia and
  metaplasia) in animals of each sex.19
2 Ethyl acrylate
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<pre> hapter 4
        Mode of action
4.1     Genotoxic mode of action
4.1.1   Gene mutation assays
        In vitro
        Ethyl acrylate was not mutagenic in bacteria.20,21 Ethyl acrylate did induce
        mitotic recombination in Saccaromyces cerevisiae.22
            In mammalian cells it induced an increase in the mutant frequency at the tk
        locus in mouse L5178Y lymphoma cells, in the absence of exogenous metabolic
        activation23-25, but not at the hprt locus in Chinese hamster ovary CHO cells.25,26
            Ciaccio et al. investigated the relationship between ethyl acrylate induced
        cytotoxicity and the mutant frequency in the mouse lymphoma assay (MLA).
        They found a concentration-dependent increase in the mutant frequency at the tk
        locus. While it was observed that ethyl acrylate was negative for direct genotoxic
        generation of single-strand breaks, it induced apoptosis, and double-strand
        breaks indicative of necrosis, at the higher concentrations only. Pulsed field gel
        electrophoresis of directly loaded high dose cell preparations revealed both high-
        and low-molecular-weight DNA double strand breaks, but only at the highest
        concentrations. These observations indicated that ethyl acrylate induced
        mutagenic response correlated best with cellular cytotoxicity.27
        Mode of action                                                                      23
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<pre>      In vivo
      No results from mammalian in vivo gene mutation assays with ethyl acrylate
      were available to the Committee.
4.1.2 Cytogenetic assays
      In vitro
      Ethyl acrylate induced an increase in cells with chromosomal aberrations in
      mouse L5178Y lymphoma cells25,28, Chinese hamster ovary CHO25 and Chinese
      hamster lung CHL cells in vitro29.
      In vivo
      In a study by Pzybojewska et al., a dose-related increase in the number of
      micronucleated polychromatic erythrocytes was observed. In this study, groups
      of four male Balb/c mice were given two intraperitoneal injections (24 hours
      apart) of ethyl acrylate (total dose, 225-1,800 mg/kg bw), and the bone marrow
      cells were examined six hours after the second injection.30 However, the purity
      of the material tested was not reported. Furthermore, 2 out of 4 mice of the
      highest dose group died and the ratio of polychromatic to normochromatic
      erythrocytes was decreased in all tested doses, except for the lowest dose. This
      provided evidence of a toxic effect of ethyl acrylate on bone marrow cells.
      However, a toxicity-mediated positive response is not supported by the activity
      observed in the lowest dose level.
          In a repeat of this experiment by Ashby et al., using groups of ten mice of
      strains Balb/c and C57BL/6 and two intraperitoneal doses, each up to 738-812
      mg/kg (purity 98.5%), no increase in the number of bone marrow cells with
      micronuclei was found.31 In this study dose-levels up to 80% of the median lethal
      dose were used.
          In a study by Kligerman et al., groups of five male C57BL/6 mice were given
      a single intraperitoneal injection of ethyl acrylate at 125, 250, 500, or 1,000
      mg/kg bw. In this study a small but statistically significant increase in
      splenocytes with micronuclei was found at the highest dose. This was, however,
      apparently due to an elevated frequency in a single animal.32
          Ethyl acrylate failed to induce an increase in mouse splenocytes with sister
      chromatid exchanges32 or chromosomal aberrations in mouse splenocytes in
      vivo32.
 4    Ethyl acrylate
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<pre>          It did not induce DNA strand breaks in peripheral white blood cells of mice17
      or in the forestomach of rats treated in vivo.33
          No increases in cells with micronuclei were observed in the bone marrow of
      groups of six male BDF1 mice given a single intraperitoneal injection of ethyl
      acrylate at 375, 500, 750, or 1,000 mg/kg. In addition, no positive effects were
      seen when doses of 188, 375, 750, or 1,000 mg/kg were delivered by stomach
      tube.34
          To evaluate the systemic genotoxicity ethyl acrylate was dermally applied to
      Tg.AC mice (3 times a week for 20 weeks). Peripheral blood leukocytes were
      evaluated for DNA damage (single-strand breaks, alkali labile sites, DNA cross
      linking) at weeks 4, 8, 12, 16 and 20. Peripheral blood polychromatic
      erythrocytes (PCE) and normachromatic erythrocytes (NCE) were evaluated for
      the presence of micronuclei at week 20. The extent of DNA migration in
      leukocytes and the frequency of micronucleated erythrocytes were not
      significantly altered by treatment with ethyl acrylate. The absence of
      genotoxicity in these two cell populations may suggest that ethyl acrylate is not
      genotoxic or not systemically available when applied dermally.17
4.1.3 Miscellaneous
      In vitro
      Ethyl acrylate did not bind to dexyribonucleosides in vitro.35 Treatment of mouse
      fibroblast NCTC 929 cells with ethyl acrylate caused increases in cellular p53
      protein levels. This protein is critical for cell cycle control and prevention of
      uncontrolled cell proliferation that can lead to cancer. Previous studies have
      shown that cells respond to DNA damage by increasing their levels of p53,
      which then acts to prevent replication of damaged DNA.36
      In vivo
      Ethyl acrylate failed to induce DNA binding in forestomach or liver of rats when
      given by gavage at doses up to 400 mg/kg37 [The IARC Working Group noted
      the inadequate method for determining DNA binding].
      Mode of action                                                                    25
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<pre>4.2 Non-genotoxic mode of action
    In vitro
    No relevant in vitro assays with ethyl acrylate were available to the Committee.
    In vivo
    Single oral administration of 100, 200 or 400 mg/kg bw ethyl acrylate by gavage
    to F344 male rats, caused dose- and time-related mucosal and submucosal
    oedema, vacuolization of the tunica muscularis of the forestomach and mild
    submucosal oedema in the glandular stomach.38 Equivalent subcutaneous or
    intraperitoneal dosing did not produce similar gastric lesions.39 The absence of
    systemic toxicity and the dependency of gastric lesions on the gavage route of
    administration suggests that a localized response to an injurious agent at the site
    of application mediates the proliferative response.10
        After repeated oral administration of 20-200 mg/kg/bw ethyl acrylate by
    gavage for two weeks to F344/N rats, dose-dependent irritation of the
    forestomach was observed. Repeated oral administration of ethyl acrylate in the
    drinking water led to a much lower incidence of forestomach irritation and less
    severe lesions at corresponding dose levels. Following 2 weeks of gavage dosing
    with ethyl acrylate a reduction in non-protein sulfhydryl content in the
    forestomach, but not in the glandular stomach or the liver was observed.40
    Interestingly, sulfhydryl-containing agents (cysteine and cysteamine) enhanced
    ethyl acrylate induced oedema of the forestomach, whereas depletion of the
    sulfhydryl content by fasting or pre-treatment with diethyl maleate was
    protective.41
        After repeated oral administration of ethyl acrylate by gavage, the glandular
    part of the rat stomach becomes refractory to the local toxicity produced by the
    chemical. Glandular portions of stomach appeared normal after two weeks of
    repeated administrations of 100 mg/kg. Adaptation of the forestomach, however,
    was proliferative in nature and featured papillomatous thickening. Cessation of
    ethyl acrylate administration for two weeks after two weeks of administration of
    100 mg/kg resulted in normalization of the forestomach epithelium.10,42,43
        After 13 weeks of oral administration of 100 or 200 mg/kg ethyl acrylate by
    gavage, forestomachs of rats either returned to normal or showed (reversible)
    mucosal hyperplasia, depending on dose and time.44,45 Another study provided
    evidence that a certain time of sustained hyperplasia of the forestomach is
 6  Ethyl acrylate
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<pre>required for effective tumorigenesis of ethyl acrylate in the forestomach of
rats.14,46
    Exposure of Fischer 344 rats and B6C3F1 mice to 0, 0.1 or 0.31 mg/L ethyl
acrylate vapour for 6 hours per day on five days per week for 27 months resulted
in dose-dependent occurrence of basal-cell hyperplasia, an increase in intra-
epithelial glands, metaplasia of respiratory epithelium and diffuse atrophy of the
olfactory epithelium in rats and in hyperplasia of submucosal glands and
metaplasia of olfactory epithelium in mice.19 Inhalation exposure of Wistar rats
to 1000 mg/m3 ethyl acrylate for 6 hours led to a significant increase in urinary
thioether excretion.47 The average concentrations of ethyl acrylate in inhaled air
that caused 50% depletion of non-protein sulfhydryl groups were estimated at
41.7 mmol/m3 for blood, 50.4 mmol/m3 for liver, 63.8 mmol/m3 for lung and
81.5 mmol/m3 for brain.
Mode of action                                                                     27
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<pre>8 Ethyl acrylate</pre>

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<pre> hapter 5
        Classification
5.1     Evaluation of data on carcinogenicity and genotoxicity
        In order to reach a conclusion on the classification of ethyl acrylate the studies
        summarized by IARC in 1986 and 1999 were used as a starting point. This
        information was supplemented with more recent data available in the public
        literature.
             Only one human study with three cohorts of workers from two plants
        manufacturing and polymerizing acrylate monomers was available, which was
        not included in the IARC evaluation. Only the earliest cohort showed an excess
        mortality from colon and rectum cancer. The two cohorts with later dates of
        employment showed no excess mortality. Since this study did not take into
        account the presence of other substances in the workplace (including possible
        carcinogens), this study can neither establish nor rule out a causal relationship of
        ethyl acrylate with cancer.
             In rats and mice dose-related increases in the incidence of squamous-cell
        papillomas and carcinomas of the forestomach were observed after oral dosing
        by gavage. Ethyl acrylate did not induce tumours after oral exposure of rats via
        drinking water, after inhalatory exposure of mice and rats and after dermal
        exposure of male mice. The forestomach neoplasia observed after gavage is
        correlated to extensive and sustained forestomach mucosal hyperplasia and cell
        proliferation.
        Classification                                                                       29
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<pre>    Ethyl acrylate has been found positive in the mouse lymphomatest in vitro.8 This
    positive finding is probably due to a clastogenic effect, since it was an increase in
    small colonies only. In most tests, ethyl acrylate was non-genotoxic in vivo.
    Ethyl acrylate does not induce tumours in experimental animals after
    subcutaneous or inhalation exposure. After long term oral exposure via gavage at
    high doses, rats and mice show chronic inflammatory changes in the forestomach
    and forestomach tumours. No tumours were seen in any other organ or tissue. In
    a drinking water study which delivered equivalent doses, neither irritation nor
    forestomach tumours were produced. Based on the available data, the
    carcinogenicity in the forestomach can be ascribed to a non-genotoxic mode of
    action.
    The most likely explanation for tumour formation in rats may be site-specific
    tissue irritation due to chronic and prolonged exposure, which results in
    hyperplasia and subsequent tumour development. In rats hyperplasia and
    squamous cell carcinoma may occur in the forestomach during prolonged oral
    exposure because the forestomach functions as a reservoir in which retention
    time for the compound may be significant, whereas other parts of the upper
    gastro-intestinal tract (i.e. above the stomach) function mainly as conduction
    organs with negligible retention times. Humans do not have a homologue for the
    forestomach. Therefore, forestomach tumours in rats are considered irrelevant
    for humans.
    The Committee concludes that the carcinogenic potency of ethylacrylate which
    has no demonstrable genotoxicity and which is exclusively carcinogenic in the
    forestomach squamous epithelium in rodents after oral administration, is rodent-
    specific and of no relevance for humans.48
5.2 Recommendation for classification
    The Committee is of the opinion that the available data are insufficient to
    evaluate the carcinogenic properties of ethyl acrylate (category 3).*
    According to the classification system of the Health Council (see Annex I).
 0  Ethyl acrylate
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<pre>  References
  IARC. Ethyl acrylate. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans 1999;
  Volume 71(Part three): 1447-1457.
  ESIS. European Chemical Substances Information System (http://esis.jrc.ec.europa.eu/), accessed
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  June, 2012.
  EU. EU Register of Chemically Defined Flavouring Substances (FI no 09.037) (http://ec.europa.eu/
  food/food/chemicalsafety/flavouring/database/index.cfm), accessed June, 2012.
  WHO. Safety evaluation of certain food additives. WHO food additives series no. 54. 2006.
  HSDB. Hazardous Substances Databank (http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB),
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  IARC. Ethyl acrylate. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans 1986;
  39: 81-98.
  Williams GM, Iatropoulos MJ. Evaluation of potential human carcinogenicity of the synthetic
  monomer ethyl acrylate. Regul Toxicol Pharmacol 2009; 53(1): 6-15.
  Walker AM, Cohen AJ, Loughlin JE, Rothman KJ, DeFonso LR. Mortality from cancer of the colon
  or rectum among workers exposed to ethyl acrylate and methyl methacrylate. Scand J Work Environ
  Health 1991; 17(1): 7-19.
0 NTP. Background Document for Ethyl Acrylate. National Toxicology Program, Report on
  Carcinogens 1998.
1 Tomenson JA, Carpenter AV, Pemberton MA. Critical review of the epidemiology literature on the
  potential cancer risks of methyl methacrylate. Int Arch Occup Environ Health 2005; 78(8): 603-612.
  References                                                                                         31
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<pre>2 Borzelleca J F, Larson PS, Hennigar GR, Huf EG, Crawford EM, Smith RB. Studies on the chronic
  oral toxicity of monomeric ethyl acrylate and methyl methacrylate. Toxicol Appl Pharmacol 1964; 6:
  29-36.
3 NTP. Carcinogenesis Studies of Ethyl Acrylate (CAS NO. 140-88-5) in F344/N Rats and B6C3F1
  Mice (Gavage Studies). National Toxicology Program, Technical Report Series 1986; No. 259.
4 Ghanayem BI, Sanchez IM, Maronpot RR, Elwell MR, Matthews HB. Relationship between the time
  of sustained ethyl acrylate forestomach hyperplasia and carcinogenicity. Environ Health Perspect
  1993; 101 Suppl 5: 277-279.
5 DePass LR, Fowler EH, Meckley DR, Weil CS. Dermal oncogenicity bioassays of acrylic acid, ethyl
  acrylate, and butyl acrylate. J Toxicol Environ Health 1984; 14(2-3): 115-120.
6 Tennant RW, Spalding J, French JE. Evaluation of transgenic mouse bioassays for identifying
  carcinogens and noncarcinogens. Mutat Res 1996; 365(1-3): 119-127.
7 Tice RR, Nylander-French LA, French JE. Absence of systemic in vivo genotoxicity after dermal
  exposure to ethyl acrylate and tripropylene glycol diacrylate in Tg.AC (v-Ha-ras) mice. Environ Mol
  Mutagen 1997; 29(3): 240-249.
8 Nylander-French LA, French JE. Tripropylene glycol diacrylate but not ethyl acrylate induces skin
  tumors in a twenty-week short-term tumorigenesis study in Tg.AC (v-Ha-ras) mice. Toxicol Pathol
  1998; 26(4): 476-483.
9 Miller RR, Young JT, Kociba RJ, Keyes DG, Bodner KM, Calhoun LL et al. Chronic toxicity and
  oncogenicity bioassay of inhaled ethyl acrylate in Fischer 344 rats and B6C3F1 mice. Drug Chem
  Toxicol 1985; 8(1-2): 1-42.
0 Haworth S, Lawlor T, Mortelmans K, Speck W, Zeiger E. Salmonella mutagenicity test results for
  250 chemicals. Environ Mutagen 1983; 5 Suppl 1: 1-142.
1 Waegemaekers TH, Bensink MP. Non-mutagenicity of 27 aliphatic acrylate esters in the Salmonella-
  microsome test. Mutat Res 1984; 137(2-3): 95-102.
2 Zimmermann FK, Mohr A. Formaldehyde, glyoxal, urethane, methyl carbamate, 2,3-butanedione,
  2,3-hexanedione, ethyl acrylate, dibromoacetonitrile and 2-hydroxypropionitrile induce chromosome
  loss in Saccharomyces cerevisiae. Mutat Res 1992; 270(2): 151-166.
3 Dearfield KL, Harrington-Brock K, Doerr CL, Rabinowitz JR, Moore MM. Genotoxicity in mouse
  lymphoma cells of chemicals capable of Michael addition. Mutagenesis 1991; 6(6): 519-525.
4 McGregor DB, Brown A, Cattanach P, Edwards I, McBride D, Riach C et al. Responses of the
  L5178Y tk+/tk- mouse lymphoma cell forward mutation assay: III. 72 coded chemicals. Environ Mol
  Mutagen 1988; 12(1): 85-154.
5 Moore MM, Harrington-Brock K, Doerr CL, Dearfield KL. Differential mutant quantitation at the
  mouse lymphoma tk and CHO hgprt loci. Mutagenesis 1989; 4(5): 394-403.
6 Moore MM, Parker L, Huston J, Harrington-Brock K, Dearfield KL. Comparison of mutagenicity
  results for nine compounds evaluated at the hgprt locus in the standard and suspension CHO assays.
  Mutagenesis 1991; 6(1): 77-85.
2 Ethyl acrylate
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<pre>7 Ciaccio PJ, Gicquel E, O'Neill PJ, Scribner HE, Vandenberghe YL. Investigation of the positive
  response of ethyl acrylate in the mouse lymphoma genotoxicity assay. Toxicol Sci 1998; 46(2):
  324-332.
8 Moore MM, Amtower A, Doerr CL, Brock KH, Dearfield KL. Genotoxicity of acrylic acid, methyl
  acrylate, ethyl acrylate, methyl methacrylate, and ethyl methacrylate in L5178Y mouse lymphoma
  cells. Environ Mol Mutagen 1988; 11(1): 49-63.
9 Ishidate MJ, Sofuni T, Yoshikawa K. Chromosomal aberration tests in vitro as a primary screening
  tool for environmental mutagens and/or carcinogens. Gann Monogr Cancer Res 1981.
0 Przybojewska B, Dziubaltowska E, Kowalski Z. Genotoxic effects of ethyl acrylate and methyl
  acrylate in the mouse evaluated by the micronucleus test. Mutat Res 1984; 135(3): 189-191.
1 Ashby J, Richardson CR, Tinwell H. Inactivity of ethyl acrylate in the mouse bone marrow
  micronucleus assay. Mutagenesis 1989; 4(4): 283-285.
2 Kligerman AD, Atwater AL, Bryant MF, Erexson GL, Kwanyuen P, Dearfield KL. Cytogenetic
  studies of ethyl acrylate using C57BL/6 mice. Mutagenesis 1991; 6(2): 137-141.
3 Morimoto K, Tsuji K, Osawa R, Takahashi A. [DNA damage test in forestomach squamous
  epithelium of F344 rat following oral administration of ethyl acrylate]. Eisei Shikenjo Hokoku
  1990;(108): 125-128.
4 Morita T, Asano N, Awogi T, Sasaki YF, Sato S, Shimada H et al. Evaluation of the rodent
  micronucleus assay in the screening of IARC carcinogens (groups 1, 2A and 2B) the summary report
  of the 6th collaborative study by CSGMT/JEMS MMS. Collaborative Study of the Micronucleus
  Group Test. Mammalian Mutagenicity Study Group. Mutat Res 1997; 389(1): 3-122.
5 McCarthy TJ, Hayes EP, Schwartz CS, Witz G. The reactivity of selected acrylate esters toward
  glutathione and deoxyribonucleosides in vitro: structure-activity relationships. Fundam Appl Toxicol
  1994; 22(4): 543-548.
6 Yang J, Duerksen-Hughes P. A new approach to identifying genotoxic carcinogens: p53 induction as
  an indicator of genotoxic damage. Carcinogenesis 1998; 19(6): 1117-1125.
7 Ghanayem BI, Burka LT, Matthews HB. Ethyl acrylate distribution, macromolecular binding,
  excretion, and metabolism in male Fisher 344 rats. Fundam Appl Toxicol 1987; 9(3): 389-397.
8 Ghanayem BI, Maronpot RR, Matthews HB. Ethyl acrylate-induced gastric toxicity. I. Effect of
  single and repetitive dosing. Toxicol Appl Pharmacol 1985a; 80(2): 323-335.
9 Ghanayem BI, Maronpot RR, Matthews HB. Ethyl acrylate-induced gastric toxicity. II. Structure-
  toxicity relationships and mechanism. Toxicol Appl Pharmacol 1985b; 80(2): 336-344.
0 Frederick CB, Hazelton GA, Frantz JD. The histopathological and biochemical response of the
  stomach of male F344/N rats following two weeks of oral dosing with ethyl acrylate. Toxicol Pathol
  1990; 18(2): 247-256.
1 Ghanayem BI, Maronpot RR, Matthews HB. Effects of sulfhydryl modulation on ethyl acrylate-
  induced forestomach toxicity. Toxicol Lett 1991a; 55(2): 215-221.
2 Ghanayem BI, Maronpot RR, Matthews HB. Association of chemically induced forestomach cell
  proliferation and carcinogenesis. Cancer Lett 1986b; 32(3): 271-278.
  References                                                                                           33
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<pre>3 Ghanayem BI, Maronpot RR, Matthews HB. Ethyl acrylate-induced gastric toxicity. III.
  Development and recovery of lesions. Toxicol Appl Pharmacol 1986a; 83(3): 576-583.
4 Ghanayem BI, Matthews HB, Maronpot RR. Sustainability of forestomach hyperplasia in rats treated
  with ethyl acrylate for 13 weeks and regression after cessation of dosing. Toxicol Pathol 1991b;
  19(3): 273-279.
5 Gillette DM, Frederick CB. Quantitation of an epithelial S-phase response in the rat forestomach and
  glandular stomach following gavage dosing with ethyl acrylate. Toxicol Appl Pharmacol 1993;
  122(2): 244-257.
6 Ghanayem BI, Sanchez IM, Matthews HB, Elwell MR. Demonstration of a temporal relationship
  between ethyl acrylate-induced forestomach cell proliferation and carcinogenicity. Toxicol Pathol
  1994; 22(5): 497-509.
7 Vodicka P, Gut I, Frantik E. Effects of inhaled acrylic acid derivatives in rats. Toxicology 1990;
  65(1-2): 209-221.
8 RIVM. Factsheets fot the (eco)toxicological risk assessment strategy of the National Institute for
  Public Health and The Environment. National Institute for Public Health and the Environment 2004;
  Part IV (report no. 601516012).
9 Valencia R, Mason JM, Woodruff RC, Zimmering S. Chemical mutagenesis testing in Drosophila.
  III. Results of 48 coded compounds tested for the National Toxicology Program. Environ Mutagen
  1985; 7(3): 325-348.
0 Guideline to the classification of carcinogenic compounds. Health Council of The Netherlands,
  editor. The Hague, The Netherlands: 2010: publication no. A10/07E.
4 Ethyl acrylate
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<pre>A Request for advice
B The Committee
C The submission letter
D Comments on the public review draft
E IARC Monograph
F Human data
G Animal data
H Genotoxicity data
  Carcinogenic classification of substances by the Committee
  Annexes
                                                             35
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<pre>6 Ethyl acrylate</pre>

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<pre>nnex A
     Request for advice
     In a letter dated October 11, 1993, ref DGA/G/TOS/93/07732A, to, the State
     Secretary of Welfare, Health and Cultural Affairs, the Minister of Social Affairs
     and Employment wrote:
     Some time ago a policy proposal has been formulated, as part of the simplification of the governmen-
     tal advisory structure, to improve the integration of the development of recommendations for health
     based occupation standards and the development of comparable standards for the general population.
     A consequence of this policy proposal is the initiative to transfer the activities of the Dutch Expert
     Committee on Occupational Standards (DECOS) to the Health Council. DECOS has been established
     by ministerial decree of 2 June 1976. Its primary task is to recommend health based occupational
     exposure limits as the first step in the process of establishing Maximal Accepted Concentrations
     (MAC-values) for substances at the work place.
     In an addendum, the Minister detailed his request to the Health Council as
     follows:
     The Health Council should advice the Minister of Social Affairs and Employment on the hygienic
     aspects of his policy to protect workers against exposure to chemicals. Primarily, the Council should
     report on health based recommended exposure limits as a basis for (regulatory) exposure limits for air
     quality at the work place. This implies:
     •    A scientific evaluation of all relevant data on the health effects of exposure to substances using a
          criteria-document that will be made available to the Health Council as part of a specific request
     Request for advice                                                                                        37
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<pre>      for advice. If possible this evaluation should lead to a health based recommended exposure limit,
      or, in the case of genotoxic carcinogens, a ‘exposure versus tumour incidence range’ and a
      calculated concentration in air corresponding with reference tumour incidences of 10-4 and 10-6
      per year.
  •   The evaluation of documents review the basis of occupational exposure limits that have been
      recently established in other countries.
  •   Recommending classifications for substances as part of the occupational hygiene policy of the
      government. In any case this regards the list of carcinogenic substances, for which the
      classification criteria of the Directive of the European Communities of 27 June 1967 (67/548/
      EEG) are used.
  •   Reporting on other subjects that will be specified at a later date.
  In his letter of 14 December 1993, ref U 6102/WP/MK/459, to the Minister of
  Social Affairs and Employment the President of the Health Council agreed to
  establish DECOS as a Committee of the Health Council. The membership of the
  Committee is given in Annex B.
8 Ethyl acrylate
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<pre>nnex B
     The Committee
     •  R.A. Woutersen, chairman
        Toxicologic Pathologist, TNO Innovation for Life, Zeist; Professor of
        Translational Toxicology, Wageningen University and Research Centre,
        Wageningen
     •  J. van Benthem
        Genetic Toxicologist, National Institute for Public Health and the
        Environment, Bilthoven
     •  P.J. Boogaard
        Toxicologist, SHELL International BV, The Hague
     •  G.J. Mulder
        Emeritus Professor of Toxicology, Leiden University, Leiden
     •  Ms M.J.M. Nivard
        Molecular Biologist and Genetic Toxicologist, Leiden University Medical
        Center, Leiden
     •  G.M.H. Swaen
        Epidemiologist, Dow Chemicals NV, Terneuzen
     •  E.J.J. van Zoelen
        Professor of Cell Biology, Radboud University Nijmegen, Nijmegen
     •  G.B. van der Voet, scientific secretary
        Health Council of the Netherlands, The Hague
     The Committee                                                              39
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<pre>  The Health Council and interests
  Members of Health Council Committees are appointed in a personal capacity
  because of their special expertise in the matters to be addressed. Nonetheless, it
  is precisely because of this expertise that they may also have interests. This in
  itself does not necessarily present an obstacle for membership of a Health
  Council Committee. Transparency regarding possible conflicts of interest is
  nonetheless important, both for the chairperson and members of a Committee
  and for the President of the Health Council. On being invited to join a
  Committee, members are asked to submit a form detailing the functions they
  hold and any other material and immaterial interests which could be relevant for
  the Committee’s work. It is the responsibility of the President of the Health
  Council to assess whether the interests indicated constitute grounds for non-
  appointment. An advisorship will then sometimes make it possible to exploit the
  expertise of the specialist involved. During the inaugural meeting the
  declarations issued are discussed, so that all members of the Committee are
  aware of each other’s possible interests.
0 Ethyl acrylate
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<pre>nnex C
     The submission letter
     Subject           : Submission of the advisory report Ethyl acrylate
     Our reference     : U-7413/BvdV/fs/246-D17
     Your Reference    : DGV/MBO/U-932342
     Enclosed          :1
     Date              : November 13, 2012
     Dear State Secretary,
     I hereby submit the advisory report on the effects of occupational exposure to
     Ethyl acrylate.
     This advisory report is part of an extensive series in which carcinogenic
     substances are classified in accordance with European Union guidelines. This
     involves substances to which people can be exposed while pursuing their
     occupation.
         The advisory report was prepared by the Subcommittee on the Classification
     of Carcinogenic Substances, a permanent subcommittee of the Health Council’s
     Dutch Expert Committee on Occupational Safety (DECOS). The advisory report
     has been assessed by the Health Council’s Standing Committee on Health and
     the Environment.
     The submission letter                                                          41
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<pre>  I have today sent copies of this advisory report to the State Secretary of
  Infrastructure and the Environment and to the Minister of Health, Welfare and
  Sport, for their consideration.
  Yours sincerely,
  (signed)
  Professor W.A. van Gool
  President
2 Ethyl acrylate
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<pre>nnex D
     Comments on the public review draft
     A draft of the present report was released in June 2012 for public review. The fol-
     lowing organisations and persons have commented on the draft document:
     • National Institute for Occupational Safety and Health (NIOSH), Cincinnati,
        USA.
     Comments on the public review draft                                                 43
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<pre>4 Ethyl acrylate</pre>

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<pre>nnex E
     IARC Monograph
     Volume 71, 1999 (excerpt from Ethylacrylate, pp 1447-1457)
     2          Studies of Cancer in Humans
     No data were available to the Working Group.
     3          Studies of Cancer in Experimental Animals
     Ethyl acrylate was tested for carcinogenicity by oral gavage in mice and rats.
     Dose related increases in the incidence of squamous-cell papillomas and
     carcinomas of the forestomach were observed in both species. Ethyl acrylate was
     tested by inhalation in the same strains of mice and rats; no treatment-related
     neoplastic lesion was observed. No treatment-related tumour was observed
     following skin application of ethyl acrylate for lifespan to male mice (IARC,
     1986).
     3.1        Oral administration
     Rat: Three groups of 25 male Fischer 344 rats, two months of age, were treated
     with 200 mg/kg bw ethyl acrylate (purity, 99%) by gavage in corn oil on five
     days per week for six or 12 months. Control rats received 5 mL corn oil/kg bw
     per day on five days per week for 12 months. Five rats from each treatment
     IARC Monograph                                                                  45
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<pre>  group were killed 24 h after the last dose. The remaining rats were killed at 24
  months of age. All animals were examined for gross lesions and the stomachs
  were collected and fixed in formalin. Microscopic examination was restricted to
  three or four sections of the stomach. No treatment-related neoplastic lesions
  were observed in the forestomach of rats exposed to ethyl acrylate for six months
  and autopsied at 24 months of age. After 12 months of ethyl acrylate
  administration, all rats showed hyperplastic lesions but no neoplastic lesions
  were detected. However, when rats received ethyl acrylate for 12 months and
  were killed after nine months of recovery, they developed squamous-cell
  carcinomas (3/13) and papillomas (1/13) (Ghanayem et al., 1993). [The Working
  Group noted that histopathological evaluation was limited to the stomach.]
  4           Other Data Relevant to an Evaluation of Carcinogenicity
              and its Mechanisms
  4.1         Absorption, distribution, metabolism and excretion
  4.1.1       Humans
  No data were available to the Working Group.
  4.1.2       Experimental systems
  De Bethizy et al. (1987) administered ethyl [2,3-14C]acrylate to rats orally by
  gavage at doses of 2, 20 and 200 mg/kg bw. The total recovery in specific tissues
  and excreta fell with increasing dose from 108% at 2 mg/kg bw to 73% at 200
  mg/kg bw. The major metabolite was 14CO2, with 52-61% exhaled within 24 h.
  The proportion of radioactivity excreted in the urine fell with increasing dose,
  from 28% at 2 mg/kg bw to 8% at 200 mg/kg bw. Three metabolites were
  identified: 3-hydroxypropionic acid and two mercapturic acids. N-Acetyl-S-(2-
  carboxyethyl)cysteine arises by glutathione conjugation of acrylic acid, while
  N-acetyl-S-(2-carboxyethyl)cysteine ethyl ester derives from the conjugation of
  intact ethyl acrylate. The percentage of the dose excreted as these mercapturic
  acids falls with increasing dose, consistent with depletion of glutathione.
  Although ethyl acrylate does not reduce non-protein sulfhydryls in the liver,
  marked and dose-dependent depletion occurs in the forestomach and glandular
  stomach, which is enhanced by pretreatment of rats with the esterase inhibitor
  tri(ortho-cresyl)phosphate. These data are consistent with the hydrolysis of ethyl
6 Ethyl acrylate
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<pre>acrylate being a systemic detoxication reaction, since acrylic acid has no effect
on non-protein sulfhydryl levels.
    Linhart et al. (1994) reported increases in urinary levels of 3-
hydroxypropanoic, lactic and acetic acids after administration of ethyl acrylate to
rats.
    Potter and Tran (1992) showed that ethyl acrylate reacts spontaneously with
glutathione and protein sulfhydryl groups in many tissues: in liver alone,
conjugation with glutathione was catalysed by cytosolic glutathione
S-transferase. Miller et al. (1981) showed a major role for the liver in the
hydrolysis of ethyl acrylate, the order of activities among tissues being liver >>
blood >> lung > kidney. The hydrolysis of ethyl acrylate in various regions of the
nose and respiratory tract was region-dependent (Frederick et al., 1994): high
activity was found in homogenates of the dorsal meatus and olfactory septum,
with much lower activity in respiratory epithelium. This distribution of activity
does not correlate well with the distribution of cytotoxicity of ethyl acrylate after
inhalation exposure.
    Stott and McKenna (1985) found that ethyl acrylate was hydrolysed in
homogenates of mouse nasal epithelium.
4.2        Toxic effects
4.2.1      Humans
No data were available to the Working Group.
4.2.2      Experimental systems
Frederick et al. (1990) treated male Fischer 344/N rats with 0, 2, 20, 50, 100 and
200 mg/kg bw ethyl acrylate by daily gavage for two weeks. Another group of
animals received 200, 1000, 2000 and 4000 ppm (mg/L) in the drinking-water
for two weeks. In the 20–200 mg/kg bw dose range, dose-dependent irritation of
the forestomach, but not of the glandular stomach, was observed. In the animals
dosed with ethyl acrylate in the drinking-water, much lower effects were
observed at corresponding dose levels. Dosage of 200 mg/kg bw led to a
reduction of about 90% in non-protein sulfhydryl content in the forestomach, but
not in the glandular stomach or the liver. Interestingly, Ghanayem et al. (1991a)
found that sulfhydryl-containing agents (cysteine and cysteamine) enhanced
ethyl acrylate-induced oedema of the forestomach, whereas depletion of the
sulfhydryl content by fasting or pretreatment with diethyl maleate was
IARC Monograph                                                                        47
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<pre>  protective. In Fischer 344 rats of both sexes receiving a single dose of 100, 200
  or 400 mg/kg bw ethyl acrylate, dose- and time-dependent occurrence of
  mucosal and submucosal oedema, vacuolization of the tunica muscularis of the
  forestomach and mild submucosal oedema in the glandular stomach were
  observed (Ghanayem et al., 1985a). Equivalent subcutaneous or intraperitoneal
  dosing did not produce similar gastric lesions. Profound gastric toxicity was also
  obtained with methyl or ethyl acrylate, while acrylic acid, nbutyl acrylate, methyl
  and ethyl propionate and methacrylic acid esters were inactive (Ghanayem et al.,
  1985b). Depending on dose and time, forestomachs of rats either returned to
  normal or showed (reversible) mucosal hyperplasia (Ghanayem et al., 1991b;
  Gillette & Frederick, 1993), while submucosal fibrosis became more prevalent in
  highdose animals with time (Ghanayem et al., 1986a). Another study (Ghanayem
  et al., 1993) provided evidence that a certain time of sustained hyperplasia of the
  forestomach is required for effective tumorigenesis of ethyl acrylate in the
  forestomach of rats. Daily gavage doses of 100 and 200 mg/kg bw ethyl acrylate
  on five days per week for two weeks resulted in a dramatic increase in
  forestomach epithelial cell proliferation in male Fischer 344 rats (Ghanayem et
  al., 1986b). Exposure of male and female Fischer 344 rats and B6C3F1 mice to
  0, 0.1 or 0.31 mg/L ethyl acrylate vapour for 6 h per day on five days per week
  for 27 months resulted in dose-dependent occurrence of basal-cell hyperplasia,
  an increase in intraepithelial glands, respiratory metaplasia and diffuse atrophy
  of the olfactory epithelium in rats, and in hyperplasia of submucosal glands and
  respiratory metaplasia of olfactory epithelium in mice (Miller et al., 1985).
  Inhalation exposure of male Wistar rats to 1000 mg/m3 ethyl acrylate for 6 h led
  to a significant increase in urinary thioether excretion (Vodicrka et al., 1990).
  The average concentrations of ethyl acrylate in inhaled air that caused 50%
  depletion of non-protein sulfhydryl groups were estimated at 41.7 mmol/m3 for
  blood, 50.4 mmol/m3 for liver, 63.8 mmol/m3 for lung and 81.5 mmol/m3 for
  brain.
  4.3         Reproductive and developmental effects
  No data were available to the Working Group.
  4.4         Genetic and related effects
  4.4.1       Humans
  No data were available to the Working Group.
8 Ethyl acrylate
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<pre>4.4.2       Experimental systems
In single studies, ethyl acrylate did not induce sex-linked recessive lethal
mutations in Drosophila melanogaster but did induce mitotic recombination in
Saccharomyces cerevisiae. It was not mutagenic to bacteria.
In mammalian cells treated in vitro, it induced mutation at the tk locus in mouse
L5178Y lymphoma cells, in the absence of exogenous metabolic activation, but
not at the hprt locus in Chinese hamster ovary CHO cells. It induced
chromosomal aberrations in mouse L5178Y lymphoma cells, Chinese hamster
ovary CHO and Chinese hamster lung CHL cells in vitro.
In a single study, ethyl acrylate failed to induce DNA binding in forestomach or
liver of rats when given by gavage at doses up to 400 mg/kg (Ghanayem et al.,
1987) [The Working Group noted the inadequate method for determining DNA
binding.] It induced micronucleus formation in mouse bone marrow and weakly
in mouse splenocytes; another study performed under the same conditions was
negative. In single studies, ethyl acrylate failed to induce sister chromatid
exchanges or chromosomal aberrations in mouse splenocytes in vivo. It did not
induce DNA damage in peripheral white blood cells of mice or in the
forestomach of rats treated in vivo.
4.4.3       Mechanistic considerations
Ethyl acrylate appears to be clastogenic to mammalian cells in vitro. The
preferential induction of small colonies rather than large ones in the mouse
lymphoma L5178Y tk mutagenicity assay is thought to indicate that mutations
arise from chromosomal damagerather than by point mutation. The clastogenic
activity of ethyl acrylate seen in vitro is not readily expressed in vivo. Ethyl
acrylate did not bind to eoxyribonucleosides in vitro (McCarthy et al., 1994).
5           Evaluation
No epidemiological data relevant to the carcinogenicity of ethyl acrylate were
available.
There is sufficient evidence in experimental animals for the carcinogenicity of
ethyl acrylate.
IARC Monograph                                                                    49
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<pre>  Overall evaluation
  Ethyl acrylate is possibly carcinogenic to humans (Group 2B).
0 Ethyl acrylate
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<pre> nnex         F
              Human data
Human studies with regard to carcinogenic effects.
 eference            Design and           Exposure            Carcinogenic         Potential         Remarks
                     population                               effects              confounders
Walker et al., 19919 Cohort               Cumulative:         Increase in colon    Other carcinogens Cumulative
                     workers in acrylic intensity score (0-5) and rectal cancer in                   exposure without
                     sheet manufacturing x number of days     workers with                           distinction between
                                          employed            highest exposure                       long term low
                                                                                                     exposure or short
                                                                                                     term high exposure
              Human data                                                                                              51
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<pre>2 Ethyl acrylate</pre>

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<pre>  nnex       G
             Animal data
  xperimental studies with regard to carcinogenic effects.
Animal species Dose and route Exposure               Carcinogenicity Remarks                            Reference   Review
sex, number)      of exposure       duration
Oral
 ischer 344 rats 0, 200 mg/kg       6 or 12 months Squamous-cell     Histopathological evaluation was Ghanayem      IARC,
25 m)             bw gavage                          papillomas and  limited to forestomach             et al.,     19991
                  (5 d/w)                            carcinomas of                                      199314
                                                     forestomach
B6C3F1 mice       0, 100 or 200     103 weeks        Squamous-cell   Increased carcinomas (m)           NTP, 198613 IARC,
50 m, 50 f)       mg/kg bw/d                         papillomas and  increased carcinomas and                       19867
                  gavage                             carcinomas of   papillomas (m+f)
                                                     forestomach     also dose-resonse of non-
                                                                     neoplastic lesions
 ischer 344/N     0, 100, 200 mg/ 103 weeks          Squamous-cell Increased carcinomas (m)             NTP, 198613 IARC,
at (50-m, 50f)    kg bw/d gavage                     carcinomas of increased carcinomas and                         19867
                                                     forestomach     papillomas (m+f)
                                                                     also d-r non-neoplastic lesions
Wister rats       0, 6-7, 60-70,    2 years          No treatment- Incomplete description of the        Borzelleca  IARC,
 25m, 25f)        2,000 mg/l                         related lesions findings. The highest dose (2,000  et al.,     19867
                  drinking water                                     ppm in drinking water)             196412
                                                                     corresponded to approximately
                                                                     170 or 120 mg/kg bw/day for
                                                                     males or females, respectively
Beagle dogs       0, 10, 100 or     2 years          No treatment- No details on survival and           Borzelleca  WHO,
 2m, 2f)          1,000 mg/kg in                     related lesions pathological examinations were     et al.,     20065
                  corn oil gelatin                                   given. The doses correspond to     196412
                  capsules                                           average daily intakes of 0.75, 7.5
                                                                     and 75 mg/kg bw, respectively
             Animal data                                                                                                  53
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<pre>Dermal
  3H/HeJ mice     23 mg/kg bw/      74-79 days        No treatment-                                         DePass et      IARC,
40m)              treatment, 3                        related lesions                                       al., 198415    19867
                  times a week
                  dermal
                  application
  g.AC (v-Ha-     dermal            20 weeks          No               Tg.AC mice are believed to           Tennant et     -
as) mice          application, 3                      papillomatous    respond to dermal applications of    al., 199616
f)                times a week                        lesions          carcinogens with a rapid
                                                                       production of papillomas in the
                                                                       site of repeated applications
  g.AC (v-Ha-     60, 300, or 600 20 weeks            No               Tg.AC mice are believed to           Nylander       -
 as) mice         µmoles/mouse                        papillomatous    respond to dermal applications of    and French,
 f)               dermal                              lesions          carcinogens with a rapid             199818
                  application, 3                                       production of papillomas in the
                  times a week                                         site of repeated applications
 nhalation
B6C3F mice        100, 310, 920     27 months         Thyroid          Increased in males but not           Miller et al., IARC,
 105m, 105f)      mg/m3                               follicular       compared to historical controls,     198519         19867
                                                      adenomas         according to the authors not
                                                                       treatment related
  ischer 344 rat  100, 310, 920     27 months         No treatment                                          Miller et al., IARC,
115m, 115f)       mg/m3                               related lesions                                       198519         19867
  xperimental studies with regard to toxic effects.
  eference Review        Animal          Dose and route of         Exposure      Toxicity                            Remarks
                         species         exposure                  duration
                         (sex, number)
  rederick et IARC,      Fischer 344/ 0, 2, 10, 20, 50, 100,       2 weeks       Irritation of the forestomach       The irritation
 l., 199040 19991        N rats (m, 14) and 200 mg/kg bw/d 5                     (20-200 mg/kg by gavage and         was less severe
                                         days/week gavage                        drinking water)                     after
                                         0, 23, 99, 197, 369 mg/                 non-protein sulfydryl (NPSH)        administration
                                         kg bw/d drinking water                  depletion (200 mg/kg by             through
                                                                                 gavage)                             drinking water
                                                                                 no lesions in glandular stomach
                                                                                 or liver
Ghanayem IARC,           Fischer 344     100 and 200 mg/kg bw/ 13 weeks          Epithelial hyperplasia of the       SH-containing
 t al.,       19991      rats (m, 50)    d 5 days/week by                        forestomach which regressed         agents (e.g.
 991a41                                  gavage                                  after 8-19 weeks of recovery        cysteine)
                                                                                 no lesions in glandular stomach     enhanced
                                                                                 or liver                            submucosal
Ghanayem IARC,           Fischer 344     100, 200 and 400 mg/kg 1, 2, 4, 14 or Concentration and exposure            Oedema in the
 t al.,       19991      rats (m, 20)    bw/d by gavage            90 days       duration dependent mucosal and      forestomach,
 991b44                                                                          sub mucosal oedema                  while SH-
                                                                                 profound epithelial cell            depletion (by
                                                                                 proliferation of the forestomach    fasting) was
                                                                                 after 90 days, reversible after 8   protective
                                                                                 weeks to 19 months recovery
  4           Ethyl acrylate
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<pre>Ghanayem IARC,        Fischer 344  100, 200 and 400 mg/kg Single dose Dose- and time-related mucosal
 t al.,       19991   rats         bw/d by gavage                     and submucosal oedema,
 985a38                                                               vacuolization of the tunica
                                                                      muscularis of the forestomach
                                                                      and mild submucosal oedema in
                                                                      the glandular stomach
Ghanayem      IARC,   Fischer 344  100, 200 and 400 mg/kg Single dose No gastric lesions
 t al.,       19991   rats         bw/d subcutaneous or
 985b39                            intraperitoneal
Ghanayem      IARC,   Fischer 344  100 and 200 mg/kg bw/ 14 days      Submucosal fibrosis and foreign
 t al.,       19991   rats         d by gavage                        body reaction became more
 986a43                                                               prevalent in high-dose animals
                                                                      with time, after 2 weeks of
                                                                      recovery, the forestomach
                                                                      returned to normal.
Ghanayem      IARC,   Fischer 344  100 and 200 mg/kg bw/ 2 weeks      Forestomach epithelial cell
 t al.,       19991   rats         d 5 d/w by gavage                  proliferation
 986b42
Ghanayem      IARC,   Fischer 344  200 mg/kg bw/d 5 days/ 3, 6, or 12 Forestomach hyperplasia after 6
 t al., 1993; 19991   rats (m, 50) week by gavage         months      months of exposure, recovery
 99414,46                                                             after 15 months of recovery
                                                                      squamous cell papillomas and
                                                                      carcinomas after 12 months of
                                                                      exposure
Miller et     IARC,   Fischer 344 0, 0.1, and 0.31 mg/L   27 months   Dose-dependent occurrence of
 l., 198519   19991   rats and     for 6 hours/day, 5 d/w             basal-cell hyperplasia, an
                      B6C3F1 mice by inhalation                       increase in intra-epithelial
                                                                      glands, respiratory metaplasia
                                                                      and diffuse atrophy of the
                                                                      olfactory epithelium in rats and
                                                                      in hyperplasia of submucosal
                                                                      glands and respiratory
                                                                      metaplasia of olfactory
                                                                      epithelium in mice
  odicka et IARC,     Wistar rats  1000 mg/m3 6 h                     Significant increase in urinary
 l., 199047 19991                                                     thioether excretion
              Animal data                                                                              55
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<pre>6 Ethyl acrylate</pre>

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<pre> nnex         H
              Genotoxicity data
Genotoxicity and mutagenicity studies.
 est system                      Endpoint          Lowest effective Result   Result  Reference         Review
                                                   dose or highest   without with
                                                   ineffective dosea meta-   meta-
                                                                     bolic   bolic
                                                                     activa- activa-
                                                                     tionb   tionb
Bacteria    S. typhymurium       Reverse mutations 670 and 1,666 µg/ -       -       Haworth et al.,   IARC, 19991
            TA100, TA1535,                         ml                                198320
            TA1537, TA1538 and                                                       Waegemaekers
            TA98                                                                     & Bensink,
                                                                                     198421
Mammali L5178Y Mouse             Gene mutation     20 µg/mL          +       NT      Moore et al.,     IARC, 19991
 n cells in lymphoma cells                                           (+)     NT      198828
 itro                                                                +       (+)     McGregor et al.,
                                                                                     198824
                                                                                     Dearfield et al.,
                                                                                     199123
            Chinese hamster      Gene mutation     23 and 80 µg/mL -         NT      Moore et al.,     IARC, 19991
            ovary (CHO) cells                                                        198925
                                                                                     Moore et
                                                                                     al.,199126
            L5178Y Mouse         Single and double 10-40 µg/mL       +       NT      Ciaccio et al.,   -
            lymphoma cells       strand DNA                                          199827
                                 breaks
            Mouse splenocytes    Sister chromatid 25 µg/mL           -       NT      Kligerman et      IARC, 19991
                                 exchages (SCE)                                      al., 199132
              Genotoxicity data                                                                                    57
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<pre>             Mouse splenocytes       Chromosome         2 µg/mL             (+)        NT       Kligerman et     IARC, 19991
                                     aberrations (CA)                                           al., 199132
             L5178Y Mouse            CA                 20 µg/mL            +          NT       Moore et al.,    IARC, 19991
             lymphoma cells                                                                     198828
                                                                                                Moore et al.,
                                                                                                198925
             Chinese hamster         CA                 21 µg/mL            +          NT       Moore et al.,    IARC, 19991
             ovary (CHO) cells                                                                  198925
             Chinese hamster lung    CA                 9.8 µg/mL           +          NT       Ishidate et al., IARC, 19991
             cells                                                                              198129
             Deoxyribonucleoside     Binding to         0.5 mN              -                   McCarthy et al., IARC, 19991
             s from red blood cells  deoxyribo-                                                 199435
             of Sprague-Dawley       nucleosides
             rats
 easts       S. cerevisiae D61,M     Mitotic            733 mg/mL           +          NT       Zimmerman        IARC, 19991
                                     recombination or                                           and Mohr,
                                     gene conversion                                            199222
Droso-       D. melanogaster         Sex-linked         40,000 ppm feed -                       Valencia et al., IARC, 19991
 hila                                recessive lethal                                           198549
                                     mutations
Mammali Fischer 344 rats             DNA strand         4% po x 1           -          NT       Morimoto et al., IARC, 19991
 n in vivo forestomach               breaks                                                     199033
             TgAC mouse              DNA strand         12 ug/mouse skin -                      Tice et al.,     IARC, 19991
             peripheral blood        breaks             x 3/wk 20 wk                            199717
             leukocytes
             rats forestomach or     DNA binding        400 mg/kg           -                   Ghanayem et      IARC, 19991
             liver                                                                              al., 198737
             C57BL/6 mouse           SCE                1,000 mg/kg bw/d    -                   Kligerman et     IARC, 19991
             splenocytes                                ip x 1                                  al., 199132
             C57BL/6 mouse           Micronucleus test 1,000 mg/kg bw/d     (+)                 Kligerman et     IARC, 19991
             splenocytes                                ip x 1                                  al., 199132
             BALB/c mouse bone       Micronucleus test 225 mg/kg bw/d       +                   Przybojewska et  IARC, 19991
             marrow                                     ip x 2                                  al., 198430
             BALB/c and C57BL/       Micronucleus test 812 mg/kg bw/d       -                   Ashby et al.,    IARC, 19991
             6J mouse bone                              ip x 2                                  198931
             marrow
             C57BL/6J mouse          Micronucleus test 738 mg/kg bw/d       -                   Ashby et al.,    IARC, 19991
             bone marrow                                ip x 1                                  198931
             Tg.AC mouse             Micronucleus test 12 ug/mouse skin     -                   Tice et al.,     IARC, 19991
             peripheral blood cells                     x 3/wk 20 wk                            199717
             BDF1 mouse              Micronucleus test 375-1000 mg/kg       -                   Morita et al.,   NTP, 199810
             (m)                                        ip x 1                                  199734
             BDF1 mouse              Micronucleus test 188-1000 mg/kg       -                   Morita et al.,   NTP, 199810
             (m)                                        po x 1                                  199734
             C57BL/6J mouse          CA                 1,000 mg/kg bw/d    -                   Kligerman et     IARC, 19991
             splenocytes                                ip x 1                                  al., 199132
     +: positive; (+): weak positive; -: negative; NT: not tested
     in vitro tests: µg/mL; in vitro tests: mg/kg bw/day; ip: intraperitoneal; po: oral; wk: week
 8             Ethyl acrylate
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<pre> nnex        I
             Carcinogenic classification of
             substances by the Committee
             The Committee expresses its conclusions in the form of standard phrases:
 ategory     Judgement of the Committee (GRGHS)                                 Comparable with EU Category
                                                                                67/548/EEC            EC No 1272/2008
                                                                                before                as from
                                                                                12/16/2008            12/16/2008
A            The compound is known to be carcinogenic to humans.                1                     1A
             • It acts by a stochastic genotoxic mechanism.
             • It acts by a non-stochastic genotoxic mechanism.
             • It acts by a non-genotoxic mechanism.
             • Its potential genotoxicity has been insufficiently investigated.
                Therefore, it is unclear whether the compound is genotoxic.
B            The compound is presumed to be carcinogenic to humans.             2                     1B
             • It acts by a stochastic genotoxic mechanism.
             • It acts by a non-stochastic genotoxic mechanism.
             • It acts by a non-genotoxic mechanism.
             • Its potential genotoxicity has been insufficiently investigated.
                Therefore, it is unclear whether the compound is genotoxic.
             The compound is suspected to be carcinogenic to man.               3                     2
3)           The available data are insufficient to evaluate the carcinogenic   not applicable        not applicable
             properties of the compound.
4)           The compound is probably not carcinogenic to man.                  not applicable        not applicable
ource: Health Council of the Netherlands. Guideline to the classification of carcinogenic compounds. The Hague: Health
 ouncil of the Netherlands, 2010; publication no. A10/07E.50
             Carcinogenic classification of substances by the Committee                                                59
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<pre>0 Ethyl acrylate</pre>

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<br><br>