<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>1,2-Dichloroethane
Dutch Expert Committee on Occupational Safety (DECOS)
A committee of the Health Council of the Netherlands
To: the State Secretary of Social Affairs en Employment
No. 2019/16, The Hague, August 27, 2019
                                                        2 2
</pre>

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

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

<pre> Contents                                                                                            1,2-Dichloroethane | page 2 of 48
 contents
      Samenvatting                                               3 3.4 Calculation of the HBC-OCRV                                 24
                                                                   3.5 Skin notation                                               26
      Executive summary                                         5 3.6 Groups with increased risk                                  26
                                                                   3.6 Conclusions and recommendation                              27
 01 Scope                                                       7
      1.1  Background                                           8 References                                                      28
      1.2  Committee and procedure                              8
      1.3  Data                                                  8 Annexes                                                         34
                                                                   A   Epidemiological studies                                     35
 02 Identity, toxicity profile and classification             10  B   Animal studies                                              39
      2.1  Identity and physical and chemical properties       11 C   BMD-analysis                                                43
      2.1  Toxicity profile                                    11 D   Recommendation of the Subcommittee on Classification of
      2.3  Existing occupational exposure limits               17     carcinogenic substances                                     44
      2.4  Classification as a carcinogenic substance          18
 03 Carcinogenicity studies                                   19
      3.1  Human studies                                       20
      3.2  Animal experiments                                  21
      3.3  Selection of the suitable study for risk estimation
           in the occupational situation                        23
1       Health Council of the Netherlands | No. 2019/16                                            2                                 3
</pre>

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

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

<pre> Samenvatting                                                                                                           1,2-Dichloroethane | page 3 of 48
 samenvatting                                                                                         mene populatie; het verbodsrisiconiveau is 4 op
                                                                                                      1.000. De commissie schat de concentraties van
                                                                                                      een stof in de lucht die overeenkomen met die
 Op verzoek van de minister van Sociale Zaken        beschouwt de commissie de stof als stochas-      risiconiveaus, uitgaande van 40 jaar beroeps-
 en Werkgelegenheid (SZW) heeft de Gezond-           tisch genotoxisch, dat wil zeggen dat de stof    matige blootstelling.
 heidsraad gezondheidskundige advieswaarden          directe schade aan het genetisch materiaal
 afgeleid voor de beroepsmatige blootstelling aan    (DNA) veroorzaakt.                               Geraadpleegde onderzoeken
 de kankerverwekkende stof 1,2-dichloorethaan.                                                        Er zijn geen onderzoeken beschikbaar naar
 Dit advies is tot stand gekomen in de Commissie     Gezondheidskundige advieswaarden op              blootstelling aan 1,2-dichloorethaan en het
 Gezondheid en beroepsmatige blootstelling aan       basis van extra risico                           optreden van kanker bij de mens die geschikt
 stoffen (GBBS). Op www.gezondheidsraad.nl           Voor kankerverwekkende stoffen die geclassifi-   zijn voor het afleiden van gezondheidskundige
 staat meer informatie over de taken van deze        ceerd zijn in categorie 1A of 1B en die directe  advieswaarden. Er zijn verschillende dieronder-
 vaste commissie van de Gezondheidsraad. De          schade aan het genetisch materiaal veroor-       zoeken gedaan naar het optreden van kanker
 samenstelling van de commissie is te vinden         zaken (stochastisch genotoxisch werkingsme-      door blootstelling aan 1,2-dichloorethaan. De
 achterin dit advies.                                chanisme) kan geen blootstellingsniveau          commissie heeft deze onderzoeken beoordeeld
                                                     worden afgeleid waar onder ze niet kankerver-    en de meest geschikte geselecteerd. In dat
 Gebruik van 1,2-dichloorethaan                      wekkend zijn. Om voor deze stoffen toch een      onderzoek werden muizen langdurig bloot-
 1,2-Dichloorethaan wordt voornamelijk gebruikt      grenswaarde te kunnen bepalen, heeft de          gesteld aan 1,2-dichloorethaan in de lucht en
 voor de productie van vinylchloride, het            minister van SZW risiconiveaus vastgelegd.       kregen ze verschillende soorten tumoren. Het
 uitgangsmateriaal voor PVC (polyvinylchloride).     Deze risiconiveaus betreffen het extra risico op aantal kwaadaardige borsttumoren in vrouwtjes-
 De stof is geclassificeerd als ‘verondersteld       kanker door beroepsmatige blootstelling          muizen is door de commissie gebruikt voor het
 kankerverwekkend voor mensen’ (gevaren-             gedurende het arbeidzame leven. Het streef-      afleiden van de gezondheidskundige
 categorie 1B). Op advies van haar Subcom-           risiconiveau is niet meer dan 4 extra gevallen   advieswaarden.
 missie Classificatie carcinogene stoffen,           van kanker op 100.000 sterfgevallen in de alge-
2       Health Council of the Netherlands | No. 2019/16                                                              2                                  4
</pre>

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

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

<pre> Samenvatting                                             1,2-Dichloroethane | page 4 of 48
 Advies aan de staatssecretaris
 De commissie schat de concentratie van
 1,2-dichloorethaan in de lucht die samenhangt
 met een extra risico op kanker van 4 per
 100.000 (het streefrisiconiveau) gelijk aan 0,126
 mg/m3. Een extra risico op kanker van 4 per
 1.000 (het verbodsrisiconiveau) komt overeen
 met een concentratie van 12,6 mg/m3. Beide
 schattingen gaan uit van een beroepsmatige
 blootstelling gedurende 40 jaar.
 Verder adviseert de commissie om een huid-
 notatie (H-aanduiding) toe te passen voor
 1,2-dichloorethaan omdat deze stof relatief
 makkelijk kan worden opgenomen via de huid
 en zo substantieel kan bijdragen aan de totale
 inwendige blootstelling.
3       Health Council of the Netherlands | No. 2019/16 2                                 5
</pre>

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

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

<pre> Executive summary                                                                                                       1,2-Dichloroethane | page 5 of 48
 executive summary                                                                                      Consulted research
                                                                                                        There are no studies available on exposure to
                                                                                                        1,2-dichloroethane and cancer in humans that
 At the request of the Ministry of Social Affairs     considers 1,2-dichloroethane as a stochastic      are suitable for deriving health-based recom-
 and Employment, the Health Council of the            genotoxic carcinogen.                             mended values. Several animal carcinogenicity
 Netherlands has derived health-based recom-                                                            studies have been performed with 1,2-dichloro-
 mended values for 1,2-dichloroethane. This           Recommended values based on extra risk            ethane. The Committee has evaluated these
 advisory report has been composed by the             of cancer                                         studies and selected the most appropriate study.
 Dutch Expert Committee on Occupational Safety        For carcinogenic substances that have been        In this study, mice that were chronically exposed
 (DECOS). More information on the tasks of this       classified in category 1A or 1B and directly      to 1,2-dichloroethane by inhalation developed
 permanent committee of the Health Council of         interact with DNA (stochastic genotoxic mecha-    different types of tumours. The number of malig-
 the Netherlands can be found at www.health-          nism), no exposure level can be derived below     nant mammary tumours was used to derive
 council.nl. The members of the Committee are         which no carcinogenic effects can occur. To be    health-based recommended values.
 listed at the end of this report.                    able to set occupational exposure limits for
                                                      these substances, the Minister of Social Affairs  Recommendation to the State Secretary
 Use of 1,2-dichloroethane                            and Employment has determined risk levels.        The Committee estimates the concentration of
 1,2-Dichloroethane is primarily being used in the    These risk levels relate to the extra risk of     1,2-dichloroethane in the air that corresponds to
 production of vinyl chloride, the monomer unit of    cancer due to occupational exposure. The target   an extra cancer risk of 4 per 100,000 (the target
 polyvinyl chloride (PVC). The substance is clas-     risk level is 4 extra cancer cases per 100,000    risk level) equal to 0.126 milligram (mg)/per
 sified as a category 1B carcinogen (presumed to      deaths in the general population; the prohibitive cubic metre air (m3). An extra risk of cancer of 4
 have carcinogenic potential for humans). As          risk level is 4 per 1,000. The Committee esti-    per 1,000 (the prohibitive risk level) corresponds
 recommended by the Subcommittee on Classifi-         mates the concentration of a substance in the     to a concentration of 12.6 mg/m3. Both estimates
 cation Carcinogenic Substances, the Committee        air that corresponds to these risk levels, taking are based on 40 years of occupational expo-
                                                      into account 40 years of occupational exposure.   sure.
4        Health Council of the Netherlands | No. 2019/16                                                               2                                   6
</pre>

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

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

<pre> Executive summary                                        1,2-Dichloroethane | page 6 of 48
 In addition, the Committee recommends to apply
 a skin notation for 1,2-dichloroethane because
 the substance is absorbed by the skin relatively
 well, and can thereby contribute substantially to
 the total internal exposure.
5       Health Council of the Netherlands | No. 2019/16 2                                 7
</pre>

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

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

<pre> chapter 01 | Scope                                      1,2-Dichloroethane | page 7 of 48
 01
 scope
6      Health Council of the Netherlands | No. 2019/16 2                                 8
</pre>

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

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

<pre> chapter 01 | Scope                                                                                                         1,2-Dichloroethane | page 8 of 48
 1.1 Background                                                               In the next phase of the three-step procedure, the Social and Economic
 In the Netherlands, occupational exposure limits for genotoxic chemical      Council advises the Minister of Social Affairs and Employment on the
 substances are set using a three-step procedure. In the first step, a scien- feasibility of using the HBC-OCRVs as regulatory occupational exposure
 tific evaluation of the data on the toxicity of the substance is made by the limits. In the final step of the procedure, the Minister sets the official occu-
 Dutch Expert Committee on Occupational Safety (DECOS), a committee           pational exposure limits.
 of the Health Council of the Netherlands, at request of the Minister of
 Social Affairs and Employment. This evaluation should lead to a health-      1.2 Committee and procedure
 based recommended exposure limit (HBROEL) for the concentration of           The present document contains the evaluation of the DECOS, hereafter
 the substance in air. Such an exposure limit cannot be derived if the toxic  called the Committee. The members of the Committee are listed at the
 action cannot be evaluated using a threshold model, as is the case for       end of this report.
 carcinogens acting by a stochastic genotoxic mechanism. In that case, an     In June 2018, the president of the Health Council released a draft of the
 exposure-response relationship is recommended for use in regulatory          report for public review. The Committee has taken the comments received
 standard setting, i.e., the calculation of so-called health-based calculated into account in deciding on the final version of the report. These
 occupational cancer risk values (HBC-OCRVs). The Committee calculates        comments, and the reply by the Committee, can be found on the website
 HBC-OCRVs for compounds, which are classified as genotoxic carcino-          of the Health Council.
 gens by the European Union or by the Committee as carcinogens in cate-
 gory 1A or 1B.                                                               1.3 Data
 For the establishment of the HBC-OCRVs, the Committee generally uses         The Committee’s recommendation has been based on scientific data,
 a linear extrapolation method, as described in the Committee’s report        which are publicly available. Data were obtained from the online data-
 Guideline for the calculation of occupational cancer risk values.1 The       bases Toxline and Medline, using carcinogenic properties, carcino*,
linear model to calculate occupational cancer risk is used as a default       cancer, neoplastic, 1,2-dichloroethane and CAS registry number as key
 method, unless scientific data would indicate that using this model is not   words. In addition, in preparing this report the following reviews were
 appropriate.                                                                 consulted: ATSDR (2001), IARC (1999), NTP (2011), OECD-SIDS (2002)
7        Health Council of the Netherlands | No. 2019/16                                                                  2                                    9
</pre>

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

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

<pre> chapter 01 | Scope                                                      1,2-Dichloroethane | page 9 of 48
 and WHO (1995).2-6 The last literature search was performed in March
 2018.
 With respect to the carcinogenic mode of action, the Committee has
 requested the Subcommittee on Classification of Carcinogenic
 Substances for an evaluation of 1,2-dichloroethane. The advice of the
 Subcommittee can be found in Annex D.
8       Health Council of the Netherlands | No. 2019/16                2                                 10
</pre>

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

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

<pre> chapter 02 | Identity, toxicity profile and classification  1,2-Dichloroethane | page 10 of 48
 02
 identity, toxicity
 profile and
 classification
9      Health Council of the Netherlands | No. 2019/16      2                                 11
</pre>

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

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

<pre> chapter 02 | Identity, toxicity profile and classification                                                                                        1,2-Dichloroethane | page 11 of 48
 2.1 Identity and physical and chemical properties                                                      2.1 Toxicity profile
 1,2-Dichloroethane is used primarily to produce vinyl chloride. Physical                               Information on the non-neoplastic effects of 1,2-dichloroethane have been
 and chemical data shown below are from http://toxnet.nlm.nih.gov (HSDB)                                summarised by the ATSDR (2001), IARC (1999), OECD-SIDS (2002),
 (accessed April 14, 2016), ATSDR and IARC.2,3                                                          WHO (1995), and Gwinn et al. (2011).2,3,5-7 A compilation of their reviews is
                                                                                                        given below. Additional information was found in the registration dossier
  Chemical name                                   : 1,2-dichloroethane
  CAS number                                      : 107-06-2
                                                                                                        on the ECHA website.8 Additional literature is specified separately.
  EC number                                       : 203-458-1
  IUPAC name                                      : 1,2-Dichloroethane
                                                                                                        2.2.1 Kinetics and metabolism
  Synonyms                                          Ethylene dichloride, ethylene chloride,
                                                  : 1,2-bichloroethane, glycol dichloride,              1,2-Dichloroethane is rapidly and extensively absorbed through the lungs,
                                                    dichloroethylene, alpha-beta-dichloroethane
  Physical description and colour                 : Clear, colourless oily liquid
                                                                                                        gastro-intestinal tract and skin. Following absorption, 1,2-dichloroethane is
  Molecular formula                               : C2H4Cl2                                             distributed throughout all tissues of the body and is principally eliminated
  Structure
                                                  :                                                     via biotransformation. A minor, yet significant fraction of the absorbed
                                                                                                        dose (<15%) is excreted as unchanged parent compound in exhaled air.7
  Molecular weight                                : 98.96
  Melting point                                   : -35.5 °C                                            Metabolism appears to occur via two principal pathways, catalysed
  Boiling point (101.3 kPa)                       : 83.5 °C                                             respectively by cytochrome P450 and by glutathione S-transferase.
  Density (20°C)                                  : 1235 kg/m3
  Solubility                                        Solubility in water (20°C) = 8.7 g/L; Miscible with
                                                                                                        Cytochrome P450 enzymes catalyse oxidative transformation of
                                                  :
                                                    most organic solvents                               1,2-dichloroethane to 2-chloroacetaldehyde, 2-chloroacetic acid and
  Octanol/water partition coefficient, Log Poct/w : 1.48
  Vapour pressure (20°C)                          : 8 kPa
                                                                                                        2-chloroethanol, which are conjugated both enzymatically and non-enzy-
  Relative vapour density (air = 1)               : No data                                             matically with glutathione (GSH). The other pathway involves direct conju-
  Flash point                                     : 13°C (closed cup) 18 °C (open cup)
                                                                                                        gation with GSH to form S-(2-chloroethyl)glutathione.3
  Odour threshold                                 : 20 mg/L (water); 12-100 ppm (air)
  Conversion factor (20 °C, 101.3 kPa)              1 mg/m3 = 0.25 ppm                                  Metabolism of 1,2-Dichloroethane occurs rapidly with a reported elimina-
                                                  :
                                                    1 ppm = 4 mg/m3
                                                                                                        tion half-life of 20-30 min in male Osborne-Mendel rats following inhalation
                                                    Flam. Liq. 2: H225; Carc. 1B: H350; Acute Tox. 4:
  EU classification
                                                  : H302; Eye Irrit. 2: H319; STOT SE 3: H335; Skin     and oral dosing, with the majority of elimination attributed to metabolism.7
  (EC No 790/2009 of 10 August 2009)
                                                    Irrit. 2: H315
10          Health Council of the Netherlands | No. 2019/16                                                                                       2                                  12
</pre>

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

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

<pre> chapter 02 | Identity, toxicity profile and classification                                                              1,2-Dichloroethane | page 12 of 48
 While activation of 1,2-dichloroethane through the oxidation pathway (by     6,400 mg/m3, respectively, have been observed. In these studies several
 CYP450) may play a role in chromosomal aberrations, the glutathione          adverse effects have been reported including liver and kidney damage,
 conjugation pathway appears to be the predominant 1,2-dichloroethane         pulmonary and visceral congestion. A dermal LD50 of 4,890 mg/kg bw has
 mutagenicity pathway.7                                                       been observed after 24 hours occluded application.
 2.2.2 Acute toxicity                                                         2.2.3 Irritation/sensitisation
                                                                              Irritation studies demonstrated that 1,2-dichloroethane is irritating to the
 Human data                                                                   skin and eye. A mouse local lymph node assay (OECD 429, GLP) indi-
 Several cases of acute exposures to humans have been reported in the         cated that the substance is not a skin sensitiser.
 literature. Accidental ingestion of 15-60 mL of 1,2-dichloroethane has been
 reported to cause death within 10-28 hours of exposure. Several of these     2.2.4 Repeated dose toxicity
 deaths have been attrib-uted to circulatory or respiratory failure. Exposure
 to concentrated 1,2-dichloroethane vapour for 30 minutes resulted in         Human data
 cardiac arrest and death 5 days after exposure.                              Repeated exposure in humans has been associated with various effects
                                                                              including respiratory and haematological effects, nausea, vomiting,
 Animal data                                                                  abdominal pain, dysfunction of liver and kidney, and neurological disor-
 The LD50 for oral exposure ranged from 770-967 mg/kg bw in rats,             ders.
 413-911 mg/kg bw in mice, and approximately 910 mg/kg bw in rabbits. In
 dogs a LD50 of >2,500 mg/kg bw was observed. Non-lethal effects              Animal data
 observed included congestion of the lungs, pale kidneys and livers, and      Effects on non-cancer endpoints upon chronic exposure to 1,2-dichloro-
 congestion of blood vessels in the intestines. LC50 values of rats after     ethane were reported for several of the carcinogenicity studies summa-
 inhalation exposure ranged from approximately 4,000 mg/m3 after 7 hours      rised in Table 4 (Annex B). in addition, results of relevant sub-chronic
 of exposure to > 49,000 mg/m3 after 30 minutes exposure. In mice (6-hour     studies are summarised below.
 exposure) and guinea-pig (7-hour exposure) a LC50 of 1,080 mg/m3 and
11       Health Council of the Netherlands | No. 2019/16                                                                2                                  13
</pre>

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

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

<pre> chapter 02 | Identity, toxicity profile and classification                                                               1,2-Dichloroethane | page 13 of 48
 Inhalation                                                                   observed. No consistent exposure-related effects on haematological
 In a two-year inhalation study by Nagano et al. (1998/2006), in which mice   parameters and clinical chemistry parameters were measured after three,
 and rats were exposed for 6 hours per day, 5 days a week, no exposure-       six, 12 or 18 months of exposure.
 related changes in the incidence of any haematological, blood biochemical
 or urinary parameter occurred in mice (40, 120, 360 mg/m3) and rats (40,     Oral exposure
 160, 640 mg/m3).9,10 There was no significant difference in survival rate,   In the oral exposure study by the National Cancer Institute (NCI), no dose-
 body weight and food consumption in males of both species and in female      related mean body weight depression was apparent in rats.14-16 From week
 rats. In female mice, increased mortality at the mid-concentration was       6 of the study, several rats in both treated groups (47 and 95 mg/kg
 attributed to the significantly increased malignant lymphoma deaths. This    bw/day) showed a hunched appearance and transient laboured respira-
 mortality was not ascribed to treatment. Incidences of subcutaneous          tion, abdominal urine stains, cloudy or squinted eyes, or eyes with a
 masses, which were found in the breast, back, and abdominal and              reddish crust. The incidence of palpable nodules and/or tissue masses
 perigenital areas were increased in the exposed groups.                      was slightly greater in the treated than in the control animals. In mice,
 In a study by Cheever et al. (1990) rats were exposed to 200 mg/m3           mean body weight depression was observed for high dose females (299
 1,2-dichloroethane by inhalation 7 hours a day, 5 days a week for 2          mg/kg bw/day). Palpable nodules and/or tissue masses and swelling
 years.11 No substance-related effects were observed on mortality, body       around the abdominal midline were observed with slightly greater
 weight, and food and water consumption. The extensive histopathology         frequency in the treated groups than in the controls. An overall high
 investigation showed no adverse effects, except increased testicular         mortality in both rats and mice in the exposed groups was present,
 lesions in 10 and 24% of the control and exposed rats, respectively.         possible due to carcinogenicity.
 As part of a chronic inhalation study by Maltoni et al. (1980), Spreafico et The toxicity of 1,2-dichloroethane after repeated oral exposure has also
 al. (1980) investigated the effect of 1,2-dichloroethane on clinical chem-   been investigated by the NTP. Three rat species (F344/N, Sprague-
 istry parameters.12,13 Rats were exposed to 20, 40, 200, or 600-1,000        Dawley, Osborne-Mendal) and the B6C3F1 mice were exposed for thir-
 mg/m3 1,2-dichloroethane for 7 hours per day, 5 days per week for 78         teen weeks via drinking water to concentrations of 0, 500, 1,000, 4,000,
 weeks. The dose of the 1,000 mg/m3 dose group was reduced to 600             8,000 ppm 1,2-dichloroethane (corresponding for rats to doses between
 mg/m3 after a few weeks because of the high toxicity and deaths that were    50-730 mg/kg bw/day). Weight gain depression in each sex of all three rat
12       Health Council of the Netherlands | No. 2019/16                                                                 2                                 14
</pre>

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

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

<pre> chapter 02 | Identity, toxicity profile and classification                                                              1,2-Dichloroethane | page 14 of 48
 strains in the 4,000 and 8,000 ppm groups was observed. Water              ATSDR (2001) and IARC (1999) reviewed a several reliable develop-
 consumption decreased by 50-60% with increasing dose for all exposed       mental toxicity studies in which female rabbits and rats were exposed to
 male and female rats. Kidney and liver weight increased in dosed rats of   1,2-dichloroethane during pregnancy.2,3 In one study the animals were
 all strains. No treatment-related lesions were observed except for a dose- exposed by inhalation for 7 hours/day on gestation days 6-18 (rabbit) or
 related increase in the incidence of renal tubular regeneration in female  6-15 (rat) at concentrations of 100 or 300 ppm (400 or 1,200 mg/m3). At
 F344/N rats. Nine out of ten female mice exposed to 8,000 ppm (corre-      400 mg/m3 no adverse effects on the dam or the offspring were observed.
 sponding to about 4,200-4,900 mg/kg bw/day) died before the end of the     Exposure of rats to 300 ppm resulted in high maternal mortality, foetole-
 study. Mean body weights of male mice exposed to 500 ppm 1,2-dichloro-     thality, and resorption of all implantations in one dam. In rabbits, 1,200
 ethane or more and female mice exposed to 1,000 ppm or more were           mg/m3 was lethal to some dams but there were no foetotoxic or terato-
 lower compared to the controls. Kidney weights were significantly          genic effects observed. In another inhalation study in rats, exposure up to
 increased for these male and female mice. Renal tubular cell regeneration  300 ppm (1,200 mg/m3, 6 hours/day on gestation days 6-20) induced no
 was seen in male mice at 8,000 ppm.17,18                                   embryo- or foetotoxicity, changes in foetal growth or teratological effects
 In the same study an extra group of F344/N rats received the substance     while maternal weight gain was decreased at the highest concentration.
 via oral gavage (males: 0, 30, 60, 120, 240, 480 mg/kg bw/day; females:    Treatment of rats by gavage on gestation days 6-20 at 198 mg/kg body
 0, 18, 37, 75, 150, 300 mg/kg bw/day). All male rats exposed to 240 or     weight resulted in reduced weight gain of the dams and embryolethal
 480 mg/kg bw/day and 9/10 females that received 300 mg/kg bw/day died      effects (increased non-surviving implants and resorptions sites per litter)
 before the end of the study. Mean body weights of the highest dose males   but no foetotoxicity or teratogenicity. At the next lower dose of 158 mg/kg
 and females were lower compared to the control. Liver and kidney weights   body weight these effects did not occur. Possible developmental effects,
 were increased for dosed males and females. Necrosis of the cerebellum,    including fetal visceral or skeletal malformations, were also examined in a
 hyperplasia, inflammation, and mineralization of the forestomach were      2-generation reproduction toxicity study in mice exposed via the drinking
 seen in animals that died or were killed in moribund condition.17,18       water (see next paragraph for dose levels). No substance-related effects
                                                                            on the offspring were observed.
 2.2.5 Reproduction toxicity                                                ATSDR and IARC described two reliable reproduction toxicity studies.2,3
 1,2-Dichloroethane is not classified for reproduction toxicity.            A study in rats showed no adverse effects on reproductive performance or
13       Health Council of the Netherlands | No. 2019/16                                                                2                                 15
</pre>

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

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

<pre> chapter 02 | Identity, toxicity profile and classification                                                               1,2-Dichloroethane | page 15 of 48
 development (until postpartum day 21) upon exposure by inhalation            Genotoxicity refers to the ability of a substance to induce mutations and/or
 (6 hours/day) at concentrations up to 150 ppm (600 mg/m3) for 60 days        chromosomal aberrations. Indicator tests can be informative, but in
 pre-mating on five days/week, and then on 7 days/week throughout             contrast to a genotoxicity test, do not allow conclusions on genotoxicity as
 mating, gestation and lactation (excluding gestation day 21 through post-    results do not provide information on permanent, heritable genetic
 partum day 4). Similarly, no effects on reproductive performance or devel-   changes.
 opment were found in a 2-generation study in mice which were exposed
 via the drinking water at concentrations up to 290 mg/L (intended to         Human data
 provide daily doses up to 50 mg/kg body weight) starting five weeks          One study on the genotoxicity of 1,2-dichloroethane in humans is avail-
 before mating of the F0 generation. In addition, ATSDR1 describes inhala-    able. In this study, sister chromatid exchange (SCE) frequency was deter-
 tion studies in rats which showed embryomortality (exposure to 4.7 ± 7       mined in 51 men employed in two vinyl chloride monomer manufacture
 ppm (19 ± 28 mg/m3) for 4 months prior to mating and during gestation) or    plants.19 These workers had increased SCE frequencies when compared
 decreased fertility and increased stillbirths and perinatal mortality (expo- to 20 office workers who were assumed to have no 1,2-dichloroethane
 sure to 14 ppm (57 mg/m3) for 6 months). However, the reliability of these   exposure. The authors concluded that an increase in SCE was associated
 studies is unclear because of deficiencies in reporting study design and     with moderate exposure levels (around 1 ppm) of 1,2-dichloroethane, but
 results.                                                                     not vinyl chloride monomer.
 Based on the above results, the Committee concludes that there is no
 convincing evidence that 1,2-dichloroethane adversely affects reproduc-      In vitro data
 tion at doses below those which cause other systemic effects.
                                                                              Mutagenicity assays
 2.2.6 Genotoxicity                                                           Several in vitro mutagenicity studies in non-mammalian cells have been
 Studies investigating the mutagenicity/genotoxicity of 1,2-dichloroethane    performed. In general, 1,2-dichloroethane was found to be not mutagenic
 have been reviewed by the IARC (1999), ATSDR (2001), WHO (1995) and          in the Salmonella typhimurium strains which detect frame-shift mutations
 Gwinn et al. (2011).2,3,6,7 A summary based on these reviews is given        (TA 98, TA 1537 and TA 1538) in the absence and presence of exogenous
 below, specific literature is referenced separately.                         metabolic activation, but mutagenicity was observed in the base-pair
14       Health Council of the Netherlands | No. 2019/16                                                                 2                                 16
</pre>

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

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

<pre> chapter 02 | Identity, toxicity profile and classification                                                               1,2-Dichloroethane | page 16 of 48
 substitution strain TA100 and TA1535 after exogenous metabolic activa-      collected 7, 14, and 28 days after the last treatment, DNA was isolated
 tion. No mutagenicity was observed in Escherischia coli and in fungal       and lacZ mutant frequency was determined. No increase in mutant
 systems. Mutagenicity was also observed in Chinese hamster ovary cells      frequency was detected.
 and in human lymphoblastoid cell lines AHH-1 and TK6.                       In a mouse spot test, the number of somatic gene mutations in progeny of
                                                                             mice exposed to 300 mg 1,2-dichloroethane/kg on gestational day 10 was
 Cytogenicity assays                                                         increased when compared to all controls (p=0.03) but not when compared
 Micronuclei were induced in AHH-1 cells in vitro without exogenous meta-    to the vehicle controls.21 Only one dose was tested.
 bolic activation.
                                                                             Cytogenicity assays
 Indicator tests                                                             Results of four micronucleus tests in mice are available, which were all
 1,2-Dichloroethane induced unscheduled DNA synthesis in the absence of      negative. In a bone marrow micronucleus test with NMRI mice, two doses
 exogenous metabolic activation (mouse and rat hepatocytes) and in the       of 396 mg/kg injected i.p. 24h apart did not result in an increased induc-
 presence of exogenous metabolic activation (human peripheral lympho-        tion of micronuclei at 6h after the last injection.22 Also no increase of
 cytes). DNA binding was observed in calf thymus DNA with and without        micronuclei was measured in peripheral blood in Eµ-PIM-1 transgenic
 exogenous metabolic activation and to mouse hepatocytes without exog-       mice treated orally with doses up to 300 mg/kg bw/d for 41 weeks23, in
 enous metabolic activation.                                                 CD-1 mice 24-48h after a single i.p. injection of 188-376 mg/kg24, or in a
                                                                             B6C3F1 mice exposed to 1,2-dichloroethane concentrations up to 8,000
 In vivo data                                                                ppm in water for 90 days25. In a recent genotoxicity study by Lone et al.
                                                                             (2016), male rats were exposed to 80.7, 161.4 or 242.1 mg/kg bw. At 24h
 Mutagenicity assays                                                         and 48h, induction of micronuclei and chromosomal aberrations were
 Hachiya et al. (2000) tested the potential of 1,2-dichloroethane to induce  detected in the bone marrow.26 Negative results were observed in a domi-
 lacZ mutations in the liver and testis of transgenic mouse model.20 Animals nant lethal test in ICR Swiss mice after 7 daily oral doses of 50 mg
 were given either a single injection of 75 or 150 mg/kg bw, or multiple     1,2-dichloroethane/kg bw.27 Positive results, however, are available from a
 injections up to total dose of 280 mg/kg bw). The liver and testes were
15       Health Council of the Netherlands | No. 2019/16                                                                 2                                 17
</pre>

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

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

<pre> chapter 02 | Identity, toxicity profile and classification                                                             1,2-Dichloroethane | page 17 of 48
 sister chromatid exchange assay in ICR Swiss mice, 24h after i.p. expo-     liver tissue (with approximately ~54% higher levels in liver tissue than in
 sure to doses up to 16 mg/kg bw.28                                          mammary tissue).
 Indicator tests                                                             In vivo, increased formation of DNA adducts following exposure to
 DNA single strand breaks were induced in B6C3F1 mice liver after oral       1,2-dichloroethane has also been shown after i.p. injection in rats and
 and intraperitoneal exposure29,30, but not after inhalation (500 ppm (2,000 mice34-36, and after inhalation exposure in rats.37 Also, the ability to bind
 mg/m3), 4h)30. In one study with CD-1 mice treated with 200 mg/kg i.p.,     DNA was observed in liver, lung, stomach, and kidney of mice after intra-
 stomach, kidney, bladder, lung, brain and bone marrow were also             peritoneal injection and to the same organs of rats after inhalation, oral
 analysed and single strand DNA breaks were detected.31 DNA strand           exposure and intraperitoneal injection.
 breaks were also observed in CD rat liver32 and rat bone marrow26 after
 oral exposure.                                                              Conclusions on genotoxicity
 In an unpublished study summarised in the ECHA registration dossier, a      Based on the recommendation of the Subcommittee, the Committee
 Comet assay was performed in mammary gland tissue of female rats,           concludes that 1,2-dichloroethane is a stochastic genotoxic carcinogen
 exposed to 0 or 200 ppm (800 mg/m3) of 1,2-dichloroethane vapour for 28     and applies a risk-based approach for the hazard quantification. The
 consecutive days (28-31 exposures).33 No DNA damage was detected.           advice of the Subcommittee can be found in Annex D.
 In this study, formation of DNA adducts in mammary tissue and liver tissue
 was also assessed. No increase in 8-hydroxy-2’-deoxyguanosine adduct        2.3 Existing occupational exposure limits
 levels in mammary tissue was observed, whereas the respective levels in     Table 1 summarizes the occupational exposure limits established by the
 the liver of exposed rats were significantly less than control rats. Endog- regulatory authorities of the Netherlands, the United Kingdom, Denmark,
 enous S-[2-(N7-guanyl)ethyl]glutathione adduct was not quantifiable in      Sweden and by the USA-ACGIH, USA-NIOSH and USA-OSHA.
 mammary or liver tissue isolated from control rats. In 1,2-dichloroethane-
 exposed animals, a statistically significant increase in S-[2-(N7-guanyl)
 ethyl]glutathione adduct levels was observed in both mammary tissue and
16       Health Council of the Netherlands | No. 2019/16                                                               2                                   18
</pre>

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

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

<pre> chapter 02 | Identity, toxicity profile and classification                                            1,2-Dichloroethane | page 18 of 48
 Table 1. Occupational exposure limits of 1,2-dichloroethane
   Country                    OELa                OEL               TWA                Type of
   (Organization)             (ppm)               (mg/m3)                              exposure limit
 The Netherlandsa             -                  7                  8h                 OEL
   UK (HSE)   a
                              5                  21   d
                                                                    8h                 WEL
   Denmark  a
                              1                  4  d
                                                                    8h                 OEL
   Sweden a
                              1                  4  d
                                                                    8h                 OEL
   Sweden a
                              5                  20   d
                                                                    15 min             OEL
   USA (ACGIH)    b
                              10                 40                 8h                 TLV
   USA (NIOSH)    c
                              1                  4                  8h                 REL
   USA (NIOSH)    c
                              2                  8                  15 min             REL
   USA (OSHA)   c
                              50                 -                  8h                 PEL
 Abbreviations: OEL: occupational exposure limit; PEL: permissible exposure limit; REL: recommended
 exposure limit; TLV: threshold limit value; TWA: time-weighted average awww.ser.nl, bwww.epa.com,
 c
   www.cdc.gov, dskin notation
 2.4 Classification as a carcinogenic substance
 The European Union has classified 1,2-dichloroethane as a category 1B
 carcinogen (presumed to have carcinogenic potential for humans). IARC
 has classified the compound as a group 2B carcinogen (possibly carcino-
 genic to humans).3
17         Health Council of the Netherlands | No. 2019/16                                            2                                 19
</pre>

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

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

<pre> chapter 03 | Carcinogenicity studies                   1,2-Dichloroethane | page 19 of 48
 03
 carcinogenicity
 studies
18     Health Council of the Netherlands | No. 2019/16 2                                 20
</pre>

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

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

<pre> chapter 03 | Carcinogenicity studies                                                                                    1,2-Dichloroethane | page 20 of 48
 3.1 Human studies                                                           from cancer or other causes was found in a cohort of males employed at a
 The Committee identified 14 epidemiological studies investigating           chemical plant.44
 mortality or cancer incidence among chemical workers or residents poten-
 tially exposed to 1,2-dichloroethane. These studies are briefly described   Case-control studies
 below. More details on the occupational studies are given in Table 2 and 3  An increased risk (odds ratio) was observed for primary breast cancer in
 of Annex A.                                                                 men employed in trades with potential exposure to gasoline and its
                                                                             combustion products (which might contain 1,2-dichloroethane) and for
 Cohort studies                                                              pancreatic cancer in white men and women with a high probability of
 In a cohort of male employees of a petrochemical plant, conducted to        occupational exposure to 1,2-dichloroethane.45,46 No increased risk associ-
 investigate a cluster of brain tumours reported earlier in this population, ated with 1,2-dichloroethane was found for primary brain tumours among
 insufficient evidence was found to conclude that these tumours were         workers of a petrochemical plant, for soft-tissue sarcoma among
 occupationally related.38,39 Another investigation of brain tumours among   employees of a multi-chemical production plant, or for renal cell carcinoma
 chemical plant employees, using a sample-based cohort method,               among men and women exposed to organic solvents.47-49
 suggested at most a slight increased risk of mortality from brain tumours
 for the overall time period, and a probable elevated risk associated with   Studies on associations of environmental factors with cancer
 first employment prior to 1945.40                                           Isacson et al. investigated possible associations between cancer inci-
 Excess mortality from tumours (total tumours, stomach cancer and            dence rates of municipal residents and the level of certain volatile organic
 leukaemia) was found in a cohort of males working in ethylene oxide         contaminants and metals in finished public drinking water supplies.50 The
 production.41 Excess mortality from pancreatic cancer and from lymphatic    results showed a statistically significant association between the presence
 and haematopoietic cancers was found in a cohort of male chlorohydrin       of detectable 1,2-dichloroethane (≥ 0.1 µg/L) and the incidence rates of
 production workers.42 Examination of another cohort of male chlorohyrin     colon cancer and rectal cancer in males. This association could not be
 production workers showed no increased risk of these cancer (pancreatic,    explained by occupational or other sociodemographic features including
 lymphopoietic) or of any other malignancies.43 Further, no excess mortality smoking. Data from this study do not permit conclusions on specific water
                                                                             quality variables which may be associated with risk of human cancer.
19       Health Council of the Netherlands | No. 2019/16                                                                2                                 21
</pre>

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

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

<pre> chapter 03 | Carcinogenicity studies                                                                                     1,2-Dichloroethane | page 21 of 48
 The results of a study by Goldberg et al. suggest that there may be          maximum of 104 weeks. In male rats the incidence of mammary gland
 increased risks for cancers of the stomach, liver, lung, prostate and cervix fibroadenoma was statistically increased in the high dose group (p<0.05).
 uteri among persons who live near a solid waste site which emitted           In female rats subcutis fibroma, mammary gland adenoma and fibroad-
 airborne 1,2-dichloroethane (among other chemicals).51 Because of the        enoma were statistically significantly increased in the high dose group
 unavailability of exposure data and inadequate control of potentially        (p<0.05). Further, dose-dependent increases in the incidences of subcutis
 confounding factors, it cannot be concluded whether the observed excess      fibroma and peritoneum mesothelioma in male rats and of adenocarci-
 cancer risks represent true associations with exposure to chemicals          noma in female rats were reported (significant positive trend by Peto’s
 released from the waste site.                                                test), but the incidences in individual exposed groups did not differ statisti-
                                                                              cally significantly from the concurrent control incidence.
 The Committee considers the epidemiological data not suitable for hazard     In the mouse study of Nagano et al. the animals were exposed to 0, 40,
 quantification, due to limitations in study design (in particular because of 120, 360 mg/m3 for 6 hours/day, 5 days/week for a maximum of 104
 the presence of co-exposures and the lack of quantitative exposure infor-    weeks. In female mice, a significant positive trend (Peto’s test) was
 mation).                                                                     observed for the incidences of bronchio-alveolar adenomas and carci-
                                                                              nomas in the lung, endometrial stromal polyps in the uterus, adenocarci-
 3.2 Animal experiments                                                       noma in the mammary gland, and hepatocellular adenomas. Though the
 In Table 4 (Annex B) carcinogenicity studies performed with experimental     incidences of these tumours did not attain statistical significance
 animals are summarized. The summarized studies comprise five inhala-         compared with concurrent controls, they exceeded the maximum historical
 tion studies of which three were performed with rats and two with mice.      control incidence (exception: carcinoma in the lung) and were ascribed to
 One oral study in mice and one in rats were performed. Furthermore, one      treatment. The statistically significant increases (compared to concurrent
 study with intra-peritoneal injections and two using dermal applications     controls) in the incidences of malignant lymphomas in the lymph node of
 were available.                                                              female mice of the low- and mid-dose groups were not likely to be related
 Nagano et al. (1998/2006) performed an inhalation carcinogenicity study      to treatment because there was no concentration-related response and
 with F344 rats and BDF1 mice.9,10 Rats were exposed to 0, 40, 160, and       the incidences in all exposed groups were in the historical control range
 640 mg/m3 1,2-dichloroethane for 6 hours/day, 5 days/week for a              whereas the concurrent control incidence was lower than observed histori-
20       Health Council of the Netherlands | No. 2019/16                                                                 2                                  22
</pre>

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

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

<pre> chapter 03 | Carcinogenicity studies                                                                                         1,2-Dichloroethane | page 22 of 48
 cally. In male mice of the mid- and high-dose groups the incidence of liver      both exposed male and female mice were also statistically significant
 hemangiosarcoma was statistically significantly increased compared with          increased compared to control.14-16
 concurrent controls. This finding is not likely to be causally related to treat- In a study performed by Maltoni et al. (1980/1982) Sprague-Dawley rats
 ment because there was no significant dose-response relationship and the         and Swiss mice were exposed to 1,2-dichloroethane via inhalation to
 incidence in the high-dose group was in the historical control range.9,10        concentrations of 20, 40, 200 or 600-1,000 mg/m3 for 7 hours/day,
 In a study, performed by the NCI, the carcinogenicity of 1,2-dichloroethane      5 days/week, for 78 weeks.12,52 Concurrent control mice and one group of
 using Osborne-Mendel rats (50 animals/sex/exposed group) was deter-              control rats were kept in a nearby room. An additional control group of rats
 mined. 1,2-dichloroethane in corn oil was administered by gavage in time         was kept in an exposure chamber under the same conditions as exposed
 weighted average (TWA) exposure doses of 0, 47, or 95 mg/kg bw/day for           rats. Tumour incidences in exposed animals did not differ from control
 78 weeks. 20 animals/sex received vehicle treatment and 20 animals/sex           incidences, except for benign mammary tumours (fibromas and fibroad-
 were left untreated. All surviving animals were sacrificed at 110 weeks.         enomas combined) in female rats. The incidence of these mammary
 A statistically significant positive association between dosage and inci-        tumours was statistically significantly increased at 20, 200 and 600-1,000
 dence of squamous-cell carcinoma of the forestomach and hemangio-                mg/m3 compared with controls kept in an exposure chamber but not
 sarcomas of the circulatory system occurred in the male rats. There was          compared with controls in a nearby room (the incidences in the two control
 also a significantly increased incidence of adenocarcinomas of the               groups differed significantly). There was no dose-related response (the
 mammary gland in female rats.14-16                                               highest incidence was observed at the lowest concentration tested). More-
 In the same study by the NCI the substance was also tested on B6C3F1             over, the onset of fibromas and fibroadenomas is known to be age-corre-
 mice (50 animals/sex/exposed group) by gavage by exposing mice to a              lated. Therefore, the intergroup differences in mammary tumour incidence
 TWA of 0, 97, 195 mg/kg bw/day for male mice and 0, 149, 299 mg/kg               probably reflected intergroup differences in survival rather than an effect
 bw/day for female mice for 78 weeks. 20 animals/sex received vehicle             of treatment.
 treatment and 20 animals/sex were left untreated. All surviving animals
 were sacrificed at 91 weeks. The incidence of mammary adenocarcinoma             In addition, four other carcinogenicity studies have been identified by the
 was statistically significantly increased in female mice exposed to              Committee, but these studies were considered to be less adequate for
 1,2-dichloroethane. The incidence of alveolar/bronchiolar adenomas in            carcinogenicity assessment due to multiple deficiencies.
21       Health Council of the Netherlands | No. 2019/16                                                                     2                                 23
</pre>

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

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

<pre> chapter 03 | Carcinogenicity studies                                                                                   1,2-Dichloroethane | page 23 of 48
 Cheever et al. (1990) exposed Sprague-Dawley rats by inhalation to 0 or     3.3 Selection of the suitable study for risk estimation in the
 200 mg/m3 1,2-dichloroethane for 7 hours/day, 5 days/week, for 2 years.11         occupational situation
 All tumour incidences found in the exposed rats were similar to the control The Committee prefers the use of epidemiological data, however, no suit-
 group.                                                                      able data are available. Therefore, the Committee has focused on animal
 In a study by Van Duuren et al. (1979) groups of 30 female Ha:ICR Swiss     carcinogenicity data. The main route of occupational exposure to
 mice received thrice-weekly skin application of 42 or 126 mg 1,2-dichloro-  1,2-dichloroethane is inhalation of its vapour. Therefore, occupational
 ethane per animal in 0.2 ml acetone or acetone alone on the shaved          cancer risk values are preferably derived from inhalation studies. The
 dorsal skin.53 The highest dose showed a significantly increased incidence  inhalation studies in rats and mice by Maltoni et al. (1980/1982)12,52 and
 of lung papilloma (p<0.0005) compared to controls (0.1 mL acetone).         the rat inhalation study by Cheever et al. (1990)11 are not suitable for deri-
 Suguro et al. (2017) tested the carcinogenic potential of dermally applied  vation of cancer risk values because these studies showed no substance-
 1,2-dichloroethane in rasH2 transgenic mice (strain CB6F1-TG (rasH2),       related increase in the incidence of any malignant tumour. In the more
 containing approximately three copies of the human c-Ha-ras proto-onco-     recent studies by Nagano et al. (1998/2006)9,10 1,2-dichloroethane induced
 gene).54 Animals (males and females) were treated 3 times a week for 26     a dose-dependent increase in the incidences of benign and malignant
 weeks with 126 mg/mouse in acetone. The incidences of bronchiolo-alve-      tumours in various organs in both rats and mice. The inhalation studies of
 olar adenomas and adenocarcinomas were increased in both sexes; bron-       Nagano et al. are well-performed, the exposure period covered the largest
 chiole-alveolar hyperplasias were increased in female mice.                 part of the standard lifespan of the experimental animals, and groups
 Theiss et al. (1977) studied the formation of lung adenoma in male A/St     sizes were adequate (individual animal data were not reported).
 mice after intra-peritoneal injections (0, 20, 40, 100 mg/kg) three times a Substance-related increases in benign and malignant tumours were also
 week for eight weeks.55 Twenty-four weeks after the first injection, the    observed in rats and mice administered 1,2-dichloroethane via the oral
 mice were sacrificed. The number of lung adenomas and the average of        route (gavage).14-16 These oral studies, conducted by NCI, are also
 lung tumours per mouse was comparable between the exposed group and         adequate for cancer risk assessment. However, as the inhalation route is
 controls.                                                                   most relevant for occupational exposure to 1,2-dichloroethane, the
22       Health Council of the Netherlands | No. 2019/16                                                               2                                  24
</pre>

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

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

<pre> chapter 03 | Carcinogenicity studies                                                                                      1,2-Dichloroethane | page 24 of 48
 Committee prefers to use the inhalation studies by Nagano et al. for deri-    of Nagano et al. (1998/2006) were not yet available at the time of the
 vation of the occupational cancer risk values.                                previous evaluation.9,10
 In the inhalation studies by Nagano et al., 1,2-dichloroethane induced a
 slight increase in the incidence of mammary gland adenocarcinomas in          3.4 Calculation of the HBC-OCRV
 both female mice and female rats at the highest concentration tested (i.e.    To calculate the carcinogenic activity expressed as the incidence per unit
 360 mg/m3 in mice and 640 mg/m3 in rats). This type of malignant tumour       air concentration (mg/m3) of 1,2-dichloroethane, the number of female
 is relevant for humans. The malignant tumours induced by 1,2-dichloro-        mice with mammary gland adenocarcinomas was used as starting point.
 ethane at sites other than the mammary gland (i.e. peritoneum mesothe-        The Committee is of the opinion that the available data do not indicate that
 liomas in male rats and lung bronchio-alveolar carcinomas in female mice)     the use of linear extrapolation is inappropriate and that the data are
 are not relevant for humans. Though the increase in mammary gland             adequate to use the benchmark dose (BMD) method for estimation of the
 adenocarcinomas was not statistically significant compared to concurrent      starting point for calculation of the carcinogenic activity. The Committee
 controls, the incidences exhibited a statistically significant positive trend prefers the benchmark dose (BMD) method for estimation of the starting
 and the maximum incidence in historical controls was exceeded. There-         point for calculation of the carcinogenic activity. Until recently, the
 fore, the Committee considers the slight increase in the incidence of         Committee used the BMDS software by U.S. EPA. The Committee has
 mammary gland adenocarcinomas biologically significant and related to         decided to use the PROAST software, which is developed by the RIVM
 treatment. The mouse study was selected for cancer risk derivation,           and made available by EFSA. PROAST provides model averaged BMDL
 because the mouse developed mammary tumours at a lower exposure               and BMDU values, taking into account all models, from which a weighted
 level than the rat.                                                           BMD can be derived. This analysis takes into account all possible values
 In its previous evaluation of 1,2-dichloroethane (published in 1997)56 the    of the true BMD based on the available data, and is therefore used for
 Committee calculated cancer risk values on the basis of the incidence of      calculation of the HBC-OCRV. The results of these BMD-analyses and the
 haemangiosarcomas in male rats in the oral carcinogenicity bioassay           criteria for model fit are given in Annex C.
 conducted by NCI.14-16 This oral study was considered most suitable           The incidence per unit concentration in air (mg/m3) (lifespan conditions,
 because the inhalation studies available at that time showed no               assuming a linear concentration-response relationship) is calculated as
 substance-related increases in tumour incidences. The inhalation studies      follows:
23       Health Council of the Netherlands | No. 2019/16                                                                  2                                 25
</pre>

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

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

<pre> chapter 03 | Carcinogenicity studies                                                                                        1,2-Dichloroethane | page 25 of 48
                                                 BMR                              risk of cancer in humans under workplace exposure conditions it is further
                                                                                =
                          Xpo Xpe exposure hours per day exposure days per week
 Iconcentration = BMD          ×     ×                       ×                    assumed that the average worker is exposed 8 hours per day, 5 days per
                           L     L           24                    7
                                                                                  week, 48 weeks per year for 40 years and inhales 10 m3 air per 8-hour
                             0.1                                                  working day.
                        728 728    6    5
                  366 x     x    x
                        750 750 24 7
                                      x   1.63 x 10-3 per mg/m3
                                                                                  Using as starting point the estimated incidence of 1.65 x 10-3 per mg/m3
 Where:                                                                           bw, the additional life-time cancer risk per mg/m3 under occupational
 • Iconcentration = the carcinogenic activity attributable to the exposure to the exposure conditions (= HBC-OCRV) amounts to:
      substance per unit concentration in air expressed per mg/m3                                               40y 48w 5d 10m3
                                                                                   HBC – OCRV = 1.63 × 10 – 3 ×    ×   × ×        = 3.18 x 10-4 per mg/m3
 • BMR = benchmark response, expressed as an increase in tumour                                                 75y 52w 7d 18m  3
      incidence of 10%
 • BMD = benchmark dose (estimate of concentration in air expected to             Based on the HBC-OCRV of 3.18 x 10-4 per mg/m3, the Committee esti-
      yield the BMR)                                                              mated that the concentration of 1,2-dichloroethane in the air, which corre-
 • Xpo and Xpe are the exposure and experimental periods, respectively            sponds to an excess cancer mortality of:
 • L = standard lifespan for the animals in question (lifespan mouse is           • per 1,000 (4 x 10-3), for 40 years of occupational exposure, equals to
      assumed to be 750 days)                                                        12.6 mg/m3
                                                                                  • per 100,000 (4 x 10-5), for 40 years of occupational exposure, equals to
 To estimate the additional lifetime risk of cancer in humans under lifespan         0.126 mg/m3.
 conditions on the basis of results in animal experiments, it is assumed that
 no difference exists between experimental animals and man with respect           Recently, SCOEL also published a report on 1,2-dichloroethane in which
 to toxicokinetics, mechanism of tumour induction, target, susceptibility etc.    cancer risk estimates of 6.3 and 0.063 mg/m3 were proposed, corre-
 Furthermore, it is assumed that the average man lives 75 years, is               sponding to risk levels of 4 x 10-3 and 4 x 10-5, respectively.57 The
 exposed 24 hours per day, 7 days per week, 52 weeks per year for life-           Committee notes that SCOEL used the same study (Nagano et al.,
 time and inhales 18 m3 air per 24 hours. To estimate the additional lifetime     2006)10 as the Committee and applied comparable methods for these
24             Health Council of the Netherlands | No. 2019/16                                                              2                                 26
</pre>

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

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

<pre> chapter 03 | Carcinogenicity studies                                                                                   1,2-Dichloroethane | page 26 of 48
 estimates. However, the Committee has based its calculations on the          the absorption of the neat material an absorption rate of 106 μg/cm²/h was
 number of adenocarcinomas in the mammary gland of the female rat,            observed after 15 minutes, while after one hour the absorption rate was
 whereas SCOEL used the number of both mammary gland adenoma and              increased to 205 μg/cm²/h. Depending on the exposure conditions, the
 fibro- adenomas.                                                             uptake of 1,2-dichloroethane ranges between 20.3 and 205 μg/cm²/h. This
                                                                              corresponds to an hourly absorption of 40.6 to 410 mg for a skin surface
 The toxicity data as summarized in this report allow the Committee to        of 2000 cm2.
 conclude that no adverse effects other than carcinogenicity at the concen-   Assuming that a volume of 10 m3 is inhaled in 8 hours and that a fraction
 tration levels associated with the target and prohibitive cancer risk levels (by default assumed to be 0.5 by ECETOC) of the atmospheric 1,2-dichlo-
 are expected.                                                                roethane is absorbed by inhalation, the maximum uptake by inhalation
                                                                              upon exposure for 8 hours at the HBC-OCRV is:
 3.5 Skin notation                                                            • 12.6 mg/m3 (HBC-OCRV, 4 x 10-3) x 10 m3 x 0.5 = 63 mg (10% hereof is
 To determine whether a skin notation needs to be applied, the Committee         6.3 mg)
 uses the ECETOC criteria for assigning a skin notation.58 According to the   • 0.126 mg/m3 (HBC-OCRV, 4 x 10-5) x 10 m3 x 0.5 = 0.63 mg (10% hereof
 guidance a skin notation should be applied when exposure of 2,000 cm2 of        is 0.063 mg).
 skin (both hands and forearms) to 1,2-dichloroethane during one hour
 could result in an absorbed amount exceeding 10% of the amount that          Based on these calculations, the Committee concludes that dermal expo-
 can be absorbed via the lungs on exposure for eight hours to the occupa-     sure can considerably contribute to the systemic exposure to 1,2-dichloro-
 tional exposure limit (HBC-OCRV).                                            ethane and that a skin notation for 1,2-dichloroethane is required.
 Skin penetration data for human skin in vitro is available in the dissemi-
 nated dossier on the ECHA website.8 The neat material (5, 10, 25 and 100     3.6 Groups with increased risk
 µl/cm2) and aqueous solutions (200 µl/cm2) of 1,2-dichloroethane were        The Committee identified no groups with increased risk.
 applied to human epidermal membranes. The absorption rate of the
 aqueous solution of 1,2-dichloroethane through the epidermal membranes
 was 25.8 μg/cm2/h after 15 minutes and 20.3 μg/cm2/hr after 1 hour. For
25       Health Council of the Netherlands | No. 2019/16                                                               2                                 27
</pre>

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

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

<pre> chapter 03 | Carcinogenicity studies                                          1,2-Dichloroethane | page 27 of 48
 3.6 Conclusions and recommendation
 The Committee is of the opinion that 1,2-dichloroethane is a human
 carcinogen and that a stochastic genotoxic mechanism underlies its carci-
 nogenicity.
 The Committee considers the increase in mammary gland adenocarci-
 nomas in the mouse as the critical effect and selected the mouse study
 from Nagano et al. for cancer risk derivation.9,10
 The Committee estimates that the concentration of 1,2-dichloroethane in
 the air, which corresponds to an excess cancer mortality of:
 • 4 per 1,000 (4 x 10-3), for 40 years of occupational exposure, equals to
    12.6 mg/m3
 • 4 per 100,000 (4 x 10-5), for 40 years of occupational exposure, equals to
    0.126 mg/m3.
26       Health Council of the Netherlands | No. 2019/16                      2                                 28
</pre>

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

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

<pre> References                                             1,2-Dichloroethane | page 28 of 48
 references
27     Health Council of the Netherlands | No. 2019/16 2                                 29
</pre>

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

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

<pre> References                                                                                                              1,2-Dichloroethane | page 29 of 48
 1
   Health Council of the Netherlands. Guideline for the calculation of      10
                                                                               Nagano K, Umeda Y, Senoh H, Gotoh K, Arito H, Yamamoto S, et al.
   occupational cancer risk values. The Hague: Health Council of the           Carcinogenicity and chronic toxicity in rats and mice exposed by
   Netherlands, 2012; publication no. 2012/16E.                                inhalation to 1,2-dichloroethane for two years. Journal of occupational
 2
   Agency for Toxic Substances and Disease Registry (ATSDR).                   health 2006; 48(6): 424-36.
   Toxicological profile for 1,2-Dichloroethane (update). 2001.             11
                                                                               Cheever KL, Cholakis JM, el-Hawari AM, Kovatch RM, Weisburger EK.
 3
   International Agency on the evaluation of carcinogenic risk of chemicals    Ethylene dichloride: the influence of disulfiram or ethanol on
   to Humans (IARC). 1,2-Dichloroethane. 1999; 71.                             oncogenicity, metabolism, and DNA covalent binding in rats. Fundam
 4
   National Toxicology Program (NTP). Report on Carcinogens.                   Appl Toxicol 1990; 14(2): 243-61.
   1,2-Dichloroethane. 2011; 12.                                            12
                                                                               Maltoni C, Valgimigli L, Scarnato C. Long-term carcinogenic bioassays
 5
   OECD SIDS. 1,2-DICHLOROETHANE cas no:107-06-2 SIDS Initial                  on ethylene dichloride administered by inhalation to rats and mice.
   Assessment Report OECD. 2002.                                               Banburt report 5, ethylene dichloride: A potential health risk?: 3-33.
 6
   World Health Organization (WHO). International programme on                 Cold Spring Harbor Laboratory; 1980.
   Chemical Safety (ICPS). Environmental Health Criteria.                   13
                                                                               Spreafico F, Zuccato E, Marcucci F, et al. Pharmacokinetics of ethylene
   1,2-Dichloroethane. Geneva, Switzerland, 1995; 176.                         dichloride in rats treated by different route and its long-term inhalatory
 7
   Gwinn MR, Johns DO, Bateson TF, Guyton KZ. A review of the                  toxicity. Editor: B A, P I and R R. Banbury report 5, ethylene dichloride:
   genotoxicity of 1,2-dichloroethane (EDC). Mutat Res 2011; 727(1-2):         A potential health risk?: 107-33. Cold Spring Harbor Laboratory; 1980.
   42-53.                                                                   14
                                                                               National Caer Institute. Bioassay of 1,2-dichloroethane for possible
 8
   European Chemicals Agency (ECHA). 1,2-Dichloroethane, registration          carcinogenicity, CAS no. 107-06-2. 1978; No. 55.
   dossier. https://echa.europa.eu/nl/registration-dossier/-/registered-    15
                                                                               Ward JM. The carcinogenicity of ethylene dichloride in osborne-mendel
   dossier/15430/1. Accessed: 14-02-2019.                                      rats and B6C3F1 mice. Banbury report 5, ethylene dichloride: A
 9
   Nagano K, Nishizawa T, Yamamoto S, Matsushima T. Inhalation                 potential health risk?: 35-53. Cold Spring Harbor Laboratory; 1980.
   carcinogenesis studies of six halogenated hydrocarbons in rats and       16
                                                                               Weisburger EK. Carcinogenicity studies on halogenated hydrocarbons.
   mice. Editor: Y C, Y H and Y A. Advances in Prevention of Occupational      Environ Health Perspect 1977; 21: 7-16.
   Respiratory Diseases: 741-6. Elsevier Science B.V.; 1998.
28     Health Council of the Netherlands | No. 2019/16                                                                  2                                 30
</pre>

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

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

<pre> References                                                                                                           1,2-Dichloroethane | page 30 of 48
 17
    Morgan DL, Bucher JR, Elwell MR, Lilja HS, Murthy AS. Comparative          2-acetylaminofluorene or benzene but not with diethyl-nitrosamine or
    toxicity of ethylene dichloride in F344/N, Sprague-Dawley and              1,2-dichloroethane. Mutat Res 1993; 302(1): 61-70.
    Osborne-Mendel rats. Food Chem Toxicol 1990; 28(12): 839-45.            24
                                                                               Crebelli R, Carere A, Leopardi P, Conti L, Fassio F, Raiteri F, et al.
 18
    National Toxicology Program. Toxicity studies of 1,2-dichloroethane        Evaluation of 10 aliphatic halogenated hydrocarbons in the mouse
    (ethylene bichloride) in F344/N, sprague dawley rats, osborne-mendal       bone marrow micronucleus test. Mutagenesis 1999; 14(2): 207-15.
    rats, and B6C3F1 mice (drinking water and gavage studies). NTP TOX      25
                                                                               National Toxicology Program. Genetic Toxicity Evaluation of
    4., 1991; No. 91-3123.                                                     1,2-Dichloroethane (107-06-2) in Micronucleus Study A32670 in
 19
    Cheng TJ, Chou PY, Huang ML, Du CL, Wong RH, Chen PC.                      B6C3F1 Mice. U.S. Department of Health and Human Services,:
    Increased lymphocyte sister chromatid exchange frequency in workers        https://tools.niehs.nih.gov/cebs3/views/index.cfm?action=main.
    with exposure to low level of ethylene dichloride. Mutation research       dataReview&bin_id=10167. Accessed: 14-02-2019.
    2000; 470(2): 109-14.                                                   26
                                                                               Lone MI, Nazam N, Hussain A, Singh SK, Dar AH, Najar RA, et al.
 20
    Hachiya N, Motohashi Y. Examination of lacZ mutant induction in the        Genotoxicity and immunotoxic effects of 1,2-dichloroethane in Wistar
    liver and testis of Muta Mouse following injection of halogenated          rats. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 2016;
    aliphatic hydrocarbons classified as human carcinogens. Ind Health         34(3): 169-86.
    2000; 38(2): 213-20.                                                    27
                                                                               Lane RW, Riddle BL, Borzelleca JF. Effects of 1,2-dichloroethane and
 21
    Gocke E, Wild D, Eckhardt K, King MT. Mutagenicity studies with the        1,1,1-thichloroethane in drinking water on reproduction and
    mouse spot test. Mutat Res 1983; 117(1-2): 201-12.                         development in mice. Toxicol Appl Pharmacol 1982; 63(3): 409-21.
 22
    King MT, Beikirch H, Eckhardt K, Gocke E, Wild D. Mutagenicity studies  28
                                                                               Giri AK, Que Hee SS. In vivo sister chromatid exchange induced by
    with x-ray-contrast media, analgesics, antipyretics, antirheumatics and    1,2-dichloroethane on bone marrow cells of mice. Environ Mol Mutagen
    some other pharmaceutical drugs in bacterial, Drosophila and               1988; 12(3): 331-4.
    mammalian test systems. Mutat Res 1979; 66(1): 33-43.                   29
                                                                               Storer RD, Conolly RB. Comparative in vivo genotoxicity and acute
 23
    Armstrong MJ, Galloway SM. Micronuclei induced in peripheral blood of      hepatotoxicity of three 1,2-dihaloethanes. Carcinogenesis 1983; 4(11):
    E mu-PIM-1 transgenic mice by chronic oral treatment with                  1491-4.
29       Health Council of the Netherlands | No. 2019/16                                                             2                                 31
</pre>

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

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

<pre> References                                                                                                            1,2-Dichloroethane | page 31 of 48
 30
    Storer RD, Jackson NM, Conolly RB. In vivo genotoxicity and acute          the metabolic pathways of 1,2-dichloroethane. IARC Sci Publ 1986;
    hepatotoxicity of 1,2-dichloroethane in mice: comparison of oral,          (70): 269-79.
    intraperitoneal, and inhalation routes of exposure. Cancer Res 1984;    37
                                                                               Baertsch A, Lutz WK, Schlatter C. Effect of inhalation exposure
    44(10): 4267-71.                                                           regimen on DNA binding potency of 1,2-dichloroethane in the rat. Arch
 31
    Sasaki YF, Saga A, Akasaka M, Ishibashi S, Yoshida K, Su YQ, et al.        Toxicol 1991; 65(3): 169-76.
    Detection of in vivo genotoxicity of haloalkanes and haloalkenes        38
                                                                               Austin SG, Schnatter AR. A cohort mortality study of petrochemical
    carcinogenic to rodents by the alkaline single cell gel electrophoresis    workers. J Occup Med 1983; 25(4): 304-12.
    (comet) assay in multiple mouse organs. Mutation research 1998;         39
                                                                               Teta MJ, Ott MG, Schnatter AR. An update of mortality due to brain
    419(1-3): 13-20.                                                           neoplasms and other causes among employees of a petrochemical
 32
    Kitchin KT, Brown JL. Dose-response relationship for rat liver DNA         facility. J Occup Med 1991; 33(1): 45-51.
    damage caused by 49 rodent carcinogens. Toxicology 1994; 88(1-3):       40
                                                                               Reeve GR, Bond GG, Lloyd JW, Cook RR, Waxweiler RJ, Fishbeck
    31-49.                                                                     WA. An investigation of brain tumors among chemical plant employees
 33
    Unpublished study report. In vivo mammalian cell study: DNA damage         using a sample-based cohort method. J Occup Med 1983; 25(5):
    and/or repair. 2014. https://echa.europa.eu/nl/registration-dossier/-/     387-93.
    registered-dossier/15430/7/7/3. Accessed: 14-02-2019.                   41
                                                                               Hogstedt C, Rohlen O, Berndtsson BS, Axelson O, Ehrenberg L. A
 34
    Hellman B, Brandt I. Effects of carcinogenic halogenated aliphatic         cohort study of mortality and cancer incidence in ethylene oxide
    hydrocarbons on [3H]thymidine incorporation into various organs of the     production workers. Br J Ind Med 1979; 36(4): 276-80.
    mouse. A comparison between 1,2-dibromoethane and                       42
                                                                               Benson LO, Teta MJ. Mortality due to pancreatic and lymphopoietic
    1,2-dichloroethane. Mutat Res 1986; 163(2): 193-9.                         cancers in chlorohydrin production workers. Br J Ind Med 1993; 50(8):
 35
    Prodi G, Arfellini G, Colacci A, Grilli S, Mazzullo M. Interaction of      710-6.
    halocompounds with nucleic acids. Toxicol Pathol 1986; 14(4): 438-44.   43
                                                                               Olsen GW, Lacy SE, Bodner KM, Chau M, Arceneaux TG, Cartmill JB,
 36
    Svensson K, Osterman-Golkar S. Covalent binding of reactive                et al. Mortality from pancreatic and lymphopoietic cancer among
    intermediates to hemoglobin in the mouse as an approach to studying        workers in ethylene and propylene chlorohydrin production. Occup
                                                                               Environ Med 1997; 54(8): 592-8.
30       Health Council of the Netherlands | No. 2019/16                                                              2                                 32
</pre>

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

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

<pre> References                                                                                                            1,2-Dichloroethane | page 32 of 48
 44
    Sweeney MH, Beaumont JJ, Waxweiler RJ, Halperin WE. An                 51
                                                                              Goldberg MS, al-Homsi N, Goulet L, Riberdy H. Incidence of cancer
    investigation of mortality from cancer and other causes of death among    among persons living near a municipal solid waste landfill site in
    workers employed at an east Texas chemical plant. Arch Environ            Montreal, Quebec. Arch Environ Health 1995; 50(6): 416-24.
    Health 1986; 41(1): 23-8.                                              52
                                                                              Maltoni C, Ciliberti A, Carretti D. Experimental contributions in
 45
    Hansen J. Elevated risk for male breast cancer after occupational         identifying brain potential carcinogens in the petrochemical industry.
    exposure to gasoline and vehicular combustion products. Am J Ind Med      Ann N Y Acad Sci 1982; 381: 216-49.
    2000; 37(4): 349-52.                                                   53
                                                                              Van Duuren BL, Goldschmidt BM, Loewengart G, Smith AC,
 46
    Kernan GJ, Ji BT, Dosemeci M, Silverman DT, Balbus J, Zahm SH.            Melchionne S, Seldman I, et al. Carcinogenicity of halogenated olefinic
    Occupational risk factors for pancreatic cancer: a case-control study     and aliphatic hydrocarbons in mice. J Natl Cancer Inst 1979; 63(6):
    based on death certificates from 24 U.S. states. Am J Ind Med 1999;       1433-9.
    36(2): 260-70.                                                         54
                                                                              Suguro M, Numano T, Kawabe M, Doi Y, Imai N, Mera Y, et al. Lung
 47
    Austin SG, Schnatter AR. A case-control study of chemical exposures       Tumor Induction by 26-week Dermal Application of 1,2-Dichloroethane
    and brain tumors in petrochemical workers. J Occup Med 1983; 25(4):       in CB6F1-Tg rasH2 Mice. Toxicol Pathol 2017; 45(3): 427-34.
    313-20.                                                                55
                                                                              Theiss JC, Stoner GD, Shimkin MB, Weisburger EK. Test for
 48
    Dosemeci M, Cocco P, Chow WH. Gender differences in risk of renal         carcinogenicity of organic contaminants of United States drinking
    cell carcinoma and occupational exposures to chlorinated aliphatic        waters by pulmonary tumor response in strain A mice. Cancer Res
    hydrocarbons. Am J Ind Med 1999; 36(1): 54-9.                             1977; 37(8 Pt 1): 2717-20.
 49
    Sobel W, Bond GG, Skowronski BJ, Brownson PJ, Cook RR. Soft-           56
                                                                              Health Council of the Netherlands. Dutch Expert Committee on
    tissue sarcoma: case-control study. J Occup Med 1986; 28(9): 804, 6,      Occupational Standards. 1,2-Dichloroethane. Rijswijk, 1997;
    8.                                                                        Publication no. 1997/01 WGD.
 50
    Isacson P, Bean JA, Splinter R, Olson DB, Kohler J. Drinking water and 57
                                                                              Scientific Committee on Occupational Exposure Limits (SCOEL).
    cancer incidence in Iowa. III. Association of cancer with indices of      SCOEL/REC/302 1,2-Dichloroethane (Ethylene dichloride).
    contamination. Am J Epidemiol 1985; 121(6): 856-69.                       Recommendation from the Scientific Committee on Occupational
                                                                              Exposure Limits. Brussels, 2016; SCOEL/REC/302.
31       Health Council of the Netherlands | No. 2019/16                                                              2                                 33
</pre>

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

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

<pre> References                                                                    1,2-Dichloroethane | page 33 of 48
 58
    European Centre for Ecotoxicology and Toxicology of Chemicals
    (ECETOC). Strategy for assigning a ‘skin notation’. 1993; ECETOC
    Document No. 31 (Revised).
 59
    Klimisch HJ, Andreae M, Tillmann U. A systematic approach for
    evaluating the quality of experimental toxicological and ecotoxicological
    data. Regul Toxicol Pharmacol 1997; 25(1): 1-5.
32      Health Council of the Netherlands | No. 2019/16                       2                                 34
</pre>

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

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

<pre> Annexes                                               1,2-Dichloroethane | page 34 of 48
 annexes
33    Health Council of the Netherlands | No. 2019/16 2                                 35
</pre>

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

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

<pre> Annexes                                                                                                                                                           1,2-Dichloroethane | page 35 of 48
 A          epidemiological studies
 Table 2. 1,2-Dichloroethane, cohort studies
  Reference                  Study design and population                    Data on exposure and health assessment                Results                                      Remarks
  Hogstedt et al., (1979) 41
                             Type of study: Retrospective cohort mortality  Rough estimates of exposure levels to various         Full-time exposed cohort: excess total       Workers potentially exposed to
                             and cancer incidence study.                    compounds based on investigation of production        mortality, mainly due to increased mortality multiple (carcinogenic)
                             Country: Sweden.                               processes.                                            from tumours (significant excess of stomach  chemicals.
                             Type of industry: ethylene oxide production.   Cause of death from death certificates.               cancer and leukaemia) and circulatory
                             Participants: male employees of a company      Diagnosis for malignancies in dead or alive subjects  system diseases;
                             producing ethylene oxide by chlorohydrin-      from Swedish Cancer Registry.                         Intermittently and non-exposed cohorts: no
                             process;                                       Expected numbers of deaths and malignancies           excess total mortality or mortality from
                             3 subcohorts:                                  calculated from national statistics.                  tumours.
                             89 full-time exposed,                          Statistical analysis: p values based on Poisson
                             86 intermittently exposed, 66 who had never    distribution.
                             worked in ethylene oxide production.
                             Follow-up period:
                             1961-77.
  Reeve et al. (1983)40      Type of study: Retrospective, sample-based     No information on exposure levels.                    SMRs suggest, at most, only a slight         Workers potentially exposed to
                             cohort mortality study.                        Sample-based standardized mortality ratios (SMRs)     increased risk of mortality from brain       multiple chemicals.
                             Country: USA.                                  were calculated from observed and expected brain      tumours for the overall time period, and a   No quantitative exposure data
                             Type of industry: petrochemical plant.         tumour deaths.                                        probable elevated risk associated with first and no data on individual
                             Participants:                                  Statistical analysis was not performed.               employment prior to 1945.                    chemicals.
                             25 brain tumour deaths in white males,         Work histories and smoking status were not taken into                                              Validity of assumptions
                             identified by a geographically limited record- account.                                                                                           underlying the modified study
                             linkage process.                                                                                                                                  design not tested.
                             Control: expected brain tumour deaths
                             extrapolated from 1,666 white males in a 5%
                             sample of the 1940-77 total workforce.
34       Health Council of the Netherlands | No. 2019/16                                                                                                          2                                          36
</pre>

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

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

<pre> Annexes                                                                                                                                                           1,2-Dichloroethane | page 36 of 48
  Reference               Study design and population                     Data on exposure and health assessment                   Results                                      Remarks
  Austin and Schnatter    Type of study: Retrospective cohort mortality   No information on exposure levels.                       Mortality:                                   Workers potentially exposed to
  (1983); Teta et al.     study.                                          Production job assignments categorized to one of 15      Initial study:                               multiple chemicals.
  (1991)38,39             Country: USA.                                   work areas (including a 1,2-dichloro-ethane area);       All causes (p<0.05):                         No quantitative exposure data
                          Type of industry: petrochemical plant.          maintenance job assignments were assigned to one         Observed 765, SMR 83 (CI 77-89);             and no data on individual
                          Participants:                                   of eight categories.                                     All malignant neoplasms: Observed 158,       chemicals.
                          Initial study: all 6,588 white males who worked Study focused on malignant brain neoplasms.              SMR 86 (73-101), not significant;
                          at the plant for >1 day in the period 1941-77;  Overall and cause-specific standardized mortality        Malignant neoplasms brain and CNS:
                          Update: 7,849 white and non-white men who       ratios (SMRs) and confidence intervals (CI) were         Observed 12, SMR 162 (83-283), not
                          worked at the plant for >1 day between 1941-    calculated for various subgroups.                        significant.
                          83.                                             Appropriate statistical analysis was performed.          Insufficient evidence to conclude that brain
                          Control: expected mortality values based on     Work histories and smoking status were not taken into    tumours were occupationally related.
                          national rates.                                 account.                                                 Update:
                                                                                                                                   Between 1978-1983 brain tumour mortality
                                                                                                                                   risk higher than expected (5 observed/3.4
                                                                                                                                   expected) but could not be explained by
                                                                                                                                   patterns of production work assignments.
  Sweeney et al. (1986)44 Type of study: Retrospective cohort mortality   No information on exposure levels.                       Mortality:                                   Workers potentially exposed to
                          study.                                          Overall and cause-specific standardized mortality        All causes: lower than expected (observed    multiple chemicals.
                          Country: USA.                                   ratios (SMRs) and confidence intervals (CI) were         156, expected 211).                          No quantitative exposure data
                          Type of industry: chemical plant.               calculated.                                              Malignancies or other causes of death: no    and no data on individual
                          Participants: 2,510 males (90% white, 10%       Appropriate statistical analysis was performed.          significant increases.                       chemicals.
                          non-white) who worked >1 day at the plant       Work histories and smoking status were not taken into                                                 Low power due to small
                          between 1952-77.                                account.                                                                                              sample size and small
                          Control: expected mortality values based on                                                                                                           observed total number of
                          national rates.                                                                                                                                       deaths.
  Benson and Teta         Type of study: Retrospective cohort mortality   No information on exposure levels.                       Mortality:                                   Workers potentially exposed to
  (1993)42                study.                                          Mean duration in chlorohydrin unit / of follow-up: 5.9 / All causes:                                  multiple chemicals.
                          Country: USA.                                   36.5 years.                                              Observed 147, SMR 104 (CI 88-123).           No quantitative exposure data
                          Type of industry: chlorohydrin production at    Overall and cause-specific standardized mortality        Excess risk for:                             and no data on individual
                          Union Carbide plant                             ratios (SMRs) and confidence intervals (CI) were         Pancreatic cancer: Observed 8, SMR 492       chemicals.
                          Participants:                                   calculated.                                              (158-1140), p<0.01;
                          278 men who were ever assigned to the           Appropriate statistical analysis was performed.          Lymphatic and haematopoietic cancers:
                          chlorohydrin production unit between 1940-67.   Work histories and smoking status were not taken into    Observed 8, SMR 294 (127-580), p<0.05.
                          Follow-up period:                               account.
                          1940-88.
                          Control: expected mortality values based on
                          national rates.
35         Health Council of the Netherlands | No. 2019/16                                                                                                        2                                           37
</pre>

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

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

<pre> Annexes                                                                                                                                                          1,2-Dichloroethane | page 37 of 48
  Reference              Study design and population                      Data on exposure and health assessment                 Results                                      Remarks
  Olsen et al. (1997) 43
                         Type of study: Retrospective cohort mortality    No information on exposure levels.                     Mortality:                                   Workers potentially exposed to
                         study.                                           Overall and cause-specific standardized mortality      All causes:                                  multiple chemicals.
                         Country: USA.                                    ratios (SMRs) and confidence intervals (CI) were       Observed 300, SMR 89 (CI 79-100).            No quantitative exposure data
                         Type of industry: chlorohydrin production at Dow calculated.                                            No excess risk for ‘all malignant neoplasms’ and no data on individual
                         Chemical plants.                                 Appropriate statistical analysis was performed.        or any specific neoplasm.                    chemicals.
                         Participants:                                    Smoking status not taken into account.
                         1,361 men with >1 month workplace experience
                         in 1940-92, in ethylene chlorohydrin and
                         propylene chlorohydrin process areas.
                         Control: expected mortality values based on
                         national rates.
 Table 3. 1,2-Dichloroethane, case-control studies
  References             Study design and population                      Data on exposure and health assessment                 Results                                      Remarks
  Austin and Schnatter   Type of study:                                   Exposure status based on employment records.           Proportion of cases exposed was              Workers potentially exposed to
  (1983)47               Case control                                     An employee was ‘exposed’ /‘unexposed’ to a given      comparable with proportion of controls       multiple chemicals.
                         Country: USA.                                    chemical if he ever / never worked in a department     exposed.                                     Small number of cases.
                         Type of industry: petrochemical plant.           associated with that chemical. Exposure                Proportions exposed: cases (total brain      No quantitative exposure data.
                         Participants:                                    determinations could not be made for 10/21 cases and   tumours), non-cancer control, 2nd control,   Potential exposure outside the
                         Cases:                                           about 60% of controls.                                 resp.:                                       plant not considered.
                         21 primary brain tumour decedents who had        Participants were potentially exposed to other         No latency:                                  No data on confounders.
                         worked at the plant, identified through death    chemicals, including known or suspected carcinogens.   45.5, 42.4 and 45.2%
                         certificate and tumour registries searches;      Study focused on malignant brain neoplasms.            At least 15 years latency:
                         Control:                                         Overall and 15-year latency analyses were performed.   40.0, 32.2 and 34.6%
                         2 groups of 80 former employees of the same      The authors note limited testing for statistical
                         plant, randomly selected from 450 decedents      significance.
                         known to the company; one group was a strictly
                         non-cancer group.
  Sobel et al. (1986)49  Type of study:                                   Exposure status based on company work histories.       No statistically significant odds ratios for Workers potentially exposed to
                         Case-control.                                    Only one case was potentially exposed to               any of the chemicals of interest.            multiple chemicals.
                         Country: USA.                                    1,2-dichloroethane.                                                                                 Small number of cases.
                         Type of industry: multi-chemical production      Participants were potentially exposed to 13 chemicals                                               No quantitative exposure data.
                         plant.                                           that have been associated with soft-tissue sarcomas in
                         Participants: 14 soft tissue sarcoma cancer      human/animal studies.
                         cases identified from death certificates;
                         9 matched controls per case.
36         Health Council of the Netherlands | No. 2019/16                                                                                                       2                                          38
</pre>

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

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

<pre> Annexes                                                                                                                                                              1,2-Dichloroethane | page 38 of 48
  References                Study design and population                     Data on exposure and health assessment                 Results                                       Remarks
  Dosemeci et al. (1999) 48
                            Type of study:                                  Exposure data from occupational history information    Odds ratio for 1,2-dichloroethane not         Workers potentially exposed to
                            Population-based case-control.                  obtained by trained interviewers.                      statistically significantly increased.        multiple chemicals.
                            Country: USA.                                   Exposure status of subjects determined by standard     Odds ratio [95% confidence interval]:         Small number of cases.
                            Type of industry: miscellaneous.                occupational and industrial classification schemes and Men:                                          Limited occupational history
                            Participants: 438 renal cell carcinoma cases    job exposure matrices for all organic solvents         1.1 [0.7-1.9];                                (only current and usual jobs).
                            identified from a state-wide cancer registry;   combined, 9 individual chlorinated aliphatic           Women:                                        No quantitative exposure data.
                            687 age- and gender- stratified controls        hydrocarbons (CAHCs) and CAHCs combined.               2.3 [0.9-5.9]                                 Potential survival bias (cases
                            obtained with random-digit dialing or from a    Only 9% of cases and 7% of controls were potentially                                                 who died were excluded from
                            health care finance listing.                    exposed to 1,2-dichloroethane.                                                                       analysis).
  Kernan et al. (1999)46    Type of study:                                  Exposure assessment based on occupation and            Increased risk associated with high           Workers potentially exposed to
                            Population-based case-control.                  industry on death certificates.                        probability of exposure to                    multiple chemicals.
                            Country: USA, 24 states                         Job exposure matrices for all organic solvents         1,2-dichloroethane for white men and          No data on duration of
                            Type of industry: miscellaneous.                combined, 9 individual chlorinated aliphatic           women:                                        employment, no data on other
                            Participants: 63,097 cases who died from        hydrocarbons (CAHCs) and CAHCs combined were           Odds ratio [95% confidence interval]:         than most recent occupation.
                            pancreatic cancer identified from death         used to evaluate exposure to solvents (intensity and   White men (16 exposed cases): 1.6 [0.9-       No quantitative exposure data.
                            certificates;                                   probability were scored as none, low, medium or high). 2.8];                                         Possible misdiagnosis of
                            252,386 matched controls who died from                                                                 White women (8 exposed cases):2.1             pancreatic cancer.
                            causes other than cancer in same period                                                                [0.9-5.0]                                     No data on confounders
                            (1984-93).                                                                                             There was no increased risk associated        (cigarette smoking
                                                                                                                                   with intensity of exposure to                 socioeconomic status, other
                                                                                                                                   1,2-dichloroethane.                           lifestyle factors).
  Hansen (2000)45           Type of study:                                  Exposure status based on job type and trade code;      Odds ratio [95% confidence interval] for      Workers potentially exposed to
                            Case-control, register based.                   blue collar workers who had had >3 months of           exposure to gasoline and combustion           multiple chemicals.
                            Country: Denmark.                               employment within companies with trade codes of        products:                                     Linking of cancer excess to
                            Type of industry: companies with specific trade service station, vehicle maintenance, wholesale trade  No lag time:                                  individual chemicals not
                            codes (see 2nd column of this table).           of gasoline or car repair shops were classified as     2.2 [1.4-3.6];                                possible.
                            Participants: male employees selected from      exposed to gasoline vapour and its combustion          >10 years lag time                            No quantitative exposure data
                            national pension fund, 230 breast cancer cases  products.                                              2.5 [1.3-4.5].                                and no data on individual
                            identified from Danish Cancer Registry;         Odds ratios, adjusted for socioeconomic status, were                                                 chemicals.
                            12,880 age-matched controls.                    estimated by conditional logistic regression analysis.
37        Health Council of the Netherlands | No. 2019/16                                                                                                            2                                          39
</pre>

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

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

<pre> Annexes                                                                                                                                                            1,2-Dichloroethane | page 39 of 48
 B         animal studies
 Table 4. 1,2-Dichloroethane, animal studies
  Reference                Study design and Data on exposure and effect          Results                                                                                     Remarks
                           animal species      endpoints
  Nagano et al. (1998);    F344/DuCrj          Inhalation exposure               Survival: After 104 weeks for 0, 40, 160, and 640 mg/m3 group, resp.: 74, 70, 64, 74%       Klimisch score: 2
  Nagano et al. (2006)9,10 rats(50/sex/group). Purity: >99%                      (males), 70, 82, 74, 76% (females), resp.                                                   Well-performed study, adequate
                                               Exposure: 0, 10, 40, 160 ppm (0,  Adverse effects: subcutaneous masses in breast, back, abdominal and perigenital areas, no   for carcinogenicity assessment
                                               40, 160, 640 mg/m3) (6h.d,        exposure-related chances in haematological, blood chemical or urinary parameters            Deficiencies: -
                                               5d.wk)                            Tumours: 0, 40, 160, 640 mg/m3 groups, resp.:
                                               Xpo= 104 weeks                    Subcutis fibroma: male: 6/50, 9/50 12/50, 15/50; female: 0/50, 0/50, 1/50, 5/50 (p<0.05)
                                               Xpe= 104 weeks                    Mammary gland adenoma: male: 1/50, 2/50, 0/50, 2/50; female: 3/50, 5/50, 5/50, 11/50
                                               Statistical analysis: Peto’s test (p<0.05).
                                               (trend), and Fisher’s exact test. Mammary gland fibroadenoma: male: 0/50, 0/50, 1/50, 5/50 (p<0.05); female: 4/50, 1/50,
                                                                                 6/50, 13/50 (p<0.05).
                                                                                 Peritoneum mesothelioma: male:1/50, 1/50, 1/50, 5/50.
                                                                                 Mammary gland adenocarcinoma: female: 1/50, 2/50, 0/50, 5/50.
  Nagano et al. (1998);    Crj:BDF1 mice (50 Inhalation exposure                 Survival: After 104 weeks for 0, 40, 120, and 360 mg/m3 group, resp.: 78, 65, 70, 74%       Klimisch score: 2
  Nagano et al. (2006)9,10 sex/group).         Purity: >99%                      (males), 69, 56, 38 (p<0.01), 52% (females) males and females, resp.                        Well-performed study, adequate
                                               Exposure: 0, 10, 30, 90 ppm (0,   Adverse effects: subcutaneous masses in breast, back, and abdominal area in females, no     for carcinogenicity assessment
                                               40, 120, 360 mg/m3) (6 h/d,       exposure-related chances in haematological, blood chemical or urinary parameters            Deficiencies: -
                                               5 d/wk)                           Tumours: 0, 40, 120, 360 mg/m3 resp.:
                                               Xpo= 104 weeks                    Only male:
                                               Xpe= 104 weeks                    Liver hemangiosarcoma: 0/50, 4/49, 6/50 (p<0.05), 5/50 (p<0.05)
                                               Statistical analysis: Peto’s test Only female.
                                               (trend), and Fisher’s exact test. Lung bronchio-alveolar adenoma: 4/49, 1/50, 3/50, 8/50, carcinoma: 1/49, 0/50, 1/50, 3/50.
                                                                                 Uterus endometrial stromal polyp: 2/49, 0/50, 1/50, 6/50.
                                                                                 Mammary gland adenocarcinoma: 1/49, 2/50, 1/50, 6/50.
                                                                                 Liver hepatocellular adenoma: 1/49, 1/50, 1/50, 6/50, carcinoma: 1/49, 0/50, 1/50, 0/50.
                                                                                 Lymph node malignant lymphoma: 6/49, 17/50 (p<0.05), 22/50 (p<0.01), 12/50.
38       Health Council of the Netherlands | No. 2019/16                                                                                                           2                                        40
</pre>

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

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

<pre> Annexes                                                                                                                                                     1,2-Dichloroethane | page 40 of 48
  Reference           Study design and Data on exposure and effect        Results                                                                                       Remarks
                      animal species    endpoints
  NCI (1978); Ward    Osborne-Mendal    Oral gavage                       Survival: Survival markedly decreased at high-dose in both sexes (only 50% survival after     Klimisch score: 2.
  (1980); Weisburger  rats.             Solvent: corn oil                 about one year).                                                                              Well performed study, adequate
  (1977)14-16         Control: 20       TWA exposure doses (mg/kg bw/     Adverse effects: hunched appearance and transient laboured respiration, abdominal urine       for carcinogenicity assessment
                      animals/sex/group day): 0, 47, 95 (5 d/wk)          stains, cloudy or squinted eyes, and eyes with a reddish crust appeared more in the           Deficiencies: doses changed
                      (untreated and    Xpo=78 weeks                      exposed groups in the first year, incidence of palpable nodules and/or tissue masses slightly during the study, high mortality in
                      vehicle treated)  Xpe= 110 weeks                    greater in treated compared to controls.                                                      high dose groups early in study,
                      Exposed: 50       Statistical analysis: one –tailed Tumours (*= sign. compared to pooled vehicle group, **= sign. compared to matched vehicle     exposure less than life-span.
                      animals/sex/      Fischer exact test.               group): pooled vehicle, matched vehicle, low dose, high dose, resp.:
                      group.                                              Hemangiosarcoma circulatory system: Male: 1/60, 0/20, 9/50 (p=0.003*, p=0.039**), 7/50
                                                                          (p=0.016*); Female: 0/59, 0/20, 4/50 (p=0.041*), 4/50 (p=0.041*).
                                                                          Pituitary chromophobe adenoma: Male: 3/60, 2/20, 1/50, 4/49; Female: 13/59, 7/20, 7/50,
                                                                          5/49 (p=0.020**).
                                                                          Subcutanous fibroma: Male : 0/60, 0/20, 5/50 (p=0.017*), 6/50 (p=0.007*).
                                                                          Tunica vaginalis mesothelioma: Male : 0/60, 0/20, 3/50, 0/50.
                                                                          Stomach squamous-cell carcinoma: Male: 0/60, 0/20, 3/50, 9/50 (p=0.001*, p=0.039**).
                                                                          Thyroid follicular-cell adenoma: Female: 0/58, 0/20, 3/50, 0/50.
                                                                          Mammary gland adenocarcinoma NOS: Female: 1/59, 0/20, 1/50, 18/50 (p<0.001*,
                                                                          p=0.002**).
                                                                          Mammary gland fibroadenoma: Female: 5/59, 0/20, 14/50 (p=0.007*, p=0.005**), 8/50.
  NCI (1978); Ward    B6C3F1 mice       Oral gavage                       Survival: Survival markedly decreased at high-dose in females, possibly tumour-related        Klimisch score: 2
  (1980); Weisburger  50 animals/sex/   Solvent: corn oil                 (72% died between week 60-80). Survival of high-dose males and vehicle control males was      Well-performed study, adequate
  (1977)14-16         exposed group     TWA exposure doses (mg/kg bw/     good whereas low-dose males and untreated control males had poor survival.                    for carcinogenicity assessment.
                      20 animals/sex/   day): 0, 97, 195 male, 0, 149,    Adverse effects: mean body weight depression for high dose females, incidence of palpable     Deficiencies: doses changed
                      control group.    299 female (5 d/wk)               nodules and/or tissue masses and swelling abdominal midline slightly greater in treated       during the study, high mortality
                                        Xpo= 78 weeks                     compared to controls.                                                                         early in study in high dose
                                        Xpe= 91 weeks                     Tumours: pooled vehicle, matched vehicle, low dose, high dose (*= sign. compared to           females, exposure less than
                                        Statistical analysis: one –tailed pooled vehicle group, **= sign. compared to matched vehicle group).                           life-span.
                                        Fischer exact test                Alveolar/bronchiolar adenoma: Male: 0/59, 0/19, 1/47, 15/48 (p<0.001*, p=0.003**); Female:
                                                                          2/60, 1/20, 7/50 (p=0.046*), 15/48 (p<0.001*, p=0.016**).
                                                                          Hematopoetic system malignant lymphoma: Male: 4/59, 2/19, 8/47, 5/48; Female: 8/60,
                                                                          4/20, 10/50, 2/48.
                                                                          Stomach squamous-cell carcinoma: Male: 1/59, 1/19, 1/46, 2/46;Female: 1/60, 1/20, 2/50,
                                                                          5/48.
                                                                          Subcutanous fibrosarcoma: Male:1/59, 0/19, 0/47, 4/48.
                                                                          Hepatocellular carcinoma liver: Male: 4/59, 1/19, 6/47, 12/48 (p=0.009*).
                                                                          Mammary gland adenocarcinoma NOS: Female: 0/60, 0/20, 9/50 (p=0.001*, p=0.039**),
                                                                          7/48 (p=0.003*).
                                                                          Endometrium/uterus adenocarcinoma NOS: Female: 1/60, 0/20, 3/49, 4/47.
                                                                          Uterus endometrial stromal polyp: Female: 0/60, 0/20, 3/49, 2/47.
                                                                          Uterus endometrial stromal sarcoma: Female: 0/60, 0/20, 2/49, 3/47.
39         Health Council of the Netherlands | No. 2019/16                                                                                                  2                                               41
</pre>

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

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

<pre> Annexes                                                                                                                                                        1,2-Dichloroethane | page 41 of 48
  Reference               Study design and Data on exposure and effect       Results                                                                                      Remarks
                          animal species    endpoints
  Maltoni et al. (1980,   Sprague-Dawley    Inhalation exposure.             Survival: at 104 weeks: Male:12/90, 16/90, 45/90, 13/90, 17/90,10/90, Female: 22/90, 36/90,  Klimisch score: 2
  1982)12,52              rats              Purity: 99.8%.                   48/90, 26/90, 29/90, 21/90 for control chamber, control nearby room, 20, 40, 200, 600-1,000  Well-performed study, adequate
                          90 animals/sex/   Exposure: 0, 5, 10, 50, 250 ppm  mg/m3, resp.                                                                                 for carcinogenicity assessment.
                          group             (0, 20, 40, 200, 1,000 mg/m3)    Adverse effects: high toxicity after a few weeks of 1,000 mg/m3.                             Deficiencies: exposure less than
                          Controls: one     (reduced to 600 mg/m3 after few  Tumours: Mammary tumours (fibromas and fibroadenoma):                                        life-span, no information on
                          group in an       weeks) (7 h/d, 5 d/wk)           Male: 7/90, 3/90, 11/90, 3/89, 7/90, 7/89;                                                   non-cancer effects, MTD
                          exposure          Xpo= 78 weeks                    Female: 27/90, 47/90 (p<0.01), 56/90 (p<0.001), 33/90, 49/90 (p<0.01), 47/90 (p<0.01) for    exceeded.
                          chamber, one      Xpe= lifespan                    controls exposure chamber, controls nearby room, 20, 40, 200, and 600-1,000 mg/m3, resp.;
                          group in nearby   Statistical analysis: Chi-Square p-values from comparisons with controls in exposure chamber.
                          room during       analysis.                        Incidences of other tumours similar to the control groups.
                          exposure of the
                          treated animals.
  Maltoni et al. (1980)12 Swiss mice        Inhalation exposure              Survival: at 78 weeks for 0, 20, 40, 200, 600-1000 mg/m3 male and female, resp.: 42/115,     Klimisch score: 2.
                          Controls: 115 and Purity: 99.8%.                   26/90, 34/90, 30/90, 26/90 (males); 76/134, 68/90, 50/90, 49/90, 44/90 (females).            Well–performed study, adequate
                          134, male and     Exposure: 0, 5, 10, 50, 250 ppm  Adverse effects: high toxicity after a few weeks of 1,000 mg/m3.                             for carcinogenicity assessment.
                          female, resp.     (0, 20, 40, 200, 1,000 mg/m3)    Tumours: tumour incidences similar between groups.                                           Deficiencies: exposure less than
                          Exposed: 90       (reduced to 600 mg/m3 after few                                                                                               life-span, no information on
                          animals/sex/      weeks) (7 h/d, 5 d/wk)                                                                                                        non-cancer effects, MTD
                          group.            Xpo= 78 weeks                                                                                                                 exceeded, housing condition on
                                            Xpe= lifespan                                                                                                                 exposure days not identical
                                            Statistical analysis: Chi-Square                                                                                              between exposed and control
                                            analysis.                                                                                                                     mice.
  Cheever et al. (1990)11 Sprague-Dawley    Inhalation exposure              Survival: After 2-years: 58, 60% (males); 54, 64% (females), control and exposed rats, resp. Klimisch score: 2.
                          rats.             Purity: >99%                     Adverse effects: no adverse effects were observed, except increased testicular lesions 10    Well performed study, adequate
                          50 animals/sex/   Exposure: 0, 50 ppm (0, 200      and 24%, for control and exposed rats, resp.                                                 for carcinogenicity assessment.
                          group.            mg/m3) (7h/d, 5d/wk)             Tumours: all tumour incidences similar between groups.                                       Deficiencies: only one
                                            Xpo= 2 years                                                                                                                  concentration tested, which was
                                            Xpe= 2 years                                                                                                                  well below the MTD.
                                            Statistical analysis: Fisher’s
                                            exact test.
40         Health Council of the Netherlands | No. 2019/16                                                                                                     2                                           42
</pre>

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

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

<pre> Annexes                                                                                                                                                                             1,2-Dichloroethane | page 42 of 48
  Reference                    Study design and Data on exposure and effect                    Results                                                                                         Remarks
                               animal species          endpoints
  Van Duuren et al.            Ha:ICR Swiss            Dermal application                      Survival: not specified, median survival range 317 to more than 589 days.                       Klimisch score: 3.
  (1979)53                     female mice.            Exposure: 0, 42, 126 mg (3 d/wk)        Tumours: 0 (0.1ml acetone), 42, 126 mg, resp.:                                                  Supportive study.
                               30 animals/group.       Solvent: 0.2 mL acetone                 Lung papilloma: 11/30, 17/30, 26/30 (p<0.0005).                                                 Deficiencies: insufficient number
                                                       Xpo= somewhere between                  Stomach papilloma and squamous-cell carcinoma: 2/30, 1/30, 3/30.                                of animals used, only tested in
                                                       440-595 days                                                                                                                            one sex, mice were not restrained
                                                       Xpe= not specified                                                                                                                      from licking, no information on
                                                       Statistical analysis: Chi-square                                                                                                        non-cancer effects, exposure and
                                                       analysis.                                                                                                                               observation period were not
                                                                                                                                                                                               specified, no appropriate negative
                                                                                                                                                                                               control used.
  Suguro et al. (2017)54       CB6FI-Tg rasH2          Dermal application                      Survival: 5 treated female mice were euthanized in a moribund condition at 7-25 weeks. One Klimisch score: 2.
                               mice.                   Exposure: 0, 126 mg (3 d/wk)            control female was euthanized in week 26, due to hemangiosarcoma of the uterus.                 Well performed study, not
                               10 animals/sex/         Solvent: 0.2 mL acetone                                                                                                                 adequate for carcinogenicity
                               group.                  Xpo= 26 weeks                           Bronchiolo-alveolar hyperplastic and neoplastic lesions:                                        assessment.
                                                       Xpe= 26 weeks                           Hyperplasia: 0/10 and 1/10 (males); 0/10 and 6/10** (females).                                  Deficiencies: Sensitive transgenic
                                                       Statistical analysis: Fisher’s          Adenoma: 0/10 and 8/10** (males); 0/10 and 7/10** (females).                                    animal model, route not
                                                       exact probability test or Aspin-        Adenocarcinoma: 0/10 and 5/10* (males); 0/10 and 10/10** (females)                              appropriate, only one dose tested.
                                                       Welch’s test.                            (*p<0.05, **p<0.01).
  Theiss et al. (1977)55       Strain A/St male        Intra-peritoneal injections.            Survival: 46/50, 14/20, 16/20, 20/20.                                                           Klimisch score: 3.
                               mice.                   Solvent: Tricaprylin.                   Tumours: average number per mouse: 0, 80, 200, 400 resp.:                                       Supportive study.
                               Control: 50             Exposure: 0, 20, 40, 100 mg/kg/         Lung adenoma: 0.39, 0.21, 0.44, 0.75.                                                           Deficiencies: no individual animal
                               animals.                injection (3x/wk)                                                                                                                       data, exposure and observation
                               Exposed: 20             Xpo= 8 weeks                                                                                                                            period too short, only one benign
                               animals/ group.         Xpe= 24 weeks                                                                                                                           tumour investigated, only one sex
                                                       Statistical analysis: student                                                                                                           used, no information on
                                                       t-test.                                                                                                                                 non-cancer effects.
 Xpo = duration of exposure; Xpe = duration of the experiment; sign. = significant; TWA = time-weighted average; MTD = maximal tolerated dose; Klimisch scores were based on Klimisch et al.59
41          Health Council of the Netherlands | No. 2019/16                                                                                                                         2                                             43
</pre>

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

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

<pre> Annexes                                                                                                                                                               1,2-Dichloroethane | page 43 of 48
 C BMD-analysis                                                                                          Table 6. Outcome of BMD-analysis for female mice
                                                                                                           Model                        No.       Log-lik.    AIC       BMDL     BMDU       BMD      Conv.       Weight
                                                                                                                                        Par.
                                                                                                           Null                         1         -39.65      81.3      NA       NA         NA       NA
  Software                     Proast, version 65.7                                                        Full                         4         -36.53      81.06     NA       NA         NA       NA
  BMR, risk type               10%, extra risk                                                             two stage                    3         -36.92      79.84     260        736      374      Yes         0.0763
  BMDL                         Lowest 95% confidence interval of the BMD                                   log.logist                   3         -36.76      79.52     235      2,920      361      Yes         0.0895
                                                                                                           Weibull                      3         -36.76      79.52     235      3,040      361      Yes         0.0895
                               The fit of a model is measured by the comparison with the best fitting      Log.prob                     3         -36.76      79.52     234      3,720      362      Yes         0.0895
                               model (the one with the lowest AIC (AICmin)). If [AICmodel < AICmin +       gamma                        3         -36.76      79.52     236      2,870      362      Yes         0.0895
                               2] then both models are similar and the tested model provides a fit         logistic                     2         -36.97      77.94     269        917      367      Yes         0.1972
  Model fit and averaging
                               comparable with the best fitting model. The weight of a model depends
                                                                                                           probit                       2         -37         78        259      1,040      371      Yes         0.1914
                               on the fit – models with lower fit are attributed lower weights for model
                                                                                                           LVM: Expon. M3-              3         -36.77      79.54     238      2,330      362      Yes         0.0886
                               averaging.
                                                                                                           LVM: Expon. M3-              3         -36.77      79.54     236      2,520      363      yes         0.0886
                               Nagano K, Umeda Y, Senoh H, et al. Carcinogenicity and chronic
  Data source                  toxicity in rats and mice exposed by inhalation to 1,2-dichloroethane
                               for two years. Journal of Occupational Health. 2006;48(6):424-436.10
                                                                                                           Final BMDL          Final BMDU           Final BMD#
                               Crj:BDF1 mice exposed via inhalation for 104 weeks (6 hours/day, 5
  Exposure design                                                                                          267                 840                  366
                               days/week); experimental period 104 weeks
                                                                                                         #
                                                                                                            If [ AICmodel > AICnull - 2 ] than there is no trend in the data. Due to the limited data, the final BMD is
  Effect parameter             Incidence of mammary gland adenocarcinoma in female mice
                                                                                                         not calculated based on geometric mean but using the separate BMDs and subsequent weights.
 Table 5. Data on exposure and response
  Dose             Number of female mice             Number of female mice with
  (mg/m3)          per dose                          mammary gland
                                                     adenocarcinoma
     0             49                                1
   40              50                                2
  120              50                                1
  360              50                                6
42         Health Council of the Netherlands | No. 2019/16                                                                                                            2                                                44
</pre>

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

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

<pre> Annexes                                                                                          1,2-Dichloroethane | page 44 of 48
                                                        D recommendation of the
                                                                 Subcommittee on Classification
                                                                 of carcinogenic substances
                                                        D.1 Scope
                                                        For carcinogens, the Dutch Expert Committee on Occupational Safety
                                                        (DECOS) of the Health Council derives either a health-based recom-
                                                        mended occupational exposure limit (HBR OEL) or a health-based calcu-
                                                        lated occupational cancer risk value (HBC-OCRV), dependent on their
                                                        mechanism of action. For non-genotoxic carcinogens and non-stochastic
                                                        genotoxic carcinogens, it is assumed that the carcinogenic effects only
                                                        occur when exposure levels exceed a certain threshold. For such
                                                        substances, the Committee derives a HBR OEL. For stochastic genotoxic
                                                        carcinogens, and genotoxic carcinogens for which the mechanism of
                                                        action is unknown but for which a stochastic mechanism is not unlikely, it
                                                        is assumed that any level of exposure is associated with a certain risk for
                                                        developing cancer. For these substances, a HBC-OCRV is derived.
 Figure 1. BMD Plots
                                                        In order to establish the appropriate approach, the Subcommittee on the
                                                        Classification of carcinogenic substances was requested by DECOS to
                                                        evaluate the carcinogenic properties of 1,2-dichloroethane and in
43      Health Council of the Netherlands | No. 2019/16                                          2                                  45
</pre>

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

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

<pre> Annexes                                                                                                                 1,2-Dichloroethane | page 45 of 48
 particular, its genotoxic mode of action. The members of the Subcom-       Subcommittee notes that the carcinogenicity data do not describe a full
 mittee are listed at the end of this Annex.                                dose-response relationship.
 This Annex contains the conclusions of the Subcommittee. A summary of      D.3 Conclusions on the genotoxicity of 1,2-dichloroethane
 the carcinogenicity and genotoxicity data is provided in separate sections 1,2-Dichloroethane is genotoxic in vitro by inducing gene mutations and
 of the report.                                                             chromosomal aberrations. The substance can also form DNA-adducts in
                                                                            the presence of a metabolic activation system. In vivo,1,2-dichloroethane
 D.2 Conclusion on the carcinogenicity of 1,2-dichloroethane                has been shown to induce DNA damage, including the formation of DNA
 The Subcommittee concludes that in all epidemiological studies workers/    adducts. Four out of 5 micronucleus tests were negative, and a mouse
 residents were likely co-exposed to numerous known or suspected human      LacZ gene mutation assay in liver and testis revealed no induction of
 carcinogens, therefore, the human data is inadequate to evaluate the       mutants.
 relationship between human cancer and exposure to 1,2-dichloroethane.
                                                                            The Subcommittee notes that 1,2-dichloroethane is a clear in vitro
 Animal studies have shown 1,2-dichloroethane can cause mammary             mutagen. In vivo, 1,2-dichloroethane binds to DNA and causes DNA
 gland fibroadenoma, subcutis fibroma, peritoneum mesothelioma, and         damage. Genotoxicity data are available that indicate that 1,2-dichloro-
 hemangiosarcomas in male rats, and subcutis fibroma, mammary gland         ethane does not induce chromosomal aberrations in mice. However, posi-
 adenoma/adeno-carcinoma, fibroadenoma and subcutis fibroma in female       tive results have been reported in a micronucleus/chromosomal aberration
 rats. 1,2-Dichloroethane also causes bronchio-alveolar adenomas and        test in rats. The Subcommittee notes that this study showed no apparent
 carcinomas in the lung, endometrial stromal polyps in the uterus, adeno-   dose-response, and negative control values were unusually low. Further,
 carcinoma in the mammary gland, and hepatocellular adenomas in female      this study has questionable reporting. No increased mutant frequency was
 mice and alveolar/bronchiolar adenomas in both female and male mice.       observed in a LacZ gene mutation assay in mice. However, this in vivo
 Based on these findings, the Subcommittee concludes that there is suffi-   gene mutation assay has not been conducted according to general guide-
 cient evidence for carcinogenicity of 1,2-dichloroethane in animals. The   lines (for instance, a positive control is lacking). Overall, the in vivo geno-
                                                                            toxicity data are limited and no definitive conclusions can be drawn from
44       Health Council of the Netherlands | No. 2019/16                                                                2                                   46
</pre>

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

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

<pre> Annexes                                                                                              1,2-Dichloroethane | page 46 of 48
 these data. The Committee concludes, based on the results of the positive
 genotoxicity assays in vitro and indicator tests in vivo and the absence of
 conclusive in vivo genotoxicity data, that 1,2-dichloroethane is a low
 potency mutagen and a stochastic genotoxic carcinogen.
 Members of the Subcommittee on Classification of carcinogenic substances and meeting dates
 •  H.P.J. te Riele, Professor of molecular biology, VU University Amsterdam, and Netherlands Cancer
    Institute, Amsterdam, chairman
 •  P.J. Boogaard, Professor of environmental health and human biomonitoring, Wageningen University
    and Research Centre, and toxicologist, SHELL International BV, The Hague
 •  M.J.M. Nivard, Molecular biologist and genetic toxicologist, Leiden University Medical Center,
    Leiden
 •  E. De Rijk, Toxicologic Pathologist, Charles River Laboratories, ‘s Hertogenbosch
 •  J.J. Vlaanderen, Epidemiologist, Institute for Risk Assessment Sciences, Utrecht
 •  J. van Benthem, Genetic toxicologist, RIVM, Bilthoven, structurally consulted expert
 Scientific secretary:
 •  S.R. Vink, The Health Council of the Netherlands, The Hague
 Meeting dates:
 •  March 20 and April 26, 2019
45         Health Council of the Netherlands | No. 2019/16                                           2                                 47
</pre>

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

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

<pre> Committee                                                                                                                                                        1,2-Dichloroethane | page 47 of 48
 Committee and consuted experts
 Members of the Dutch Expert Committee on Occupational Safety (DECOS) for the advisory                  Observers:
 report 1,2-dichloroethane:                                                                             •  H. Stigter, Inspectorate SZW, Ministry of Social Affairs and Employment, Utrecht
 •  Prof. F.G.M. Russel, Professor of Pharmacology and Toxicology, Radboud University, Nijmegen,        •  D. Theodori, Social and Economic Council, The Hague
    chairperson
 •  Prof. P.J. Boogaard, Professor of Environmental Health and Human Biomonitoring, Wageningen          Scientific secretary:
    University and Research Centre, and Toxicologist, Shell International BV, The Hague                 •  S.R. Vink, The Health Council of the Netherlands, The Hague
 •  R. Houba, Occupational Hygienist, The Netherlands Expertise Centre for Occupational Respiratory
    Disorders, Utrecht                                                                                  Consulted expert:
 •  E.D. Kroese, Toxicologist, TNO, Zeist                                                               •  Bas Bokkers, RIVM, Bilthoven
 •  C.F. Kuper, Toxicologic Pathologist, Utrecht
 •  Prof. H. van Loveren, Professor of Immunotoxicology, Maastricht University, Maastricht
 •  Prof. I.M.C.M. Rietjens, Professor of Toxicology, Wageningen University and Research Centre,
    Wageningen
 •  G.B.G.J. van Rooy, MD PhD, Occupational medicine specialist, Arbo Unie Expert Centre for
    Chemical Risk Management and Radboudumc Outpatient Clinic for Occupational Clinical
    Toxicology, Nijmegen
 •  L.A. Smit, Epidemiologist, Institute for Risk Assessment Sciences, Utrecht
 •  Prof. R.C.H. Vermeulen, Professor of Environmental Epidemiology and Exposome Science,
    Institute for Risk Assessment Sciences and Julius Center for Health Sciences and Primary Care,
    Utrecht
 •  Prof. A.H. Piersma, Professor of Reproductive Toxicology, Utrecht University, Utrecht, and National
    Institute for Public Health and the Environment, Bilthoven, structurally consulted expert
46         Health Council of the Netherlands | No. 2019/16                                                                                                       2                                 48
</pre>

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

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

<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 and Sport, Infrastructure and Water Management, Social
 Affairs and Employment, and Agriculture, Nature and Food Quality. 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.
 This publiation can be downloaded from www.healthcouncil.nl.
 Preferred citation:
 Health Council of the Netherlands. 1,2-Dichloroethane. The Hague: Health Council of the
 Netherlands, 2019; publication no. 2019/16.
 All rights reserved
47         Health Council of the Netherlands | No. 2019/16
</pre>

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

<br><br>