<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-Dibromoethane
Health-based recommendation on occupational exposure limits
To: the State Secretary of Social Affairs and Employment
No. 2017/22, The Hague, December 1, 2017
</pre>

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

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

<pre>                                                                                                    1,2-Dibromoethane | page 2 of 32
contens
contents
   Samenvatting                                          3 03 Carcinogenicity studies                                             16
                                                              3.1 Human studies                                                   16
   Executive summary                                    5    3.2 Animal experiments                                              17
                                                              3.3 Selection of the suitable study for risk estimation
01 Scope                                                7        in the occupational situation                                   25
   1.1  Background                                      7    3.4 Calculation of the health-based occupational cancer risk values 26
   1.2  Committee and procedure                         7
   1.3  Data                                             7 04 Skin notation                                                       27
02 Identity, toxicity profile and classification        8    References                                                          28
   2.1  Identity, and physical and chemical properties  8
   2.2  Classification as a carcinogenic substance      9
   2.3  Toxicity profile                                9
   2.4  Existing occupational exposure limits          15
     Health Council of the Netherlands | No. 2017/22
</pre>

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

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

<pre>                                                                         1,2-Dibromoethane | page 3 of 32
samenvatting                                            directe interactie aangaan met het genetisch
                                                        materiaal (stochastisch genotoxisch
                                                        werkingsmechanisme) heeft de minister van
Op verzoek van de minister van Sociale Zaken            SZW risiconiveaus vastgelegd. Deze
en Werkgelegenheid (SZW) heeft de                       risiconiveaus betreffen het extra risico op kanker
Gezondheidsraad het advies over beroeps-                door beroepsmatige blootstelling gedurende het
matige blootstelling aan de kankerverwekkende           arbeidzame leven. De commissie GBBS schat
stof 1,2-dibroomethaan geactualiseerd. De               de concentraties van een stof in de lucht die
Gezondheidsraad schat de concentraties van              overeenkomen met die risiconiveaus. Dit
1,2-dibroomethaan in de lucht die samenhangen           worden risicogetallen genoemd. Voor de
met het streefrisiconiveau en het verbodsrisico-        schatting maakt de commissie gebruik van de
niveau op respectievelijk 0,002 en 0,2 milligram        Leidraad berekening risicogetallen voor
(mg) per kubieke meter (m3), bij 40 jaar                carcinogene stoffen van de Gezondheidsraad.1
beroepsmatige blootstelling. Deze concentraties
komen overeen met de waarden die de                     Streefrisiconiveau en verbodsrisiconiveau
Gezondheidsraad eerder heeft berekend. Verder           in Nederland
adviseert de raad om een huidnotatie toe te             Het streefrisiconiveau is 4 op 100.000. Dat
passen voor 1,2-dibroomethaan, wat betekent             betekent dat bij blootstelling overeenkomend
dat maatregelen noodzakelijk zijn om                    met 4 of minder extra sterfgevallen op 100.000
huidcontact met de stof te vermijden. Een               beroepsmatig blootgestelde mensen geen extra
huidnotatie wordt geadviseerd als verwacht              beschermende maatregelen genomen hoeven
wordt dat blootstelling via de huid bijdraagt aan       te worden.
gezondheidsschade die optreedt na inademing             Het verbodsrisiconiveau is 4 op 1.000. Dat
van de stof.                                            betekent dat blootstelling overeenkomend met 4
        Health Council of the Netherlands | No. 2017/22
</pre>

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

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

<pre>                                                                                                       1,2-Dibromoethane | page 4 of 32
extra sterfgevallen op 1.000 beroepsmatig            Advies aan de staatssecretaris
blootgestelde mensen niet overschreden mag           De commissie schat de concentratie van
worden.                                              1,2-dibroomethaan in de lucht die samenhangt
De Gezondheidsraad berekent welke                    met een extra risico op kanker van 4 per
blootstellingniveaus overeenkomen met deze           100.000 (het streefrisiconiveau) gelijk aan 0,002
risiconiveaus, uitgaande van iemand die 40 jaar      mg/m3. Een extra risico op kanker van 4 per
lang, 5 dagen per week en 8 uur per dag werkt.       1.000 (het verbodsrisiconiveau) komt overeen
                                                     met een concentratie van 0,2 mg/m3. Beide
Geraadpleegde onderzoeken                            schattingen gaan uit van een 40 jaar
In 1999 heeft de commissie WGD, de                   beroepsmatige blootstelling. Verder adviseert de
voorganger van de commissie GBBS,                    commissie om een huidnotatie toe te passen
risicogetallen afgeleid voor 1,2-dibroomethaan.      voor 1,2-dibroomethaan.
Er zijn nog steeds geen gegevens beschikbaar
over blootstelling aan 1,2-dibroomethaan en
kanker bij de mens. De commissie gaat bij haar
risicoschatting daarom, net als de WGD destijds,
uit van een rattenstudie die is uitgevoerd in het
kader van het Amerikaanse ‘National Toxicology
Program’. Hoewel de commissie nu andere
tumortypen als uitgangspunt gebruikt, komt de
nieuwe schatting van het risico overeen met de
eerdere schatting uit 1999.
        Health Council of the Netherlands | No. 2017/22
</pre>

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

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

<pre>                                                                                                                     1,2-Dibromoethane | page 5 of 32
executive summary                                                                                   occupational exposure. DECOS estimates the
                                                                                                    concentrations in the air that correspond to
                                                                                                    these risk levels. These estimates are referred
At the request of the Minister of Social Affairs    (DECOS). This permanent Committee of the        to as cancer risk values. For this estimation, the
and Employment, the Health Council has              Health Council evaluates the adverse health     Committee follows the Guideline for the
updated its recommendation on occupational          effects of substances to which people can be    calculation of occupational cancer risk values.1
exposure to 1,2-dibromoethane and the risk of       occupationally exposed. Additional information
cancer. The Health Council estimates the            on the task of the Committee and the members    Target risk level and prohibitive risk level
concentrations 1,2-dibromoethane in the air that    can be found on www.gezondheidsraad.nl.         applied in the Netherlands
correspond to the target risk level and the                                                         The target risk level is 4 per 100,000. This
prohibitive risk level to be 0.002 en 0.2 milligram Use of 1,2-dibromoethane                        means that for concentrations leading up to 4
(mg) per cubic meter (m3), respectively,            1,2-Dibromoethane is being used as              extra cancer cases per 100,000 occupationally
considering 40 years of occupational exposure.      intermediate in the synthesis of chemical       exposed people, no additional measures need
These concentrations are similar to those           compounds, mainly for the production of vinyl   to be taken.
derived by the Health Council previously. In        bromide, and as a non-flammable solvent for     The prohibitive risk level is 4 per 1,000. This
addition, the Health Council recommends to          resins, gums and waxes.                         means that the concentration leading to 4 extra
apply a skin notation for 1,2-dibromoethane.                                                        cancer cases per 1,000 occupationally exposed
This notation means that measures needs to be       Risk levels for carcinogenic substances         people, cannot be exceeded.
taken to prevent skin contact with the substance    The Minister of Social Affairs and Employment   The Health Council estimates which exposure
since this could attribute to the adverse health    has set risk levels for carcinogenic substances levels correspond to these risk levels,
effects that can develop after exposure by          that have been classified in category 1A or 1B  considering someone is exposed for 40 years,
inhalation.                                         and directly interact with the DNA (stochastic  5 days a week and 8 hours a day.
This advisory report has been drafted by the        genotoxic mechanism). These risk levels relate
Dutch Expert Committee on Occupational Safety       to the extra risk of cancer due to life time
       Health Council of the Netherlands | No. 2017/22
</pre>

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

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

<pre>                                                        1,2-Dibromoethane | page 6 of 32
Consulted research
In 1999, the Committee WGD (the predecessor
of DECOS) has derived cancer risk values for
1,2-dibromoethane. Like in 1999, no data are
available on exposure to 1,2-dibromoethane and
cancer in humans. Again, the Committee has
based its estimation on a study in rats that was
conducted within the US National Toxicology
Program. The new estimation corresponds to
the previous estimation of 1999, although the
Committee used different tumor types as starting
point.
Recommendation to the State Secretary
The Committee estimates the concentration of
1,2-dibromoethane in the air that corresponds to
an extra cancer risk of 4 per 100,000 (the target
risk level) equal to 0.002 mg/m3. An extra risk of
cancer of 4 per 1,000 (the prohibitive risk level)
corresponds to a concentration of 0.2 mg/m3.
Both estimates are based on 40 years of
occupational exposure. In addition, the
Committee recommends to apply a skin notation
for 1,2-dibromoethane.
        Health Council of the Netherlands | No. 2017/22
</pre>

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

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

<pre>                                                                                                                          1,2-Dibromoethane | page 7 of 32
01 scope                                                                    In the next phase of the three-step procedure, the Social and Economic
                                                                            Council advises the Minister of Social Affairs and Employment on the
1.1 Background                                                              feasibility of using the HBC-OCRVs as regulatory occupational exposure
In the Netherlands, occupational exposure limits for chemical substances    limits. In the final step of the procedure, the Minister sets the official
are set using a three-step procedure. In the first step, a scientific       occupational exposure limits.
evaluation of the data on the toxicity of the substance is made by the      In 1999, the Committee WGD (the predecessor of DECOS) derived
Dutch Expert Committee on Occupational Safety (DECOS), a committee          cancer risk values for 1,2-dibromoethane.2 In this report, the Committee
of the Health Council of the Netherlands, at request of the Minister of     provides an update.
Social Affairs and Employment. This evaluation should lead to a health-
based recommended exposure limit for the concentration of the substance     1.2 Committee and procedure
in air. Such an exposure limit cannot be derived if the toxic action cannot The present document contains the evaluation of the DECOS, hereafter
be evaluated using a threshold model, as is the case for substances with    called the Committee.
stochastic genotoxic carcinogenic properties. In that case, an exposure-    In 2017, the president of the Health Council released a draft of the report
response relationship is recommended for use in regulatory standard         for public review. The Committee has taken the comments received into
setting, i.e., the calculation of so-called health-based calculated         account in deciding on the final version of the advisory report. The
occupational cancer risk values (HBC-OCRVs). The Committee calculates       individuals and organizations that commented on the draft, the
HBC-OCRVs for compounds, which are classified by the European Union         comments and the replies by the Committee can be found on the website
or by the Committee as carcinogens in category 1A or 1B.                    of the Health Council.
For the establishment of the HBC-OCRVs, the Committee generally uses
a linear extrapolation method, as described in the Committee’s report       1.3 Data
‘Calculating cancer risk due to occupational exposure to genotoxic          The Committee’s recommendation has been based on scientific data,
carcinogens’.1 The linear model to calculate occupational cancer risk is    which are publicly available. Data were obtained from the online
used as a default method, unless scientific data would indicate that using  databases Toxline and Medline, using carcinogenic properties, carcino*,
this model is not appropriate.                                              cancer, neoplastic, 1,2-dibromoethane and CAS registry number as key
         Health Council of the Netherlands | No. 2017/22
</pre>

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

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

<pre>                                                                                                                                  1,2-Dibromoethane | page 8 of 32
words. In addition, in preparing this report the following reviews were    the uses of 1,2-dibromoethane as pesticide have also been discontinued.
consulted:                                                                 Physical and chemical data shown below are from http://toxnet.nlm.nih.
• Agency for Toxic Substances and Disease Registry (ATSDR)3                gov (HSDB), ATSDR3 and IARC4.
• International Agency for Research on Cancer (IARC)4
• US Environmental Protection Agency (US EPA)5
                                                                            Chemical name                                   : 1,2-dibromoethane
• European Commission: Scientific Committee on Occupational                 CAS number                                      : 106-93-4
   Exposure Limits (SCOEL)6                                                 EC number                                       : 203-444-5
                                                                            IUPAC name                                      : 1,2-dibromoethane
• National Toxicology Program (NTP)7.                                       Synonyms                                        : Ethylene dibromide; 1,2-ethylene dibromide;
                                                                                                                              dibromoethane, ethylene bromide; EDB; glycol
                                                                                                                              bromide; glycol dibromide
The last literature search was performed in May 2017.                       Physical description and colour                 : Colourless liquid
                                                                            Molecular formula                               : C2H4Br2
                                                                            Structure                                       :
02 identity, toxicity profile and                                           Molecular weight
                                                                            Melting point
                                                                                                                            :
                                                                                                                            :
                                                                                                                              187.86
                                                                                                                              9.9°C
                                                                            Boiling point (101.3 kPa)                       : 131.6°C
         classification                                                     Density (20°C)
                                                                            Solubility
                                                                                                                            :
                                                                                                                            :
                                                                                                                              2.172 g/cm3
                                                                                                                              Solubility in water (30°C) = 4.3 g/L; Miscible
                                                                                                                              with acetone, benzene, diethyl ether and
                                                                                                                              ethanol
2.1 Identity, and physical and chemical properties                          Octanol/water partition coefficient, Log Poct/w : 1.96
                                                                            Vapour pressure (25°C)                          : 11.2 mmHg (1.5 kPa)
1,2-dibromoethane is being used as a chemical intermediate in synthesis,
                                                                            Relative vapour density (air = 1)               : 6.5
mainly in the production of vinyl bromide, and as a non-flammable solvent   Flash point                                     : Not flammable
                                                                            Odour threshold                                 : 62.50 - 76.80 mg/m3
for resins, gums and waxes. A primary use of 1,2-dibromoethane in the
                                                                            Conversion factor (20°C, 101.3 kPa)             : 1 mg/m3 = 0.13 ppm
past has been as a lead scavenger in antiknock mixtures added to            (mg/m3 = molecular weight / 24.45 * ppm)          1 ppm = 7.69 mg/m3
                                                                            EU classification                               : Acute Tox. 3: H331, H311, H301; Eye Irrit. 2:
gasoline. This use has decreased with banning the use of lead-containing    (EC No 790/2009 of 10 August 2009)                H319 ; Skin Irrit. 2: H315; STOT SE 3: H335;
fuels in nearly all countries. Another major use in the past was as a                                                         Carc. 1B: H350
pesticide and ingredient in soil and grain fumigant formulations.6 Many of
        Health Council of the Netherlands | No. 2017/22
</pre>

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

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

<pre>                                                                                                                         1,2-Dibromoethane | page 9 of 32
2.2 Classification as a carcinogenic substance                               about 20 hours after the accident, contained 1,2-dibromoethane at
In the European Union, 1,2-dibromoethane is classified as a category 1B      concentrations between 15-41 ppm (115-315 mg/m3, average 28 ppm
carcinogen (presumed to have carcinogenic potential for humans).8            (215 mg/m3)). The other reports concern cases of suicidal poisoning via
IARC has classified the compound as a group 2A carcinogen (Probably          ingestion of 1,2-dibromoethane. Saraswat et al. (1986) reported on six
carcinogenic to humans).4 This evaluation was based on sufficient            young individuals who ingested an ampule of commercial 1,2-dibromo-
evidence in animals but inadequate evidence in humans. However,              ethane, two of which died 1-2 days after hospital admission.10 Another
IARC considered that 1,2-dibromoethane is genotoxic in a broad range of      fatal poisoning occurred in a woman who ingested about 9 capsules
in vitro and in vivo assays and binds covalently with DNA in vivo to elevate containing 1.5 mL of 1,2-dibromoethane each (140 mg/kg body weight),
the overall evaluation from 2B (possibly carcinogenic to humans) to 2A.      and died 54 hours later (Olmstead et al. (1960).11 A woman who
                                                                             intentionally ingested a capsule containing 6.5 g of 1,2-dibromoethane
2.3 Toxicity profile                                                         died 8 days later (Singh et al. (1993).12 More recently, Singh et al. (2007)
                                                                             reported on 64 patients with 1,2-dibromoethane poisoning.13 Death
2.3.1 Human studies                                                          occurred between 12 hours and 5 days in 38 of these patients. About half
Five reports on acute toxicity following accidental or suicidal poisoning    an ampule (1.5 ml) of 1,2-dibromoethane was fatal.
and three epidemiological studies on human reproduction toxicity have        Common clinical symptoms in the above studies included nausea,
been summarised by the IARC, ATSDR, EPA and European                         vomiting, abdominal pain and diarrhea. Neurological and respiratory
commission.3-6 A compilation hereof is given below.                          symptoms and urinary changes were also observed. Pathological
                                                                             examination consistently showed hepatic and renal damage (including
Acute toxicity                                                               necrosis), and gastrointestinal toxicity (erosion and ulceration).
Letz et al. (1984) reported on two workers who collapsed shortly after       Cardiotoxicity occurred in the accidentally exposed workers and in
entering a pesticide storage tank containing residues of 1,2-dibromo-        patients examined by Singh et al. (2007).13 Hypoglycaemia was another
ethane.9 These workers were exposed for about 45 minutes or 20-30            symptom observed in these patients.
minutes, and died 12 and 64 hours after collapse, respectively. Neither
worker had respiratory or skin protection. Air samples from the tank, taken
        Health Council of the Netherlands | No. 2017/22
</pre>

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

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

<pre>                                                                                                                       1,2-Dibromoethane | page 10 of 32
Reproduction toxicity                                                       all 10 exposed men and in only two unexposed men.
The epidemiological studies summarized below have significant
shortcomings (including small sample size, inadequate exposure data,        2.3.2 Animal studies
inappropriate control groups, and general methodological weakness in
assessing fertility status and antispermatogenic effects), but provide some Acute toxicity
indication of potential adverse effects of 1,2-dibromoethane on male        Experimental data on acute toxicity of 1,2-dibromoethane have been
fertility and sperm production.3                                            compiled by the European Commission6 and on the ECHA website8. A
Wong et al. (1979) observed a decrease in male fertility in workers from    compilation is given below.
four plants manufacturing 1,2-dibromoethane.14 Two exposures categories     In acute oral toxicity studies (following OECD guideline 401) in different
were distinguished: <0.5 ppm (<3.8 mg/m3) and 0.5-5 ppm (3.8-38             species the following LD50 values were obtained: rat (male, female) 140,
mg/m3). Based on the men’s reproductive histories subsequent to their       rat (male) 146, rat (female) 117, mouse (female) 420, rabbit (female) 55,
occupational exposure, the number of live births to their wives was 29%     chick (male, female) 79, and guinea pig (male, female) 110 mg/kg body
below expected values (this difference was not statistically significant at weight.
p = 0.05).                                                                  In an acute inhalation study (predating OECD guidelines) rats were
The effect of long-term exposure, with an average of five years, to         exposed (whole body) to concentrations of 1,2-dibromoethane (vapour)
1,2-dibromoethane (8-hr time-weighted average 88 ppb [0.68 mg/m3]) on       between 100 and 10,000 ppm (769 and 76,900 mg/m3) for 0.02 to 16
semen quality was studied by Ratcliffe et al. (1987) among 46 men           hours. The LC50 (4-hours) was >200 ppm (>1,538 mg/m3). At 400 ppm
employed in the papaya fumigation industry.15 The comparison group          (3,076 mg/m3) exposure for 2 hours or longer resulted in 64-100%
consisted of 43 unexposed men from a sugar refinery. Significant            mortality. The most sensitive non-lethal effects consisted of an increase in
decreases in sperm count, viability and motility, and increases in sperm    liver weight and slight histopathological changes in this organ. In the same
with morphological abnormalities were observed among exposed men.           study guinea pigs were exposed to 200 ppm (for 7 hours) and 400 ppm
Schrader et al. (1988) conducted a longitudinal study in 10 forestry        (for 2-7 hours) (1,538 and 3,076 mg/m3, respectively). Fifty per cent of the
employees exposed for about six weeks (8-hr time-weighted average 60        guinea pigs exposed to 400 ppm (3,076 mg/m3) for 3 hours died while no
ppb [0.46 mg/m3]) and six unexposed men.16 Sperm velocity decreased in      mortality occurred at 200 ppm (1,538 mg/m3).
          Health Council of the Netherlands | No. 2017/22
</pre>

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

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

<pre>                                                                                                                          1,2-Dibromoethane | page 11 of 32
In rats, a dermal application of 0.25 ml of neat 1,2-dibromoethane was         exposure by inhalation 1,2-dibromoethane (10 and 40 ppm (77 and 308
lethal.                                                                        mg/m3)) caused mortality and growth retardation at the highest
                                                                               concentration in rats.17 Clinical symptoms consisted of weakness of limbs
Skin and eye irritation and corrosion                                          or body at 40 ppm (308 mg/m3). In male mice (all groups), early mortality
In vitro, 1,2-dibromoethane was negative in a human epidermis model for        occurred due to urinary tract infection. Increased mortality was observed
skin corrosion. In vivo, the substance caused slight irritation, characterized at 10 ppm (77 mg/m3) and for females only, at 40 ppm (308 mg/m3).
by erythema and exfoliation, upon repeated application to rabbit ear. The      Growth retardation was observed only at the highest concentration.17
undiluted substance was irritating to the rabbit eye, causing reversible       Histopathological examination of animals exposed by inhalation revealed
conjunctival irritation and slight superficial necrosis of the cornea, in a    treatment-related non-neoplastic lesions in the respiratory system
study similar to OECD 405. In the same study, a 10% dilution of                (including epithelial hyperplasia and inflammation) of rats and mice, and
1,2-dibromoethane in propylene glycol caused more severe (but still            hepatic necrosis, toxic nephropathy, degeneration of the testis, retina and
reversible) conjunctival and corneal irritation than the undiluted material.8  adrenal cortex, and atrophy of the spleen in rats.17,18
                                                                               In another inhalation carcinogenicity study in rats, exposure to 20 ppm
Skin sensitisation                                                             1,2-dibromoethane (154 mg/m3) resulted in an increased mortality.19
1,2-Dibromoethane was negative in a mouse local lymph node assay               Effects unrelated to the carcinogenicity of 1,2-dibromoethane were not
(OECD 429) in which the substance was tested at concentrations of 25,          reported.
50 and 100% in acetone/olive oil (4:1). The stimulation index values for       The oral (gavage) carcinogenicity studies by NCI in rats and mice (doses
these concentrations were 0.7, 0.63 and 1.39, respectively.8                   reported of 41 and 38 mg/kg/day for male rats, 39 and 37 mg/kg/day for
                                                                               female rats and 107 and 62 mg/kg/day for mice of both sexes) showed
Repeated dose toxicity                                                         treatment-related mortality, reduced weight gain and various clinical
Effects on non-cancer endpoints upon chronic exposure to                       symptoms.20,21
1,2-dibromoethane were reported for several of the carcinogenicity studies     In studies by Van Duuren et al., mice given 1,2-dibromoethane in their
summarized in Table 3.                                                         drinking water (equivalent doses of 50 and 110 mg/kg, for males and
The NTP conducted carcinogenicity studies in rats and mice. Long-term          females combined) showed reduced water consumption, growth
        Health Council of the Netherlands | No. 2017/22
</pre>

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

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

<pre>                                                                                                                       1,2-Dibromoethane | page 12 of 32
retardation and increased mortality (the authors did not report on clinical  In another 13-week inhalation study, conducted to estimate the maximum
signs or non-neoplastic histopathological changes).22,23                     tolerated exposure levels for carcinogenicity studies, male and female
Full histopathological examination was conducted only in the oral            Fischer 344 rats and B6C3F1 mice were exposed to 3, 15 or 75 ppm (23,
(gavage) carcinogenicity studies conducted by NCI.20 This examination        115 or 577 mg/m3) of 1,2-dibromoethane (6 hours/day, 5 days/week).17,25
showed that acanthosis and hyperkeratosis in the forestomach were the        All rats survived whereas 4 male mice exposed to 3 ppm (23 mg/m3) and
main non-neoplastic changes in both rats and mice (at both dose levels).     one female mouse exposed to 75 ppm (577 mg/m3) died. Growth was
In addition, rats showed testicular atrophy and degenerative changes in      retarded (dose-dependently) in all dosed groups except in high-dose
the liver and adrenals.                                                      females. Treatment-related histopathological changes were observed in
                                                                             the nasal cavity at 15 ppm (115 mg/m3; squamous cell metaplasia, focal
The toxicity of 1,2-dibromoethane after sub-chronic repeated exposure        hyperplasia, cytomegaly and loss of cila in rats) and 75 ppm (577 mg/m3;
was examined in several animal studies. These studies have been              severe necrosis and atrophy of the olfactory epithelium in rats and mice).
summarised by the IARC in 1999.4 A short compilation hereof is given         In a sub-acute study on systemic and immunologic toxicity, female B6C3F1
below.                                                                       mice received 1,2-dibromoethane by daily oral gavage at 100, 125, 160 or
Male and female Fischer 344 rats were exposed by inhalation to 0, 3, 10      200 mg/kg body weight (vehicle corn oil) for 14 days.26 Decreases were
or 40 ppm (0, 23, 77 or 308 mg/m3) of 1,2-dibromoethane for 13 weeks         seen in relative thymus and spleen weights, red blood cells, haemoglobin,
(6 hours/day, 5 days/week).24 The lowest concentration (3 ppm (23            haematocrit and responses of immunological cells in culture. Relative
mg/m3)) was a No-Observed-Adverse-Effect concentration. At 10 ppm            weights of liver and kidney were increased.
(77 mg/m3) slight epithelial hyperplasia of the nasal turbinates was seen in In another sub-acute study, male Fischer 344 rats were treated by daily
animals examined after one, six or 13 weeks of exposure. At 40 ppm (308      (5 days/week) oral gavage with 1,2-dibromoethane (40 and 80 mg/kg
mg/m3) the substance induced hyperplasia and non-keratinizing squamous       body weight/day) to identify early forestomach lesions following gavage
metaplasia of the respiratory epithelium of the nasal turbinates and         administration of known stomach carcinogens.27 At 80 mg/kg the
increases in liver and kidney weights. The nasal lesions at 10 and 40 ppm    substance caused epithelial cell proliferation and hyperkeratosis in the
(77 and 308 mg/m3) were no longer observed after a recovery period of 88     forestomach (in 4/8 and 6/8 rats, respectively). The only finding at 40
days.                                                                        mg/kg was hyperkeratosis in 1/8 rats.
        Health Council of the Netherlands | No. 2017/22
</pre>

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

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

<pre>                                                                                                                     1,2-Dibromoethane | page 13 of 32
Following short-term intraperitoneal administration (40 mg/kg body weight  smears showed that the oestrous cycle was significantly prolonged at the
in corn oil; twice daily for two consecutive days) 1,2-dibromoethane       highest dose.
induced impairment of renal function in male but not in female Fischer 344 Pregnant CD rats and CD-1 mice were exposed by inhalation to 20, 38
rats. Hepatotoxicity was not observed.28                                   and 80 ppm (154, 292, and 615 mg/m3) of the substance for 23 hours per
                                                                           day over 10 days, beginning on day 6 of gestation.29 The animals were
Reproduction toxicity                                                      killed on gestational days 20 (rats) and 18 (mice). Significant adult
The effect of 1,2-dibromoethane on reproduction was studied in male and    mortality occurred in rats at 80 ppm (615 mg/m3) and in mice at 38 and 80
female CD rats exposed by inhalation to 0, 19, 39 or 89 ppm (0, 146, 300,  ppm (292 and 615 mg/m3; at the highest dose all mice died untimely).
684 mg/m3) for 10 weeks (7 hours/day, 5 days/week).29 At 89 ppm (684       Adverse effects on maternal welfare, as assessed from weight change,
mg/m3) morbidity and mortality occurred and males of this group had        feed consumption and survival, occurred at all concentrations in both
reduced testicular weight, reduced serum testosterone concentration and    species. Fetal mortality was increased in rats at 80 ppm (615 mg/m3) and
failed to impregnate any females during a 2-week mating period. Atrophy    in mice at 38 ppm (292 mg/m3). Fetal body weights were reduced in rats
of the testes, epididymis, prostate and seminal vesicles was also          at 38 ppm (292 mg/mg3) and in mice at 20 and 38 ppm (154 and 292
observed. Females exposed to 89 ppm (684 mg/m3) did not cycle normally     mg/m3).
until several days after termination of exposure.                          Male Fischer 344 rats were treated by sub-acute intraperitoneal injection
Male New Zealand white rabbits were given subcutaneous injections of       of a daily dose of 1.25, 2.5, 5 or 10 mg/kg body weight 1,2-dibromoethane
15, 30 or 45 mg/kg body weight of 1,2-dibromoethane per day for five       on five successive days.32 Four or nine weeks after the last injection,
days.30 Semen samples were taken before exposure, during treatment         males were crossed with virgin females. Significant differences in the
and during 12 weeks after exposure and analysed. Mortality,                development of motor coordination and motor activity were observed in
hepatotoxicity and alterations in measured semen parameters (velocity,     the F1 progeny.
percentage motility, amplitude of lateral head displacement) were
observed in the highest-dose group.                                        2.3.3 Genotoxicity
Female B6C3F1 mice were given 31.25, 62.5 or 125 mg/kg body weight of      Studies investigating the genotoxicity of 1,2-dibromoethane have been
1,2-dibromoethane by gavage for 12 weeks (5 days/week).31 Vaginal          reviewed by the IARC4 and the EPA.5 A summary of the most relevant
        Health Council of the Netherlands | No. 2017/22
</pre>

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

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

<pre>                                                                                                                       1,2-Dibromoethane | page 14 of 32
data is given below. Additional literature is noted where appropriate.    Cytogenetic tests
                                                                          1,2-Dibromoethane has been tested in an in vivo rat alkaline comet
Gene mutation tests                                                       assay.34 1,2-Dibromoethane was administered to 5 male Sprague-Dawley
1,2-Dibromoethane has been tested for mutagenicity in vivo in the         rats per group (25, 50, and 100 mg/kg/day) by oral gavage at 48, 24, and
transgenic Big Blue® mice assay (utilizing the cII gene).33 Male mice     3 h before analysis. Single cells were collected from the liver and
(5/group) were treated with 1,2-dibromoethane (30 mg/kg bw i.p. in corn   glandular stomach at 3 h after the final dosing. From the same animals
oil), whereas control animals were treated with corn oil only.            also bone marrow cells were collected for measuring the induction of
Dibromoethane treatment increased the cII mutant frequency in the liver   micronuclei. 1,2-Dibromoethane tested positive in the comet assay, and
6-fold at 6 hours after treatment.                                        negative in the micronucleus assay.
1,2-Dibromoethane was mutagenic in Eschericia coli and in the             In addition, 1,2-dibromoethane has been shown to induce DNA strand
Salmonella typhimurium strains TA98, TA100 and TA1535 both in the         breaks in vivo in liver cells of rats treated orally; in testicular germ cells of
absence and the presence of an exogenous metabolic system, and in         rats treated intraperitoneally; in the stomach, kidney, liver, lung and
Streptomyces coelicolor and Aspergillus nidulans (the fungal strains were bladder of mice treated intraperitoneally. 1,2-Dibromoethane was negative
not tested with metabolic activation). The substance was negative, with   in dominant lethal tests in rats treated orally and in mice treated orally or
and without metabolic activation, in Salmonella typhimurium strains       intraperitoneally. The substance was also negative when tested for
TA1537 and TA1538. Mutations were also induced in cultured mammalian      micronuclei in bone marrow or peripheral erythrocytes of mice treated
cells: Chinese hamster ovary cells and mouse lymphoma L5178Y cells,       intraperitoneally.
tk-locus (with and without metabolic activation); two human               In vitro, sister chromatid exchanges and chromosomal aberrations were
lymphoblastoid cell lines (AHH-1 and TK6; tested without metabolic        induced in Chinese hamster lung V79 cells (tested only without metabolic
activation).                                                              activation) and in Chinese hamster ovary cells (with and without metabolic
In vivo, the substance induced somatic mutations and sex-linked           activation). Sister chromatid exchanges were also induced in human
recessive lethal mutations in Drosophila melanogaster.                    peripheral lymphocyte cultures (tested only without metabolic activation).
                                                                          The substance was positive in unscheduled DNA synthesis assays in rat
                                                                          spermatocytes and primary hepatocytes (tested only without metabolic
        Health Council of the Netherlands | No. 2017/22
</pre>

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

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

<pre>                                                                                                                                             1,2-Dibromoethane | page 15 of 32
activation). Micronuclei were induced in cultured human lymphocytes           and by the USA-NIOSH and USA-OSHA. The European Union did not
(tested only without metabolic activation). Transformations were induced      assign occupational exposure limits because the Scientific Committee on
in BALB/c-3T3 cells in the absence and presence of a metabolic activation     Occupational Exposure Limits (SCOEL) concluded that the quantitative
system. The substance induced DNA strand breaks in vitro in hepatocytes       data on carcinogenicity and the present state of toxicokinetic interspecies
and testicular germ cells of rats (tested only without metabolic activation), modelling do not permit a reasonable and reliable quantitative cancer risk
and in testicular cells isolated from human organ transplant donors.          assessment for humans.6
Miscellaneous                                                                 Table 1. Occupational exposure limits of 1,2-dibromoethanea
In vivo, treatment with 1,2-dibromoethane (30 mg/kg bw i.p. in corn oil)        Country                         OEL                OEL                 TWA                 Type of
                                                                                (Organization)                  (ppm)              (mg/m3)                                 exposure limit
increased dibromoethane-GSH DNA adducts (N7-guanyl) in a transgenic
                                                                                The Netherlandsb                -                  0.002               8h                  OEL
mouse model.    33                                                              European Union                  - d
                                                                                                                                   - d
                                                                                                                                                       -                   -
                                                                                Germany (DFG)                   -                  -                   -                   -
In vitro, 1,2-dibromoethane produced DNA-adducts in calf thymus DNA             Germany (AGS)                   -                  -                   -                   -
(tested with metabolic activation system) and in human and rat                  France                          -                  -                   -                   -
                                                                                UK (HSE)b                       0.5d               3.9d                8h                  WEL
hepatocytes (tested without metabolic activation). Intraperitoneal              Denmark     b
                                                                                                                0.1 d
                                                                                                                                   1  d
                                                                                                                                                       8h                  OEL
administration of the substance to rats and mice resulted in binding to         Sweden                          -                  -                   -                   -
                                                                                USA (NIOSH)        c
                                                                                                                0.045              -                   8h                  REL
DNA, RNA and proteins in various organs (liver, kidney, stomach, lung).         USA (OSHA)       c
                                                                                                                20                 -                   8h                  PEL
In 1987, DECOS concluded that 1,2-dibromoethane should be considered          a
                                                                                 http://limitvalue.ifa.dguv.de/WebForm_ueliste2.aspx [accessed May 3rd, 2017]; WEL: workplace exposure limit;
                                                                                 PEL: permissible exposure limit; REL: recommended exposure limit; TWA: time-weighted average
a genotoxic carcinogen.35 In 2011, SCOEL concluded that                       b
                                                                                 www.ser.nl,
                                                                              c
                                                                                 www.osha.gov
1,2-dibromoethane should be regarded as a genotoxic carcinogen with no        d
                                                                                 skin notation
threshold.6
2.4 Existing occupational exposure limits
Table 1 presents the occupational exposure limits established by the
regulatory authorities of the Netherlands, the United Kingdom, Denmark,
        Health Council of the Netherlands | No. 2017/22
</pre>

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

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

<pre>                                                                                                                              1,2-Dibromoethane | page 16 of 32
03 carcinogenicity studies                                                 Table 2. Epidemiological studies
                                                                            Study design and           Data on        Results                     Remarks
3.1 Human studies                                                           population (Reference)     exposure and
                                                                                                       health
The Committee identified four epidemiological studies investigating                                    assessment
                                                                            Type of study:             No information Mortality death rate due to Study contains several
mortality among workers (potentially) exposed to 1,2-dibromoethane.         Retrospective cohort study on exposure    cancer per 1000 man years   flaws. No data on
Two studies examined the mortality of grain workers/chemical production     Country: UK                levels and     (workers/controls):         exposure levels and
                                                                            Follow-up period:          duration. No                               duration, no follow-up
workers, in order to relate occupational exposure to multiple chemicals     unknown                    statistical    Factory A:                  time reported, small
                                                                            Participants: 117 exposed  analysis       25-44 y: 0/0.32;            number of participants,
with specific causes of death. In these studies workers were exposed to     male workers (factory A)                  45-64 y: 0.69/3.44;         no statistical analysis
                                                                            and 195 exposed workers                   65-74 y: 11.30/11.65;       performed
multiple substances, making it impossible to determine the effect of
                                                                            (factory B)                               ≥75 y: 21.28/16.99
exposure to solely 1,2-dibromoethane on mortality.36,37 The studies were    Control: local population
                                                                            (Turner et al. (1979)39)                  Factory B:
therefore excluded from further evaluation.                                                                           25-44 y: 0.6/0.3;
                                                                                                                      45-64 y: 4.2/4.0;
In a retrospective cohort study by Ott et al. (1980), a total of 161                                                  65-74 y: 12.3/12.9;
1,2-dibromoethane exposed male workers from two production units were                                                 ≥75 y: not reported/21.5
                                                                           y: year of age
studied. However, exposure to multiple other (potentially carcinogenic)
         38
substances at various times in the past made it impossible to determine
the specific effect of 1,2-dibromoethane on mortality. This study was,     (factory B). Workers were divided in four age groups (25-44, 45-64, 65-74,
therefore, also excluded from further evaluation.                          ≥75). The death rates from all causes, including cancer, within each age
Turner et al. (1979) examined mortality data for individuals who had been  group were compared with the values for the general population in the
employed in two factories producing halogenated hydrocarbons.39 Both       same part of the country over a similar period. The death rates due to
factories were situated remotely from any other chemical industry. A       cancer for the workers were comparable to, or lower than those for the
summary of this study is presented in Table 2. In this study, 117 men from local population in both factories, except for the ≥75 age group in plant A
factory A and 195 men from factory B were identified as potentially        which was higher for the workers. Also this study has several limitations
exposed workers. The workers were exposed to 1,2-dibromoethane for at      (i.e. no information on exposure levels and duration, small number of
least four years during the periods 1940-1970 (factory A) and 1954-1975    participants, no follow-up time, no statistical analysis performed).
        Health Council of the Netherlands | No. 2017/22
</pre>

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

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

<pre>                                                                                                                      1,2-Dibromoethane | page 17 of 32
The Committee considers the epidemiological studies on                     circulatory system in both sexes, of mesotheliomas of the tunica vaginalis
1,2-dibromoethane exposure and cancer not suitable for risk calculation.   in male rats, and of mammary gland fibroadenomas and lung tumours
                                                                           (predominantly alveolar/bronchiolar carcinomas) in female rats. The
3.2 Animal experiments                                                     incidences of the tumours in the nasal cavity, tunica vaginalis and
In Table 3, the carcinogenicity studies in experimental animals are        mammary gland were increased statistically significantly at 10 and 40 ppm
summarised. These studies comprise five inhalation studies (three in rats, (77 and 308 mg/m3), whereas the incidences of the pulmonary and
two in mice), five oral studies (one in rats, four in mice), and one       circulatory system tumours reached statistical significance at 40 ppm (308
intraperitoneal study and one dermal study in mice. The carcinogenicity    mg/m3) only. In mice, 1,2-dibromoethane induced lung tumours (alveolar/
results of these studies are presented below, starting with the most       bronchiolar carcinomas and adenomas) in both sexes, and tumours of the
reliable studies. Results on non-cancer endpoints seen in these studies    nasal cavity (predominantly carcinomas), of hemangiosarcomas of the
(body weight, mortality and other) are presented in Section 2.3 ‘Toxicity  circulatory system, of mammary gland adenocarcinomas, and of
profile’.                                                                  fibrosarcomas in subcutaneous tissue or rib in female mice. The
                                                                           incidences of the tumours in the circulatory system, mammary gland and
Inhalation exposure                                                        subcutaneous tissue/rib were statistically significantly increased at 10 and
The National Toxicology Program (NTP) performed inhalation                 40 ppm (77 and 308 mg/m3) whereas the nasal and pulmonary tumours
carcinogenicity bioassays in rats and mice.17 Male and female Fisher 344   reached statistical significance at 40 ppm (308 mg/m3) only. See Table 3
rats and B6C3F1 mice (50 animals/sex/group) were exposed to                for incidences and statistical significances of the above tumours in rats
concentrations 10 or 40 ppm (77 or 308 mg/m3) 1,2-dibromoethane for 6      and mice.
hours/day, 5 days/week for a maximum of 103 weeks. Due to high             Adkins et al. (1986) used 1,2-dibromoethane as a model compound to
mortality, high dose male and female rats, all male mice and high dose     validate a short-term (6 months) in vivo model, using strain A/J mice
female mice were sacrificed about 3-6 months before the scheduled          exposed by inhalation, for predicting the carcinogenic potential of
termination. In rats 1,2-dibromoethane caused increased incidences of      chemicals.40 Examination for tumours was limited to the lungs. At the
tumours in the nasal cavity (carcinomas, adenocarcinomas, adenomas         concentrations tested (20 and 50 ppm, 154 and 385 mg/m3) 1,2-dibromo-
and adenomatous polyps) in both sexes, of hemangiosarcomas of the          ethane induced a dose-related increase in grossly visible lung adenomas.
        Health Council of the Netherlands | No. 2017/22
</pre>

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

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

<pre>                                                                                                                                                                 1,2-Dibromoethane | page 18 of 32
Table 3. Animal carcinogenicity studies
 Study design and animal     Data on exposure and effect endpoints              Results                                                              Remarks
 species
 Inhalation exposure
 F344 rats                   Inhalation exposure (whole body), 6 hr/day, 5      Survival: decreased at 40 ppm in both sexes (resulting in early      Klimisch score: 2
 Control and exposed groups: days/wk                                            termination at wk 89/91 for males/females). Survivors at termination Well-performed study, adequate for carcinogenicity
 50 rats/sex/group (NTP      Purity: 99.3-99.4%                                 at 0, 10 and 40 ppm: males 38/50, 35/50, 5/50;                       assessment and derivation of cancer risk values
 (1982)17)                   Target concentrations: 10 and 40 ppm (77 and       females 38/50, 39/50, 8/50                                           Deficiencies:
                             308 mg/m3, actual resp. 10.02±0.84 and             Adverse effects: weakness of limbs or body at 40 ppm from wk 52;     maximum tolerated dose exceeded in high-dose group,
                             38.93±2.55 ppm)                                    lower body weight at 40 ppm throughout study; hepatic necrosis,      individual animal data not reported, no statistical
                             Xpo=103 wk (control, low), 88 wk (males high),     toxic nephropathy, testicular degeneration, retinal degeneration,    analysis conducted on non-neoplastic lesions, no
                             91 wk (females high)                               adrenal cortex degeneration at 10 and 40 ppm (incidence generally    adjustment for intergroup differences in survival in
                             Xpe=104-106 wk (control, low), 89 wk (males        decreased with dose); epithelial hyperplasia, squamous metaplasia    statistical analysis of tumour data
                             high), 91 wk (females high)                        and suppurative inflammation were prominent in respiratory system
                             Statistical analysis tumour incidences: one-tailed Tumours: at 0, 10, 40 ppm, resp
                             Fisher exact test to compare dosed groups with     (m / f = males / females):
                             control;                                           Nasal cavity:
                             Cochran-Armitage test for linear trend;            • carcinoma: m 0/50, 0/50, 21/50 (p<0.001) ; f 0/50, 0/50, 25/50
                             approximate 95% confidence interval for relative     (p<0.001)
                             risk of each dosed group compared with its         • adenocarcinoma: m 0/50, 20/50 (p<0.001), 28/50 (p<0.001) ;
                             control                                              f 0/50, 20/50 (p<0.001), 29/50 (p<0.001)
                                                                                • adenoma: m 0/50, 11/50 (p=0.001), 0/50; f 0/50, 11/50 (p<0.001),
                                                                                  3/50
                                                                                • adenomatous polyp: m 0/50, 18/50 (p<0.001), 5/50 (p=0.028) ;
                                                                                  f 0/50, 5/50 (p=0.028), 5/50 (p=0.028)
                                                                                • squamous cell carcinoma: m 0/50, 3/50, 3/50 ; f 1/50, 1/50, 5/50
                                                                                • above nasal cavity tumours combined: m 0/50, 39/50 (p<0.001),
                                                                                  41/50 (p<0.001); f 1/50, 34/50 (p<0.001), 43/50 (p<0.001)
                                                                                Hemangiosarcoma (circulatory system): m 0/50, 1/50, 15/50
                                                                                (p<0.001); f 0/50, 0/50, 5/50 (p=0.028)
                                                                                Only male:
                                                                                Mesothelioma:
                                                                                • tunica vaginalis: 1/50, 8/50 (p=0.015), 25/50 (p<0.001)
                                                                                • multiple organs: 0/50, 5/50 (p=0.028), 1/50
                                                                                Only female:
                                                                                Lung: carcinoma or adenoma: 0/50, 0/48, 5/47 (p=0.024)
                                                                                Mammary gland: adenocarcinoma: 1/50, 0/50, 4/50
                                                                                Mammary gland: fibroadenoma: 4/50, 29/50 (p<0.001), 24/50
                                                                                (p<0.001)
           Health Council of the Netherlands | No. 2017/22
</pre>

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

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

<pre>                                                                                                                                                             1,2-Dibromoethane | page 19 of 32
                                                                               The above tumours were related to treatment. The incidences of
                                                                               the following tumours showed a dose-related positive linear trend.
                                                                               However, as Fisher’s test for differences between dosed groups
                                                                               and controls was not significant the relationship to treatment was
                                                                               not clear
                                                                               Thyroid: follicular cell adenomas or carcinomas in males:
                                                                               0/48, 0/50, 3/46
                                                                               Salivary gland: sarcomas (unspecified or invasive) in males:
                                                                               0/49, 1/50, 3/48
                                                                               Subcutaneous tissue: fibroma or fibrosarcoma, in females:
                                                                               0/50, 0/50, 4/50
                                                                               Liver: hepatocellular carcinoma in females:
                                                                               0/50, 1/49, 3/48
B6C3F1 mice                 Inhalation exposure (whole body), 6 hr/day, 5      Survival: poor survival in control and dosed males due to ascending Klimisch score: 2
Control and exposed groups: days/wk                                            suppurative urinary tract infection which was not related to        Well-performed study, adequate for carcinogenicity
50 mice/sex/group (NTP      Purity: 99.3-99.4%                                 treatment (resulting in early termination of all males at wk 79);   assessment
(1982)17)                   Target concentrations: 10 and 40 ppm (77 and       Compared with controls, survival was decreased at 10 ppm in         Deficiencies: poor survival in males, maximum tolerated
                            308 mg/m3, actual resp. 10.02±0.84 and 38.93       males and, dose-dependently at 10 and 40 ppm in females.            dose exceeded in high-dose females, individual animal
                            ±2.55 ppm)                                         Survivors at termination at 0, 10 and 40 ppm: males 13/50, 11/50,   data not reported, no statistical analysis conducted on
                            Xpo=78 wk (all males), 103 wk (females control,    18/50; females 40/50,19/50, 7/50                                    non-neoplastic lesions, no adjustment for intergroup
                            low), 91 wk (females high)                         Adverse effects: weakness of limbs or body at 40 ppm in 2nd year;   differences in survival in statistical analysis of tumour
                            Xpe=79 wk (all males), 104-106 wk (females         lower body weight at 40 ppm throughout study; epithelial            data
                            control, low), 90 wk (females high)                hyperplasia throughout respiratory system at 10 and 40 ppm
                            Statistical analysis tumour incidences: one-tailed Tumours: at 0, 10, 40 ppm, resp
                            Fisher exact test to compare dosed groups with     (m / f = males / females):
                            control;                                           Lung (alveolar/bronchiolar):
                            Cochran-Armitage test for linear trend;            • carcinoma: m 0/41, 3/48, 19/46 (p<0.001); f 1/49, 5/49, 37/50
                            Approximate 95% confidence interval for relative     (p<0.001)
                            risk of each dosed group compared with its         • adenoma: m 0/41, 0/48, 11/46 (p<0.001); f 3/49, 7/49, 13/50
                            control                                              (p=0.007)
                                                                               Lung (bronchus):
                                                                               • adenoma or adenomatous polyp: m 0/41, 0/48, 5/46 (p=0.037);
                                                                                 f 0/49, 0/49, 6/50 (p=0.014)
                                                                               Circulatory system:
                                                                               • hemangiosarcoma: m 0/45, 0/50, 4/50 (significant positive trend);
                                                                                 f 0/50, 11/50 (p<0.001), 23/50 (p<0.001)
                                                                               Only female:
                                                                               Mammary gland adenocarcinoma: 2/50, 14/50 (p<0.001), 8/50
                                                                               (0.046)
                                                                               Subcutaneous tissue or rib: fibrosarcoma: 0/50, 5/50 (p=0.028),
                                                                               11/50 (p<0.001)
         Health Council of the Netherlands | No. 2017/22
</pre>

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

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

<pre>                                                                                                                                                                1,2-Dibromoethane | page 20 of 32
                                                                                Nasal cavity:
                                                                                • carcinoma : 0/50, 0/50, 6/50 (p=0.013)
                                                                                • carcinoma or adenoma: 0/50, 0/50, 8/50 (p=0.003)
                                                                                • adenomatous polyp or adenoma: 0/50, 0/50, 5/50 (p=0.028)
                                                                                Circulatory system: hemangioma: 0/50, 1/50, 4/50 (significant
                                                                                positive trend)
Short-term lung tumour       Inhalation exposure (whole body), 6 hr/day, 5      Survival: decreased survival at 20 and 50 ppm in study 1 (number     Klimisch score: 3
bioassay                     days/wk                                            of survivors 30/30 control, 11/30 in both exposed groups)            Supportive study
female A/J mice              Purity: 98-99%                                     Adverse effects: alveolar epithelial hyperplasia (frequently located Deficiencies: only one sex used, individual animal data
Control and exposed groups:  Target concentrations: 20 and 50 ppm (154 and      parabronchiolar; not seen in controls), multifocal hyperplasia and   not reported, limited information on non-cancer effects,
30 (study 1) or              385 mg/m3, actual concentrations not reported)     cellular atypia of bronchiolar epithelium, chronic inflammation      exposure period too short, tumour detection limited to
60 (study 2) mice/group      Xpo=Xpe=6 months                                   (mononuclear cells in bronchiolar lamina propria)                    grossly visible lung tumours
(Adkins et al. (1986)40)     Effect parameter:                                  Tumours:
                             Number of lung adenomas observed at necropsy       % of mice with lung adenoma at 0, 20 and 50 ppm, resp:
                             Statistical analysis: Kruskal-Wallis analysis of   Study 1: 51, 100, 100
                             variance followed by Duncan’s new multiple-        Study 2: 26, 68, 100
                             range test for comparison with control             Mean no. of lung adenoma/mouse
                                                                                ±SD at 0, 20 and 50 ppm, resp:
                                                                                Study 1: 0.97±1.07, 6.51±3.67, 17.0±4.09
                                                                                Study 2: 0.31±0.54, 1.28±1.18, 15.3±5.01 (p<0.05 at both
                                                                                concentrations in both studies)
B6C3F1 mice                  Inhalation exposure                                Survival: not reported                                               Klimisch score: 3
 Control and exposed groups: (whole body), 6 hr/day, 5 days/wk                  Adverse effects: in nasal cavity:                                    Supportive study
50 mice/sex/ group (Stinson  Target concentrations: 10 and 40 ppm (77 and       focal epithelial hyperplasia in 2-6% low-dose mice and ca. 20%       Deficiencies: tumour detection limited to nasal cavity, no
et al. (1981)18)             308 mg/m3, actual concentrations were kept         high-dose mice.                                                      information on non-cancer endpoints (except for
                             within 10% of target)                              Tumours: in nasal cavity,                                            non-neoplastic lesions in nasal cavity), individual animal
                             Purity: 99.3%                                      at 0, 10 and 40 ppm resp.                                            data not reported, no statistical analysis
                             Xpo = 90 (high), 103 (low) or 104 (control) weeks  (m / f = males / females)
                             Xpe = 91 (high), 104 (low, control) weeks          Benign neoplasms:
                             Histopathological examination limited to the nasal • squamous papilloma: m 0/45, 0/44, 3/46; f 0/50, 0/49, 7/49
                             cavity.                                            • adenoma: m none; f 0/50, 0/49, 2/49
                             Statistical analysis:                              Carcinoma:
                             not performed                                      • squamous carcinoma: m none; f 0/50, 0/49, 2/49
                                                                                • adenocarcinoma: m none; f 0/50, 0/49, 2/49
                                                                                • mixed carcinoma: m none; f 0/50, 0/49, 3/49
                                                                                Sarcoma:
                                                                                • hemangiosarcoma: m none; f 0/50, 0/49, 2/49
                                                                                • poorly differentiated: m none; f 0/50, 1/49, 0/49
          Health Council of the Netherlands | No. 2017/22
</pre>

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

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

<pre>                                                                                                                                                               1,2-Dibromoethane | page 21 of 32
Sprague-Dawley rats male/      Inhalation exposure                               Survival: decreased in exposed rats; ca. 90% of controls and 10% / Klimisch score: 3
female                         (whole body), 7 hr/day, 5 days/wk                 23% (male/female) exposed rats alive at 18 months                  Supportive study
Control and exposed groups:    Purity: 99%                                       Adverse effects: reduced weight gain (food intake was not          Deficiencies: only one concentration tested, individual
48 rats/sex/Group (Wong et al. Target concentration: 20 ppm (154 mg/m3, actual   affected), spleen atrophy (males only),                            animal data not reported, high mortality in exposed rats,
(1982)19)                      18.6±3.1 ppm)                                     Tumours:                                                           exposure period less than life-span, in case of different
                               Xpo=Xpe=18 months                                 at 0 and 20 ppm resp.                                              types of tumours in the same organ only combined
                               Statistical analysis tumour incidences: Fisher’s  (m / f = males / females)                                          incidence is reported, nasal cavity not examined
                               exact test                                        Spleen:
                                                                                 • hemangiosarcoma: m 0/48, 10/46 (p<0.05); f 0/48, 6/48 (p<0.05)
                                                                                 Adrenal:
                                                                                 • pheochromocytoma, cortical adenoma or carcinoma: m 2/48,
                                                                                   11/46 (p<0.05); f 1/48, 6/48 (p<0.05)
                                                                                 Subcutaneous:
                                                                                 • mesenchymal tumour: m 3/48, 11/46 (p<0.05); f 0/48, 1/48
                                                                                 Mammary gland:
                                                                                 • adenoma, fibroadenoma, carcinoma, adenocarcinoma: f 2/48,
                                                                                   25/48 (p<0.05)
                                                                                 Number of rats with tumour:
                                                                                 m 8/48, 25/46 (p<0.05); f 7/48, 29/48 (p<0.05)
Oral and intraperitoneal exposure
B6C3F1 mice                    Drinking water Exposure level: 2 mM (0.375 g/L)   Survival: decreased survival in exposed group                      Klimisch score: 3
Male/female                    in drinking water, equivalent to a mean substance Adverse effects: decreased water consumption and body weight       Supportive study
exposed: 50/sex                intake of ca. 50 mg/kg bw/day in both sexes       Tumours: in control and exposed resp.                              Deficiencies: no data on compound purity, only one dose
control:100/sex                Xpo=control 24 months, exposed 18 months          (m / f = males / females)                                          tested, exposure less than life-span, Xpe and Xpo for
(Van Duuren et al. (1986)22)   Xpe=Xpo                                           Forestomach:                                                       exposed mice shorter than for controls, individual animal
                               Statistical analysis tumour incidences:           • squamous cell carcinomas: m 2/99, 41/48 (p<0.0005); f 0/96,      data not reported, limited information on non-cancer
                               chi-square analysis                                 20/49 (p<0.0005)                                                 effects, no adjustment for intergroup differences in
                                                                                 • papillomas: m 5/99, 6/48; f 9/96, 29/49 (p<0.0005)               survival in statistical analysis of tumour data
                                                                                 Oesophagus:
                                                                                 • squamous cell carcinomas: m 0/99, 4/48(p<0.01); none in
                                                                                   females
                                                                                 • papillomas: m 0/99, 4/48 (p<0.01); f 0/96, 4/49
                                                                                 Tongue:
                                                                                 • squamous carcinoma in situ: f 0/96, 1/49 ; none in males
B6C3F1 mice                    Drinking water                                    Survival: exposed mice were killed before scheduled termination    Klimisch score: 3
Male/female                    Purity >99%                                       because of morbidity from stomach tumours                          Supportive study
exposed: 30/sex                Exposure level: 4 mM in drinking water,           Median survival time was 389/465 days in males and females resp.   Deficiencies: only one dose tested, exposure less than
control: 50/sex (van Duuren    equivalent to a mean substance intake of 103      Survival controls: ca. 70% at 18 months                            life-span, Xpe and Xpo for exposed mice shorter than for
et al. (1985)23)               and 116 mg/kg bw/day in males and females         Adverse effects: water consumption decreased by 34% / 25%          controls, low number of exposed animals, individual
                               resp.                                             (males/ females); body weight 10-20% lower than control from ca. 9 animal data not reported, limited number of organs
                               Xpo=control 18 months, exposed ca. 13 (males) or  months                                                             examined, limited information on non-cancer effects, no
                               15 (females) months                               Tumours: in control and exposed resp.                              adjustment for intergroup differences in survival in
          Health Council of the Netherlands | No. 2017/22
</pre>

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

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

<pre>                                                                                                                                                                 1,2-Dibromoethane | page 22 of 32
                            Xpe=Xpo                                            (m / f = males / females)                                             statistical analysis of tumour data
                            Histopathological examination limited to lung,     Forestomach:
                            liver, kidneys, stomach and gross lesions          • squamous cell carcinomas: m 0/45, 26/28 (p<0.005); f 0/50,
                            Statistical analysis tumour incidences:              22/29 (p<0.005)
                            chi-square analysis                                • papillomas: m 1/45, 0/28); f 1/50, 5/29
                                                                               Glandular stomach:
                                                                               • quamous cell carcinomas: m 0/45, 8/28 (p<0.005); none in
                                                                                 females
                                                                               Oesophagus:
                                                                               • papillomas: f 0/50, 3/29 (p<0.0005), none in males
Osborne-Mendal rats         Oral gavage,                                       Survival: dose related decrease in survival of both sexes. Treated    Klimisch score: 3
Exposed:                    5 days/week                                        rats terminated in week 49 (males) and 61 (females) due to poor       Supportive study
50 rats/sex/dose            Purity: ≥99%                                       survival associated with early onset of stomach cancer                Deficiencies: early termination because of high mortality,
Vehicle control:            Vehicle: corn oil                                  Adverse effects: reduced body weight from wk 10 in all dosed          doses changed and discontinued during study, dose per
20/sex                      Doses: TWA (mg/kg body weight/day):                groups; reddened ears, hunched appearance, firm distended             animal based on group mean instead of individual
Untreated control:          • male: 38, 41                                     abdomen, abdominal urine stains; acanthosis and hyperkeratosis in     animal body weight, individual animal data not reported,
20/sex (started 15 wk later • female: 37, 39                                   forestomach, degenerative changes in liver and adrenals, testicular   animals housed in room with animals treated with other
than vehicle and dosed      Initial doses were 40 and 80 mg; high              atrophy                                                               halogenated hydrocarbons
groups) (NCI (1978)20)      discontinued ≥wk 17 and reduced to 40 ≥wk 30;      Tumours: In vehicle control, low- and high-dose, resp
                            low & high not dosed in wk 42                      (m / f = males / females)
                            Xpo dosed and vehicle control = 48/60 wk           Forestomach: quamous cell carcinoma: m 0/20, 45/50 (p<0.001),
                            (males/females)                                    33/50 (p<0.001); f 0/20, 40/50 (p<0.001), 29/50 (p<0.001)
                            Xpe dosed = 49/61 wk (males/females)               Hemangiosarcoma (circulatory system): m 0/20, 11/50 (p=0.017),
                            Xpe vehicle control = 63 wk                        4/50; f 0/20,1/49, 3/48
                            Untreated controls: 5/sex killed wk 59, remaining  Liver:
                            wk 107                                             • hepatocellular carcinoma: m 0/20, 1/50, 1/50; f 0/20, 1/47, 5/48
                            Statistical analysis tumour incidences: (time-       (p<0.05 time-adjusted Fisher)
                            adjusted) one- tailed Fisher exact test to compare • neoplastic nodules: m 0/20, 2/50, 1/50; f 0/20, 0/47, 1/48
                            dosed groups with control; (time-adjusted)         Thyroid follicular-cell adenoma or carcinoma: m 0/20, 5/50, 8/49
                            Cochran-Armitage test for linear trend;            (p<0.05 trend); no increase in females
                            approximate 95% confidence interval for relative
                            risk of each dosed group compared with its
                            control
B6C3F1 mice                 Oral gavage,                                       Survival: dose related decrease in survival of both sexes, leading to Klimisch score: 3
Exposed:                    5 days/week                                        termination before scheduled termination in wk 90. Vehicle controls   Supportive study
50 mice/sex/dose            Purity: ≥99%                                       were terminated before wk 90 because they approached moribund         Deficiencies: early termination because of high mortality,
Vehicle control:            Vehicle: corn oil                                  state                                                                 doses changed during the study, dose per animal based
20/sex                      Doses: TWA (mg/kg body weight/day):                Adverse effects: reduced body weight from wk 10 in all dosed          on group mean instead of individual animal body weight,
Untreated control:          62, 107                                            groups; alopecia, body sores, soft faeces at low and high dose, thin  individual animal data not reported, animals housed in
20/sex(1978)20)             Initial doses were 60 and 120 mg; increased to     and hunched appearance at high dose; acanthosis and hyper-            room with animals treated with other halogenated
                            100 and 200 wk11-12, next 60, 120; high reduced    keratosis in forestomach mainly at high-dose                          hydrocarbons
         Health Council of the Netherlands | No. 2017/22
</pre>

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

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

<pre>                                                                                                                                                                                    1,2-Dibromoethane | page 23 of 32
                                      to 60 ≥wk 40; ≥wk 54 vehicle, low and high no              Tumours: In untreated, vehicle control, low- and high-dose, resp.
                                      longer gavaged                                             (m / f = males / females)
                                      Xpo=53 wk                                                  Forestomach: squamous cell carcinoma: m 0/20, 0/20, 45/50
                                      Xpe=59-60 wk (vehicle control),                            (p<0.001), 29/49 (p<0.001); f 0/20, 0/20, 46/49(p<0.001), 28/50
                                      78 wk (untreated controls, low and high males,             (p<0.001)
                                      high females),                                             Lung: alveolar/bronchiolar adenomas: m 0/18, 0/20, 4/45, 10/47
                                      90 wk (low females)                                        (p=0.029); f 0/20, 0/20, 10/43 (p=0.015), 6/46
                                      Statistical analysis tumour incidences: (time-
                                      adjusted) one- tailed Fisher exact test to compare
                                      dosed groups with control; (time-adjusted)
                                      Cochran-Armitage test for linear trend;
                                      approximate 95% confidence interval for relative
                                      risk of each dosed group compa-red with its
                                      control
 A/J mice                             Intraperitoneal (ip) injection or oral gavage, 3           Survival: all animals survived                                          Klimisch score: 3
 exposed:                             times/wk for 8 weeks                                       Adverse effects: not reported                                           Supportive study
 16/sex/dose/route                    Purity: reagent grade                                      Tumours: treatment-related increase observed only in ip-treated         Deficiencies: only one dose tested orally, exposure and
 vehicle control:                     Vehicle (both routes): glycerol trioctanoate, 0.1          females at highest dose;                                                observation period too short, individual animal data not
 16/sex                               ml/mouse                                                   % of mice with lung adenoma:                                            reported, no information on non-cancer effects,
 untreated control:                   Doses (total, mg/kg):                                      Intraperitoneal injection:                                              histopathology limited to randomly selected lung
 136 males,                           Ip: 168, 420, 840 (= 0.2, 0.5 and 1 x MTD)                 untreated, vehicle, 168, 420, 840 mg/kg resp.                           nodules, liver and gross lesions in other organs
 131 females (Stoner et al.           Oral: 840 mg/kg                                            (m / f = male / female)
 (1986)43)                            (=1xMTD)                                                   m 38, 30,14, 20, 44;f 25, 30, 24, 56, 88 (p<0.001)
                                      Xpo=8 weeks                                                Oral:
                                      Xpe=24weeks                                                untreated, vehicle, 840 mg/kg resp
                                      Statistical analysis: Wilcoxon nonpara-metric rank         m 38, 20, 44; f 25, 14, 31
                                      test for pairwise comparisons; Jonckheere
                                      non-parametric trend test
 Dermal exposure
 Ha:ICR Swiss mice                    Dermal exposure, 3 applications/week in 0.2 ml             Survival: not specified per substance (median ranged from 317           Klimisch score: 3
 Vehicle control and exposed:         acetone                                                    days to >589 days).                                                     Supportive study
 30 females/ group (Van               Purity: determined but not reported                        Adverse effects: not reported                                           Deficiencies: only sex used, small number of animals
 Duuren et al. (1977)44               Doses: 25 and 50 mg/application/mouse                      Tumours:                                                                used, duration of exposure and observation period not
                                      Xpo and Xpe not specified per substance (range             vehicle control, 25, 50 mg, resp:                                       specified and probably too short, individual animal data
                                      440-594 days)                                              Skin (application site)                                                 not reported, no information on non-cancer effects,
                                      Statistical analysis: Chi-square analysis                  • papilloma: 0/30, 2/30, 8/30 (p<0.001)                                 histopathology limited to gross lesions, skin, liver,
                                                                                                 • squamous cell carcinoma: 0/30, 2/30, 3/30                             stomach and kidney, no information on prevention of oral
                                                                                                 Lung: benign papillomas:                                                exposure
                                                                                                 11/30, 24/30 (p<0.005), 26/30 (p<0.0005)
                                                                                                 Forestomach:
                                                                                                 • papillomas: 2/30, 3/30, 3/30
                                                                                                 • squamous cell carcinoma: in 1/3 low-dose mice with papillomas
Xpo = duration of exposure; Xpe = duration of the experiment; SD = standard deviation; ip = intraperitoneal, TWA = time-weighted average, MTD = maximum tolerated dose. Klimisch scores were based on Klimisch et al.46
           Health Council of the Netherlands | No. 2017/22
</pre>

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

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

<pre>                                                                                                                      1,2-Dibromoethane | page 24 of 32
Stinson et al. (1981) exposed B6C3F1 mice by inhalation to 10 or 40 ppm    authors). In both studies 1,2-dibromoethane induced squamous cell
(77 or 308 mg/m3) of 1,2-dibromoethane (for 90 and 103 weeks,              carcinomas in the forestomach in both sexes. Squamous cell carcinomas
respectively) to examine the characteristics of chemical-induced           were also induced in the glandular stomach at 4mM and in the
proliferative lesions in the nasal cavity.18 Hence, histopathological      oesophagus at 2 mM, though at lower incidences than in the forestomach.
examination was limited to the nasal cavity. Exposure to 1,2-dibromoethane Further, the incidences of papillomas in the forestomach and oesophagus
was associated with a broad spectrum of proliferative lesions, including   were increased in exposed mice.
carcinomas (in high-dose females only), benign neoplasms, focal epithelial In a bioassay performed by the National Cancer Institute (NCI) the
hyperplasia, and hemangiosarcomas.                                         carcinogenicity of 1,2-dibromoethane upon oral administration (by gavage)
In a chronic inhalation study performed by Wong et al. (1982) Sprague-     was examined in Osborne-Mendal rats (time-weighted average (TWA)
Dawley rats exposed to 20 ppm (154 mg/m3) of 1,2-dibromoethane for 18      dose: about 40 mg/kg body weight/day in each of two treated groups) and
months developed tumours in the spleen (hemangiosarcoma), adrenals         B6C3F1 mice (TWA 62 and 107 mg/kg body weight/day).20,41,42 In both
(pheochromocytoma, cortical adenoma or carcinoma), subcutaneous tissue     species treatment was terminated after about one year because of high
or mammary gland (adenoma, fibroadenoma, carcinoma,                        mortality which was associated with the early onset of stomach cancer.
adenocarcinoma).19                                                         Most of the treated rats and mice developed squamous cell carcinomas in
                                                                           the forestomach. In addition, rats showed treatment-related increases in
Oral and intraperitoneal exposure                                          the incidences of hemangiosarcoma of the circulatory system (males),
Van Duuren and colleagues used 1,2-dibromoethane as positive control       hepatocellular carcinomas (females) and thyroid follicular-cell adenomas
substance in carcinogenicity studies in B6C3F1 mice.22,23 The mice         or carcinomas (males), and mice showed a treatment-related increase in
received 1,2-dibromoethane via the drinking water, at concentrations of 2  lung alveolar/bronchiolar adenomas.
mM or 4 mM until sacrifice at 13-18 months (controls were terminated at    Stoner et al. (1986) used 1,2-dibromoethane as a model compound to
24 months). These concentrations in drinking water provided daily doses    examine carcinogens representing different chemical classes for their
of about 50 mg/kg body weight (2 mM, calculated by the Committee from      ability to induce lung tumours in strain A/J mice following administration by
the daily substance intake and the average body weight data reported by    oral gavage (840 mg/kg) or intraperitoneal injection (168, 420, 840 mg/kg)
the authors) and 100 mg/kg body weight (4 mM, calculated by the            for 8 weeks (3 doses/week).43 A significant increase in lung tumours
        Health Council of the Netherlands | No. 2017/22
</pre>

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

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

<pre>                                                                                                                           1,2-Dibromoethane | page 25 of 32
(adenomas) was observed only in intraperitoneally treated females at 840      available to the Committee. Therefore, the Committee used the
mg/kg.                                                                        carcinogenicity data summarized by Gold et al. (1984)45, i.e. the total
                                                                              number of animals with tumours. Combining numbers of tumours of
Dermal exposure                                                               different origin is not preferred by the Committee, as the mechanisms of
Van Duuren treated female Ha:ICR Swiss mice with thrice-weekly skin           tumourigenesis may not be comparable. Since the NTP report is now
applications of 1,2-dibromoethane (25 or 50 mg per animal) for at least       available, the Committee can derive cancer risk values based on specific
440 days.44 Upon dermal exposure 1,2-dibromoethane caused a                   types of tumours.
significant increase in the incidence of benign papillomas in the lung at     The Committee considers the tumours in the nose of the rat most critical.
both dose levels. In addition, the incidences of papilloma and, to a lesser   In this case, the Committee combined the numbers of benign and
extent, squamous cell carcinoma in the skin (application site) were           malignant nasal tumours (adenomatous polyp, adenoma,
increased.                                                                    adenocarcinoma, carcinoma, squamous-cell carcinoma, papillary
                                                                              adenoma and squamous cell papilloma) as basis for cancer risk
3.3 Selection of the suitable study for risk estimation in the                derivation, because the simultaneous occurrence suggests that benign
      occupational situation                                                  nasal tumours can develop into the malignant type. The combined number
The Committee considers the epidemiological studies on                        of nasal tumours has the highest incidence, and is dose-dependently and
1,2-dibromoethane exposure and cancer not suitable for risk calculation.      statistically significantly increased at the lowest exposure concentration
In 1999, the Committee considered the NTP rat carcinogenicity study17 to      tested (10 ppm, 77 mg/m3). The incidences of tumours at other sites than
be the most suitable study for the estimation of the potential cancer risk in the nose were increased to a lesser extent. The same is true for the
humans under occupational exposure conditions. In this evaluation, the        treatment-related tumours observed at 10 ppm (77 mg/m3) in NTP’s
Committee reaches the same conclusion. The study is well performed, the       inhalation carcinogenicity study in mice.
exposure route (inhalation) is appropriate, the exposure period covered
the largest part of the standard lifespan of the experimental animals, and
group sizes are adequate.
In the previous report, it was stated that the NTP study report was not
        Health Council of the Netherlands | No. 2017/22
</pre>

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

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

<pre>                                                                                                                                 1,2-Dibromoethane | page 26 of 32
3.4 Calculation of the health-based occupational cancer risk                  The incidence per unit concentration in air (mg/m3) (lifespan conditions
      values                                                                  assuming a linear concentration-response relationship) is calculated as
                                                                              follows:
3.4.1 Carcinogenic activity in experimental animals, lifetime
                                                                              							                                    Ie - Ic
       exposure                                                               Iconcentration=
                                                                              				                 Xpo × Xpe exposure hours per day exposure days per week
                                                                              			             C×             ×				                 ×
To calculate the carcinogenic activity expressed as the incidence per unit    				                  L      L		        24				                  7
air concentration (mg/m3) of 1,2-dibromoethane, the number of male rats
                                                                                                     39    0
                                                                              				                      -
which developed nasal cavity tumours upon exposure to the lowest              				                   50 50			                        mg
                                                                                     =                              = 10.8 ×10-2 per
concentration (10 ppm, i.e. 77 mg/m3) tested in the carcinogenicity study     				               721 728 6 5			                      m3
                                                                              		           77 ×       ×       ×
performed by NTP was used as a starting point. In this study, male and                 		       1000 1000 24 7
female rats were exposed to the same concentrations. Since the highest
incidence of nasal cavity tumours was observed in male rats (the              Where:
incidence in female rats was only slightly lower), the incidence in male rats Iconcentration = the carcinogenic activity attributable to the exposure to the
was used to derive the cancer risk levels.                                    substance per unit daily concentration in air expressed per mg/m3
For the calculation of the occupational cancer risk values, the Committee     Ie and Ic = incidence of tumour bearing animals in exposed and control
prefers to use the benchmark dose method. Though two doses have been          animals, respectively.
tested (77 and 308 mg/m3) in the NTP rat study, the highest dose              C = concentration at which animals were exposed expressed in mg/m3.
exceeded the maximum tolerated dose. The significantly shortened              Xpo and Xpe are the exposure and experimental periods, respectively.
survival in the highest dose group may have curtailed the number of           L = standard lifespan for the animals in question (L rat is assumed to be
tumours in this group. Therefore, the Committee considers only the            1,000 days).
low-dose data from the NTP rat study adequate, and therefore, the
benchmark dose method cannot be applied.                                      3.4.2 Health risk to humans, exposure under occupational
                                                                                           conditions
                                                                              For the calculation of cancer risk values on the basis of results from
       Health Council of the Netherlands | No. 2017/22
</pre>

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

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

<pre>                                                                                                                          1,2-Dibromoethane | page 27 of 32
animal experiments, the Committee does not apply default assessment            The Committee notes that these values are (rounded off) equal to the
factors (e.g. for differences between experimental animals and man with        cancer risk values calculated by the Committee in 1999.2 Based on the
respect to toxicokinetics, mechanism of tumour induction, target,              toxicity data as summarized in this report, the Committee concludes that
susceptibility). Furthermore, it is assumed that the average man lives 75      no adverse effects other than carcinogenicity are expected at these
years, is exposed 24 hours per day, 7 days per week, 52 weeks per year         concentrations.
for lifetime and inhales 18 m3 air per 24 hours. To estimate the additional
lifetime risk of cancer in humans under workplace conditions it is further
assumed that the average worker is exposed 8 hours per day, 5 days per         04 skin notation
week, 48 weeks per year for 40 years and inhales 10 m3 air per 8-hour-
working day.                                                                   Experimental animal data indicate that 1,2-dibromoethane is absorbed
Using as starting point the estimated incidence of 10.8 x 10-2 per mg/m3,      through the skin. In rats, mortality occurred following a single application
the additional life-time cancer risk per mg/m3 under occupational exposure     (see Section 2.3.2) and lung tumours were observed following repeated
conditions (= HBC-OCRV) amounts to:                                            administration (see Section 3.2). Further, the substance was absorbed
                                                                               rapidly through the skin of guinea pigs as demonstrated by the rapidly
						                      40y 48w 5d 10m3
HBC - OCRV = 10.8 × 10 ×         ×          ×       ×
                         -2
                                                         = 2.1 x10-2 per mg/m3 increasing blood levels of the substance following dermal exposure.3
						                      75y 52w 7d 18m3
                                                                               Based on the mortality in rats following a single dermal application, the
3.4.3 Occupational cancer risk values                                          SCOEL concluded that a skin notation appears justified.
Based on the HBC-OCRV of 2.1 x 10-2 per mg/m3, the Committee                   The Committee considers a skin notation warranted when exposure of
estimated that the concentration of 1,2-dibromoethane in the air, which        2,000 cm2 of skin (both hands and forearms) to the substance during one
corresponds to an excess cancer risk of:                                       hour could result in an absorbed amount exceeding 10% of the amount
• 4 per 1,000 (4x10-3), for 40 years of occupational exposure, equals to       that can be absorbed via the lungs on exposure for eight hours to the
    0.2 mg/m3                                                                  occupational exposure limit (HBC-OCRV).
• 4 per 100,000 (4x10-5), for 40 years of occupational exposure, equals to     For an HBC-OCRV of 0.2 mg/m3 (see Section 3.4), the estimated systemic
    0.002 mg/m3.                                                               exposure on a 8-h working day is 2 mg (0.2 mg/m3 x 10 m3; assuming
         Health Council of the Netherlands | No. 2017/22
</pre>

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

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

<pre>                                                                                                                       1,2-Dibromoethane | page 28 of 32
100% retention in the lungs (worst-case scenario)). Calculations with       7
                                                                               NTP (National Toxicology Program). 2016. Report on Carcinogens,
Skinperm (AIHA version 130), applying a single dermal exposure of 50           Fourteenth Edition. Research Triangle Park, NC: U.S. Department of
mg, result in an estimated uptake of 0.82 mg. This uptake far exceeds an       Health and Human Services, Public Health Service.
amount 10% of the systemic exposure at a level of the HBC-OCRV.             8
                                                                               European Chemicals Agency (ECHA). Summary of Classification and
Therefore, the Committee concludes that a skin notation is warranted for       Labelling. https://echa.europa.eu/nl/information-on-chemicals/
1,2-dibromoethane.                                                             cl-inventory-database/-/discli/details/111405. Consulted: February 5th,
                                                                               2017.
         references                                                            Letz GA, Pond SM, Osterloh JD, Wade RL, Becker CE. Two fatalities
                                                                            9
                                                                               after acute occupational exposure to ethylene dibromide. JAMA 1984;
1
   Health Council of the Netherlands. Guideline for the calculation of risk    252(17): 2428-31.
   values for carcinogenic compounds. The Hague, 2012; publication no.      10
                                                                               Saraswat PK, Kandara M, Dhruva AK, Malhotra VK, Jhanwar RS.
   2012/16E.                                                                   Poisoning by ethylene di-bromide-six cases: a clinicopathological and
2
   Health Council of the Netherlands. 1,2-Dibromoethane. The Hague,            toxicological study. Indian journal of medical sciences 1986; 40(5):
   1999; publication no. 1999/07OSH.                                           121-3.
3
   Agency for Toxic Substances Disease Registry. Toxicological profile for  11
                                                                               Olmstead EV. Pathological changes in ethylene dibromide poisoning.
   1,2-dibromoethane. 1992.                                                    AMAarchives of industrial health 1960; 21: 525-9.
4
   IARC. Monographs on the evaluation of the carcinogenic risk of           12
                                                                               Singh S, Chaudhry D, Garg M, Sharma BK. Fatal ethylene dibromide
   chemicals to humans: Ethylene dibromide (1,2-dibromoethane). Lyon,          ingestion. The Journal of the Association of Physicians of India 1993;
   1999.                                                                       41(9): 608.
5
   U.S. EPA. Toxicological review of 1,2-dibromoethane. Washington DC,      13
                                                                               Singh N, Jatav OP, Gupta RK, Tailor MK, Jain R. Outcome of sixty four
   2004.                                                                       cases of ethylene dibromide ingestion treated in tertiary care hospital.
6
   European Commission. Recommendation from the Scientific                     The Journal of the Association of Physicians of India 2007; 55: 842-5.
   Committee on Occupational Exposure Limits for 1,2-dibromoethane          14
                                                                               Wong O, Utidjian HM, Karten VS. Retrospective evaluation of
   (ethylene dibromide). 2011.                                                 reproductive performance of workers exposed to ethylene dibromide
       Health Council of the Netherlands | No. 2017/22
</pre>

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

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

<pre>                                                                                                                      1,2-Dibromoethane | page 29 of 32
   (EDB). Journal of occupational medicine: official publication of the       health perspectives 1986; 69: 109-17.
   Industrial Medical Association 1979; 21(2): 98-102.                     23
                                                                              Duuren BL van, Seidman I, Melchionne S, Kline SA. Carcinogenicity
15
   Ratcliffe JM, Schrader SM, Steenland K, Clapp DE, Turner T, Hornung        bioassays of bromoacetaldehyde and bromoethanol--potential
   RW. Semen quality in papaya workers with long term exposure to             metabolites of dibromoethane. Teratogenesis, carcinogenesis, and
   ethylene dibromide. British journal of industrial medicine 1987; 44(5):    mutagenesis 1985; 5(6): 393-403.
   317-26.                                                                 24
                                                                              Nitschke KD, Kociba RJ, Keyes DG, McKenna MJ. A thirteen week
16
   Schrader SM, Turner TW, Ratcliffe JM. The effects of ethylene              repeated inhalation study of ethylene dibromide in rats. Fundamental
   dibromide on semen quality: a comparison of short-term and chronic         and applied toxicology, 1981; 1(6): 437-42.
   exposure. Reproductive toxicology (Elmsford, NY) 1988; 2(3-4): 191-8.   25
                                                                              Reznik G, Stinson SF, Ward JM. Respiratory pathology in rats and mice
17
   National Toxicology Program. Carcinogenesis bioassay of                    after inhalation of 1,2-dibromo-3-chloropropane or 1,2 dibromoethane
   1,2-dibromoethande (CAS no. 106-93-4) in F344 rats B6C3F1 mice             for 13 weeks. Archives of Toxicology 1980; 46(3-4): 233-40.
   (inhalation study). 1982; Technical Report Series, No. 210.             26
                                                                              Ratajczak HV, Aranyi C, Bradof JN, Barbera P, Fugmann R, Fenters
18
   Stinson SF, Reznik G, Ward JM. Characteristics of proliferative lesions    JD, et al. Ethylene dibromide: evidence of systemic and immunologic
   in the nasal cavities of mice following chronic inhalation of              toxicity without impairment of in vivo host defenses. In vivo (Athens,
   1,2-dibromoethane. Cancer letters 1981; 12(1-2): 121-9.                    Greece) 1994; 8(5): 879-84.
19
   Wong LC, Winston JM, Hong CB, Plotnick H. Carcinogenicity and           27
                                                                              Ghanayem BI, Maronpot RR, Matthews HB. Association of chemically
   toxicity of 1,2-dibromoethane in the rat. Toxicology and applied           induced forestomach cell proliferation and carcinogenesis. Cancer
   pharmacology 1982; 63(2): 155-65.                                          letters 1986; 32(3): 271-8.
20
   National Cancer Institute. Bioassay of 1,2-dibromoethane for possible   28
                                                                              Kluwe WM, McNish R, Hook JB. Acute nephrotoxicities and
   carcinogenicity, CAS no. 106-93-4. 1978.                                   hepatotoxicities of 1,2-dibromo-3-chloropropane and
21
   Weisburger EK. Carcinogenicity studies on halogenated hydrocarbons.        1,2-dibromoethane in male and female F344 rats. Toxicology letters
   Environmental health perspectives 1977; 21: 7-16.                          1981; 8(6): 317-21.
22
   Duuren BL van, Melchionne S, Seidman I, Pereira MA. Chronic             29
                                                                              Short RD, Minor JL, Winston JM, Seifter J, Lee CC. Inhalation of
   bioassays of chlorinated humic acids in B6C3F1 mice. Environmental         ethylene dibromide during gestation by rats and mice. Toxicology and
        Health Council of the Netherlands | No. 2017/22
</pre>

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

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

<pre>                                                                                                                          1,2-Dibromoethane | page 30 of 32
   applied pharmacology 1978; 46(1): 173-82.                                   36
                                                                                  Alavanja MC, Blair A, Masters MN. Cancer mortality in the U.S. flour
30
   Williams J, Gladen BC, Turner TW, Schrader SM, Chapin RE. The                  industry. Journal of the National Cancer Institute 1990; 82(10): 840-8.
   effects of ethylene dibromide on semen quality and fertility in the rabbit: 37
                                                                                  Sweeney MH, Beaumont JJ, Waxweiler RJ, Halperin WE. An
   evaluation of a model for human seminal characteristics. Fundamental           investigation of mortality from cancer and other causes of death among
   and applied toxicology, 1991; 16(4): 687-700.                                  workers employed at an east Texas chemical plant. Archives of
31
   Ratajczak HV, Thomas PT, Gerhart J, Sothern RB. Immunotoxicologic              Environmental Health 1986; 41(1): 23-8.
   effects of ethylene dibromide in the mouse and their modulation by the      38
                                                                                  Ott MG, Scharnweber HC, Langner RR. Mortality experience of 161
   estrous cycle. In vivo, 1995; 9(4): 299-304.                                   employees exposed to ethylene dibromide in two production units.
32
   Fanini D, Legator MS, Adams PM. Effects of paternal ethylene                   British journal of industrial medicine 1980; 37(2): 163-8.
   dibromide exposure on F1 generation behavior in the rat. Mutation           39
                                                                                  Turner D, Barry PSI. An epidemiological study of workers in plants
   research 1984; 139(3): 133-8.                                                  manufacturing ethylene dibromide. Arhhigrada toksikol 1979; 30: 621-6.
33
   Cho SH, Guengerich FP. In vivo roles of conjugation with glutathione        40
                                                                                  Adkins B, Jr., Van Stee EW, Simmons JE, Eustis SL. Oncogenic
   and O6-alkylguanine DNA-alkyltransferase in the mutagenicity of the            response of strain A/J mice to inhaled chemicals. Journal of
   bis-electrophiles 1,2-dibromoethane and 1,2,3,4-diepoxybutane in               toxicology and environmental health 1986; 17(2-3): 311-22.
   mice. Chem Res Toxicol 2013; 26(11): 1765-74.                               41
                                                                                  Chu KC, Milman HA. Review of experimental carcinogenesis by
34
   Takasawa H, Takashima R, Narumi K, Kawasako K, Hattori A,                      compounds related to vinyl chloride. Environmental health perspectives
   Kawabata M, et al. Results of the International Validation of the in vivo      1981; 41: 211-20.
   rodent alkaline comet assay for the detection of genotoxic carcinogens:     42
                                                                                  Olson WA, Habermann RT, Weisburger EK, Ward JM, Weisburger JH.
   Individual data for 1,2-dibromoethane, p-anisidine, and o-anthranilic          Induction of stomach cancer in rats and mice by halogenated aliphatic
   acid in the 2nd step of the 4th phase Validation Study under the               fumigants. Journal of the National Cancer Institute 1973; 51(6): 1993-5.
   JaCVAM initiative. Mutat Res Genet Toxicol Environ Mutagen 2015;            43
                                                                                  Stoner GD, Conran PB, Greisiger EA, Stober J, Morgan M, Pereira MA.
   786-788: 144-50.                                                               Comparison of two routes of chemical administration on the lung
35
   Werkgroep van Deskundigen. Rapport inzake grenswaarde                          adenoma response in strain A/J mice. Toxicology and applied
   dibroomethaan. Ministerie SZW, 1987;  rapportnummer RA 5/87.                   pharmacology 1986; 82(1): 19-31.
        Health Council of the Netherlands | No. 2017/22
</pre>

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

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

<pre>                                                                             1,2-Dibromoethane | page 31 of 32
44
   Duuren BL van, Goldschmidt BM, Loewengart G, Smith AC,
   Melchionne S, Seldman I, et al. Carcinogenicity of halogenated olefinic
   and aliphatic hydrocarbons in mice. Journal of the National Cancer
   Institute 1979; 63(6): 1433-9.
45
   Gold LS, Sawyer CB, Magaw R, Backman GM, de Veciana M,
   Levinson R, et al. A carcinogenic potency database of the standardized
   results of animal bioassays. Environ Health Perspect 1984; 58: 9-319.
46
   Klimisch HJ, Andreae M, Tillmann U. A systematic approach for
   evaluating the quality of experimental toxicological and ecotoxicological
   data. Regulatory toxicology and pharmacology, 1997; 25(1): 1-5.
        Health Council of the Netherlands | No. 2017/22
</pre>

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

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

<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 Economic Affairs and Climate Policy. 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 publication can be downloaded from www.healthcouncil.nl.
Preferred citation:
Health Council of the Netherlands. 1,2-Dibromoethane. The Hague: Health Council
of the Netherlands, 2017; publication no. 2017/22.
All rights reserved
          Health Council of the Netherlands | No. 2017/22
</pre>

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

<br><br>