<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>1,1,1-Trichloroethane
     Evaluation of the carcinogenicity and genotoxicity
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<pre></pre>

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<pre>Aan de staatssecretaris van Sociale zaken en Werkgelegenheid
Onderwerp                 : aanbieding advies 1,1,1-Trichloroethane
Uw kenmerk                : DGV/MBO/U-932342
Ons kenmerk               : U-7253/SV/fs/246-L16
Bijlagen                  :1
Datum                     : 24 juli 2012
Geachte staatssecretaris,
Graag bied ik u hierbij het advies aan over de gevolgen van beroepsmatige blootstelling aan
1,1,1-trichloorethaan.
Dit advies maakt deel uit van een uitgebreide reeks waarin kankerverwekkende stoffen
worden geclassificeerd volgens richtlijnen van de Europese Unie. Het gaat om stoffen
waaraan mensen tijdens de beroepsmatige uitoefening kunnen worden blootgesteld.
     Dit advies is opgesteld door een vaste subcommissie van de Commissie Gezondheid en
beroepsmatige blootstelling aan stoffen (GBBS), de Subcommissie Classificatie van
carcinogene stoffen. Het advies is getoetst door de Beraadsgroep Gezondheid en omgeving
van de Gezondheidsraad.
Ik heb het advies vandaag ter kennisname toegezonden aan de staatssecretaris van
Infrastructuur en Milieu en aan de minister van Volksgezondheid, Welzijn en Sport.
Met vriendelijke groet,
prof. dr. H. Obertop,
waarnemend voorzitter
Bezoekadres                                                         Postadres
Parnassusplein 5                                                    Postbus 16052
2 5 11 V X D e n          Haag                                      2500 BB Den            Haag
Te l e f o o n ( 0 7 0 ) 3 4 0 5 5 0 8                              Te l e f a x ( 0 7 0 ) 3 4 0 7 5 2 3
E - m a i l : s r. v i n k @ g r. n l                               w w w. g r. n l
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<pre></pre>

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<pre>1,1,1-Trichloroethane
Evaluation of the carcinogenicity and genotoxicity
Subcommittee on the Classification of Carcinogenic Substances of
the Dutch Expert Committee on Occupational Safety,
a Committee of the Health Council of the Netherlands
to:
the State Secretary of Social Affairs and Employment
No. 2012/12, The Hague, July 24, 2012
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<pre>The Health Council of the Netherlands, established in 1902, is an independent
scientific advisory body. Its remit is “to advise the government and Parliament on
the current level of knowledge with respect to public health issues and health
(services) research...” (Section 22, Health Act).
     The Health Council receives most requests for advice from the Ministers of
Health, Welfare & Sport, Infrastructure & the Environment, Social Affairs &
Employment, Economic Affairs, Agriculture & Innovation, and Education,
Culture & Science. The Council can publish advisory reports on its own
initiative. It usually does this in order to ask attention for developments or trends
that are thought to be relevant to government policy.
     Most Health Council reports are prepared by multidisciplinary committees of
Dutch or, sometimes, foreign experts, appointed in a personal capacity. The
reports are available to the public.
                  The Health Council of the Netherlands is a member of the European
                  Science Advisory Network for Health (EuSANH), a network of science
                  advisory bodies in Europe.
                  The Health Council of the Netherlands is a member of the International Network
                  of Agencies for Health Technology Assessment (INAHTA), an international
                  collaboration of organisations engaged with health technology assessment.
 I NA HTA
This report can be downloaded from www.healthcouncil.nl.
Preferred citation:
Health Council of the Netherlands. 1,1,1-Trichloroethane. Evaluation of the
carcinogenicity and genotoxicity. The Hague: Health Council of the Netherlands,
2012; publication no. 2012/12.
all rights reserved
ISBN: 978-90-5549-904-5
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<pre>   Contents
   Samenvatting 9
   Executive summary 11
   Scope 13
.1 Background 13
.2 Committee and procedure 13
.3 Data 14
   General information 15
.1 Identity and physicochemical properties 15
.2 IARC conclusion 16
   Carcinogenicity studies 17
.1 Observations in humans 17
.2 Carcinogenicity studies in animals 20
   Genotoxicity 23
.1 In vitro assays 23
.2 In vivo assays 25
.3 Carcinogenic mechanism of action 26
   Contents                                   7
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<pre>    Classification 27
 .1 Evaluation of data on carcinogenicity and genotoxicity 27
 .2 Recommendation for classification 28
    References 29
    Annexes 35
A   Request for advice 37
B   The Committee 39
C   Submission letter (in English) 41
D   Comments on the public review draft 43
E   IARC Monograph 45
F   Human studies 49
G   Animal studies 51
H   Genotoxicity data 53
    Carcinogenic classification of substances by the Committee 57
    1,1,1-Trichloroethane
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<pre>Samenvatting
Op verzoek van de minister van Sociale Zaken en Werkgelegenheid evalueert en
beoordeelt de Gezondheidsraad de kankerverwekkende eigenschappen van stof-
fen waaraan mensen tijdens de beroepsmatige uitoefening kunnen worden bloot-
gesteld. De evaluatie en beoordeling worden verricht door de Subcommissie
Classificatie van Carcinogene Stoffen van de Commissie Gezondheid en
Beroepsmatige Blootstelling aan Stoffen van de Raad, hierna kortweg
aangeduid als de commissie. In het voorliggende advies neemt de commissie
1,1,1-trichloorethaan onder de loep. De stof wordt onder andere gebruikt als
oplosmiddel van hechtmiddelen, voor het ontvetten in de metaal- en elektroni-
sche industrie en in de synthese van vinylideenchloride.
Op basis van de beschikbare gegevens is de commissie van mening dat de gege-
vens over 1,1,1-trichloorethaan niet voldoende zijn om de kankerverwekkende
eigenschappen te evalueren (categorie 3).*
Volgens het classificatiesysteem van de Gezondheidsraad (zie bijlage I).
Samenvatting                                                                  9
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<pre>0 1,1,1-Trichloroethane</pre>

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<pre>Executive summary
At the request of the Minister of Social Affairs and Employment, the Health
Council of the Netherlands evaluates and judges the carcinogenic properties of
substances to which workers are occupationally exposed. The evaluation is
performed by the Subcommittee on Classifying Carcinogenic Substances of the
Dutch Expert Committee on Occupational Standards of the Health Council,
hereafter called the Committee. In this report the Committee evaluates 1,1,1-
trichloroethane. The compound is being used as a solvent for adhesives, for
degreasing in metallic and electronic industries, and in the manufacture of
vinylidene chloride.
The Committee is of the opinion that the available data are insufficient to
evaluate the carcinogenic properties of 1,1,1-trichloroethane (category 3).*
According to the classification system of the Health Council (see Annex I).
Executive summary                                                              11
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<pre>2 1,1,1-Ttichloroethane</pre>

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<pre>Chapter 1
        Scope
1.1     Background
        In the Netherlands, a special policy is in force with respect to occupational use
        and exposure to carcinogenic substances. Regarding this policy, the Minister of
        Social Affairs and Employment has asked the Health Council of the Netherlands
        to evaluate the carcinogenic properties of substances and to propose a
        classification (see Annex A). In addition to classifying substances, the Health
        Council also assesses the genotoxic properties of the substance in question. The
        assessment and the proposal for a classification are expressed in the form of
        standard sentences (see Annex I).
        This report contains the evaluation of the carcinogenicity and genotoxicity of
        1,1,1-trichloroethane.
1.2     Committee and procedure
        The evaluation is performed by the Subcommittee on Classifying Carcinogenic
        Substances of the Dutch Expert Committee on Occupational Standards of the
        Health Council, hereafter called the Committee. The members of the Committee
        are listed in Annex B.
            In 2012, the President of the Health Council released a draft of the report for
        public review. The individuals and organisations that commented on the draft are
        Scope                                                                               13
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<pre>    listed in Annex D. The Committee has taken these comments into account in
    deciding on the final version of the report.
1.3 Data
    The evaluation and recommendation of the Committee is standardly based on
    scientific data, which are publicly available. The starting points of the
    Committees’ reports are, if possible, the monographs of the International Agency
    for Research on Cancer (IARC). This means that the original sources of the
    studies, which are mentioned in the IARC-monograph, are reviewed only by the
    Committee when these are considered most relevant in assessing the
    carcinogenicity and genotoxicity of the substance in question. In the case of
    1,1,1-trichloroethane, such an IARC-monograph is available, of which the
    summary and conclusion of IARC is inserted in Annex E.
         More recently published data were retrieved from www.inchem.org,
    Medline, XToxline, and Chemical Abstracts. The last updated online search was
    in July 2011. The relevant data were included in this report.
 4  1,1,1-Trichloroethane
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<pre>Chapter 2
        General information
2.1     Identity and physicochemical properties
        1,1,1-Trichloroethane is used as a solvent for adhesives, for degreasing in metal
        and electronic industries, and in the manufacture of vinylidene chloride. Other
        applications include: its use in pesticides; textile processing; cutting fluids;
        aerosols; lubricants; cutting oil formulations; drain cleaners; shoe polishes; spot
        cleaners; printing inks; and stain repellents.1,2
             Occupational exposure occurs during manufacturing of 1,1,1-trichloroethane
        and products containing this substance. In addition, workers engaged in dry-
        cleaning, or degreasing processes in the metal and electronic industries, may be
        exposed. The general population is predominantly exposed via contaminated air,
        food or drinking water.1
        The identity of 1,1,1-trichloroethane and some of its physicochemical properties
        are given below.*
        The data have been retrieved from the European Substance Information System (ESIS, which can be
        accessed via the ECB-site (http://ecb.jrc.ec.europa.eu/esis/), the Hazardous Substances Data Bank
        (http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB) and the INCHEM database of the
        International Programme on Chemical Safety (IPCS) (http://www.inchem.org/).
        General information                                                                               15
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<pre>    Chemical name               : 1,1,1-trichloroethane
    CAS registry number         : 71-55-6
    EC/EINECS number            : 200-756-3
    Synonyms                    : methylchloroform, chloroethene
    Molecular formula           : CH3 -CCl3
    Structural formula          :
    Colour and physical state   : colourless liquid
    Melting                     : -30.4 °C
    Boiling point                 74 °C
    Molecular weight            : 133.40
    Relative density of vapour/ : 4.6
    air mixture at 20 °C
    Vapour pressure             : 13.3 kPa at 20 °C
    Solubility                  : slightly soluble in water (0.07 g/100 ml at 20 °C); soluble in
                                  acetone, benzene, carbon tetrachloride, methanol, ethanol and
                                  diethyl ether
    Conversion factors          : 1 ppm = 0.18 mg/m3
    (25 °C, 760 mm Hg)            1 mg/m3 = 5.46 x ppm
    EU classification             H332 - Harmful if inhaled
                                  (Based on Regulation (EC) No. 1272/2008 of the European
                                  Parliament of the Council on Classification, labelling, and
                                  packaging of substances and mixtures; 16 December 2008).
2.2 IARC conclusion
    In 1999, IARC concluded that there is inadequate evidence for the
    carcinogenicity of 1,1,1-trichloroethane in experimental animals and humans.
    Therefore, according to the IARC guidelines, 1,1,1-trichloroethane was
    considered to be not classifiable as to its carcinogenicity to humans (Group 3).2
 6  1,1,1-Trichloroethane
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<pre>Chapter 3
        Carcinogenicity studies
3.1     Observations in humans
        The relevant epidemiological studies are summarised below and presented in a
        table in Annex F.
        Cohort studies
        In a Finnish cohort study of cancer incidence and exposure to halogenated
        hydrocarbons, 2,050 male and 1,924 female workers were followed up from
        1967 to 1992.3 Exposure to 1,1,1-trichloroethane was assessed in 140 men, and
        131 women, by biological monitoring. Seventeen cases of cancer were seen in
        the exposed workers (standardized incidence ratio (SIR) of 1.6; 95% CI 0.9-2.5).
        No statistically significant increases were found for cancer of the pancreas, lung,
        cervix, kidney and non-Hodgkin lymphomas. Statistically significant increases
        of cancer were observed for the nervous system (SIR of 6.1; 95% CI 1.25-17.7),
        and multiple myeloma (SIR of 16.0; 95% CI 1.9-57.7). However, as these results
        are based on only three observed cases for nervous system tumours, and two
        cases (both females) for multiple myeloma, and furthermore co-exposure to other
        solvents was noted, no conclusions can be made based on this study.
        Another cohort study involved 14,457 workers at an aircraft maintenance
        facility, which have been potentially exposed to many solvents, such as
        Carcinogenicity studies                                                             17
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<pre>  1,1,1-trichloroethane.4 Exposure to 1,1,1-trichloroethane was assessed on a
  qualitative (ever or never exposed) basis. Subjects had been working at least for
  one year at the facility between 1952 and 1956, and were followed up to 1982.
  The only increased standardized mortality ratio (SMR) observed was for
  multiple myeloma in female workers (SMR of 56.6 (95% CI 6.85-204.5)),
  although this increase was based on only two cases.
      This cohort has been updated by Blair et al. (1998), extending follow up to
  the end of 1990.5 Again, an increased risk of multiple myeloma in women was
  found (RR of 13.2 (95% CI 2.2-80.4)). However, this increase is based on the
  same two cases of multiple myeloma as no additional cases were reported during
  the extended follow up.
      No conclusions can be drawn based on this cohort, as it only involves a
  limited number of multiple myeloma cases, and most workers were exposed to a
  number of solvents subsequently or simultaneously.
  Case-control studies
  The most recent case-control study involved the relationship between multiple
  myeloma, and the exposure to several chlorinated solvents, including 1,1,1-
  trichloroethane.6 One-hundred-eighty-one cases were matched with 481
  population controls, which were selected for an ongoing non-Hodgkin
  lymphoma case-control study. Occupational histories and information on jobs
  with likely 1,1,1-trichloroethane exposure were obtained by in-person
  interviews. Exposure to 1,1,1-trichloroethane was associated with an increased
  OR of 1.8 (95% CI 1.1-2.9) for subjects ever exposed versus non-exposed. When
  occupations with low confidence for 1,1,1-trichloroethane exposure were
  included in the unexposed category, the OR increased to 2.2 (95% CI 1.1-4.4).
  The association found in this study is difficult to interpret, as information bias
  cannot be excluded. Also, there was no trend observed between the incidence of
  multiple myeloma, and cumulative exposure (10-year lagged and unlagged) or
  exposure duration to 1,1,1-trichloroethane.
  In Montreal, Canada, a population-based case-control study was conducted to
  study the association between several types of cancer following exposure to 293
  workplace substances.7 Approximately one per cent of the study subjects (3,730
  cancer patients, and 533 age-stratified control from the general population) had
  ever been exposed to 1,1,1-trichloroethane. For most types of cancer examined
  (oesophagus, stomach, colon, rectum, pancreas, prostate, bladder, skin
  melanoma, lymphoma) no indication of excess risk was found. For lung cancer,
8 1,1,1-Trichloroethane
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<pre>in French Canadians, the OR was 3.5 (90% CI 1.0-12.0; 7 cases exposed at any
level). For kidney cancer among the whole population, the OR was 2.4 (90% CI
1.0-6.0; 4 cases exposed at any level). The workers included in this study have
been exposed to multiple solvents.
Another population-based case-control study evaluated the risk of pancreatic
cancer in residents from 24 US states (based on death certificates) exposed to
solvents, including 1,1,1-trichloroethane.8 Of the total of 63,097 cases 5,866 had
a low, medium or high probability of exposure to 1,1,1-trichloroethane. For each
case, four controls were matched by state, race, gender and 5-year age group. An
increased odds ratio for pancreatic cancer was found for black men (OR of 2.9
for group with high probability of exposure; 95% CI 1.2-7.5; based on 8 exposed
cases only) on exposure to 1,1,1-trichloroethane. No positive association was
found for this group with chlorinated hydrocarbons or organic solvents
combined. No conclusion could be drawn due to limitations of the study, as no
information on duration of employment, cigarette smoking, socioeconomic
status and other lifestyle factors was available.
In a population-based case-control study by Dosemeci et al. (1999) among
workers residential in Minnesota, US, and exposed to several organic solvents,
including 1,1,1-trichloroethane, no increased risk of renal cell carcinoma was
found (OR of 1.26; 95% CI 0.6-2.8; n=13).9 Of the total of 438 renal cell cancer
cases and 687 controls, 66 and 74 had been exposed to 1,1,1-trichloroethane.
Odds ratios were adjusted for: age; smoking; hypertension status; use of
diuretics; anti-hypertension drugs; and, body mass index, for men and women
separately. As all cases who died (35%) were excluded from the analysis to avoid
using next-of-kin interviews, a potential survival bias confounded the study. Also
data on exposure and duration of employment were limited, as only current and
usual jobs were assessed.
A case-control study among white males on the risk of astrocytic brain cancer
was carried out in three US states with prominent workforce representation in the
petroleum refining, and chemical manufacturing industries.10 Based on death
certificates, 300 cases and 320 matched controls were included, whereas
occupational information was retrieved from next-of-kin. No increased risk was
found for exposure to 1,1,1-trichloroethane, although a trend was found for the
average intensity of exposure for 21+ years (expressed by an OR of 1.6 (95% CI
0.9-3.1) for low-medium intensity exposure compared to an OR of 3.7 (95% CI
0.7-27.9) for high intensity exposure (Chi for trend 2.28 (p<0.05)). As the
Carcinogenicity studies                                                            19
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<pre>    population for high intensity exposure was only based on six cases and two
    controls, the Committee considers this result uncertain. Also in this study, most
    workers were exposed to multiple other solvents for which trends were observed.
    Another population-based case-control study examined the association between
    maternal exposure to occupational solvents, including 1,1,1-trichloroethane, and
    childhood acute lymphoblastic leukaemia (ALL).11 The study included 790 cases
    and 790 controls. The cases were up to seven times more exposed to 1,1,1-
    trichloroethane then controls, taking into account an exposure period of 2 years
    before pregnancy up to giving birth. Exposure was associated with an increased
    incidence of childhood ALL in their offspring. This increase however, was not
    statistically significant (OR of 7.55; 95% CI 0.92-61.97).
    Additional studies have been referred to by US EPA in which no association was
    found between occupational exposure to 1,1,1-trichloroethane, and some types of
    cancer. These include oesophageal cancer or stomach cancer in workers at an
    industrial facility in California (Garland, 1987; Garabrant, 1986; Cited by US
    EPA).12
        Also, US EPA reported on an environmental study in which no significant
    correlation was found between the release of 1,1,1-trichloroethane and age-
    adjusted incidence of childhood brain tumours in 26 Florida counties (Mulla,
    1996; cited by US EPA).12
3.2 Carcinogenicity studies in animals
    Several carcinogenicity studies have been conducted, in rats as well as in mice
    (Annex F).
    Inhalation
    Quast et al. conducted chronic bioassays in Fischer 344 rats and B6C3F1 mice,
    exposed to 1,1,1-trichloroethane by inhalation (both species 80/sex/dose).13 The
    animals were exposed to 1,1,1-trichloroethane (at concentrations of 0, 820, 2,700
    or 8,200 mg/m3 (0, 150, 500 or 1,500 ppm), 6 hr/day, 5 days/week for 24 months.
    Interim sacrifices of 10 animals/sex/group were conducted after 6, 12 and 18
    months of exposure. In this study, clinical signs of toxicity, mortality,
    haematology, serum chemistry, urinalysis endpoints (rats only), body weight,
    organ weights, gross pathology, and histopathology were comprehensively
    assessed.
 0  1,1,1-Trichloroethane
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<pre>    Rats showed no statistically significant difference in survival between
exposed and control groups; body weight was decreased in females at the two
higher exposure concentrations. A statistically significantly increased number of
rats with bilateral testicular interstitial cell neoplasm was noted. However, no
dose dependency was observed, nor the total number of male rats with testicular
interstitial cell tumours was increased. As Fischer 344 rats show a high
background incidence of this tumour type, the Committee considers this finding
not to be related to the treatment.
    In mice, no differences in body weight and survival were observed for the
exposed groups compared to controls. In females, a statistical significant
increase of adenoma or cystadenoma of the lacrimal/Harderian gland (7 at 8,200
mg/m3 compared to 3 in the controls). As this was only observed at the highest
dose level, and no dose response was noted, the Committee does not consider the
observed effect to be toxicologically relevant.
Rampy et al. (as cited in 13,14) administered 1,1,1-trichloroethane to rats (96/sex/
dose) via inhalation at a concentration of 4,700 and 9,500 mg/m3 (875 or 1,750
ppm), for 6 hrs/day, 5 days/week, for 12 months, followed by observation up to
30 months. The authors stated that the tumour incidences in treated rats were
comparable to controls. The Committee notes that only an abstract has been
published and several details on methods and results are lacking, hampering the
interpretation of the study.
Oral administration
Technical-grade 1,1,1-trichloroethane was administered by gavage at 500 mg/kg
bw per day (in olive oil) to male and female Sprague-Dawley rats (50/sex for
control groups, and 40/sex for the exposure groups), 4-5 days/week for 104
weeks.15 A complete necropsy was performed on all animals. Exposure did not
affect survival, whereas a reduction of body weight was only observed in female
rats from 80 weeks of exposure onwards.
    An increase in leukaemias/lymphomas was found in treated males and
females. The incidences of leukaemia were 3/50 and 9/40 for control and treated
males, and 1/50 and 4/40 for control and treated females, respectively. These
involved mainly immunoblastic lymphosarcomas in the lung.
    The Committee considers the findings in this study inconclusive, due to
inherent limitations of the experimental design (only one dose and one species
was assessed) and incomplete analysis and reporting of results.
Carcinogenicity studies                                                              21
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<pre>  In a bioassay conducted by the National Cancer Institute, technical grade 1,1,1-
  trichloroethane was administered in corn oil by gavage to 50 male and 50 female
  Osborne-Mendel rats, and B6C3F1 mice, 5 days per week for 78 weeks.16
      Rats, exposed to 750 mg/kg bw or 1,500 mg/kg bw, showed a high mortality
  rate during the whole study. Average weight gain in male rats appeared to be
  treatment related during the first year of the study. During study, in the treatment
  groups, increasing numbers of females and to a lesser extent, males, showed
  urine staining of the abdominal fur.
      In mice, exposed to average dose of 2,807 mg/kg bw or 5,615 mg/kg bw*, a
  decreased body weight was observed in both sexes. A reduced survival was
  noted in females of the high-dose group in the first year. Male mice showed also
  high early mortality rate in both control and treated groups.
      Several types of tumours were observed both for rats and mice. Incidences
  and types in the exposure group were similar to those observed in the untreated
  controls. However, no conclusion can be made from this study due to the very
  low survival at study termination. A high incidence of chronic pneumonia was
  present in all control and treated rats and mice of both sexes, and was considered
  by the authors as the cause for the high incidence of early death.
  Consecutive exposure to 2,000 mg/kg bw for 10 weeks, 2,500 mg/kg bw for 10 weeks and 3,000
  mg/kg bw for 58 weeks; or 4,000 mg/kg bw for 10 weeks, 5,000 mg/kg bw for 10 weeks and 6,000
  mg/kg bw for 58 weeks, respectively.
2 1,1,1-Trichloroethane
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<pre>Chapter 4
        Genotoxicity
        The summary in this chapter is primarily based on the information given in
        IARC (1999) and ATSDR.2,17 In vitro and in vivo genotoxicity data are
        summarized below and presented in a table in Annex H.
4.1     In vitro assays
        Both positive and negative findings have been reported in in vitro genotoxicity
        assays. Negative results might be attributed to low exposure levels, as for most of
        these studies it is not clear to the Committee whether measures were taken to
        prevent evaporation of the highly volatile 1,1,1-trichloroethane. However,
        also for those assays reported to be conducted using a desiccator (thereby
        preventing evaporation), both positive as well as negative results have been
        observed. Importantly, it is not exactly clear whether technical or purified 1,1,1
        trichloroethane has been tested. As technical 1,1,1-trichloroethane contains
        (suspected) genotoxic stabilizers such as 1,2-epoxybutane and 1,4-dioxane, no
        conclusions can be drawn from these positive results.
        Prokaryotic cell systems
        1,1,1-Trichloroethane has been extensively tested in several bacterial
        mutagenicity assays, in which also inconsistent results have been obtained.
        Genotoxicity                                                                        23
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<pre>  Ames tests have shown predominantly positive results in strains TA100 and
  TA1535, both with and without metabolic activation.18-27 A positive result was
  found for TA104 with metabolic activation.27 One out of six tests with TA98 was
  also positive (with and without metabolic activation), as was the only test with
  TA97.18,19,21,22,27,28 Tests with TA1537 and TA1538 were all negative.18,19,21,22,24
  Two mutation tests with S. typhimurium showed negative results.29,30 One of the
  three reverse mutation tests with Escherichia coli was positive without metabolic
  activation.18,19,28 Legault et al. tested 1,1,1-trichloroethane in four different
  bacterial assays, namely the Ames plate incorporation assay; the fluctuation test
  with TA98 and TA100; the SOS Chromotest (E.coli PQ37); and, the Mutatox
  assay (V. fischeri M169).31 All results were negative. Furthermore, 1,1,1-
  Trichloroethane did not induce an SOS response in the umu test with tester strain
  S. typhimurium TA1535/pSK1002.32
      Tests conducted with S. cerevisiae for mutations, gene conversions, and
  induction of DNA damage or aneuploidy, were all negative.33-38 An intra-
  chromosomal recombination assay in S. cerevisiae showed equivocal results.39
  The fungus A. nidulans showed no genetic crossing-over or aneuploidy without
  metabolic activation.40
  Mammalian cell systems
  Mixed results have been observed in mammalian genotoxicity assays. Assays for
  the induction of micronuclei in cytochalasin B-induced binucleate cells of human
  lymphoblastoid cell lines of varying metabolic activity (AHH-1 with CYP1A1
  activity, h2E1 with CYP2E1, and MCL-5 with multiple CYP activities), were all
  positive.41 An increase of cells with chromosomal aberrations was found in
  Chinese hamster ovary cells without metabolic activation, but not with metabolic
  activation.42 Additionally, two sister chromatid exchange tests have been
  performed in Chinese hamster ovary cells. One was negative with metabolic
  activation and the other was inconclusive, either with or without metabolic
  activation.42,43
      Mouse lymphoma tests showed no increase in the mutant frequency in the tk
  locus of L5178Y cells without metabolic activation, but in two out of three tests
  with metabolic activation the result was inconclusive.44-46
      Cultured rat hepatocytes exposed to 1,1,1-trichloroethane vapour at
  concentrations of 0.1-2.5% (non-stabilized), and 0.1-5% (stabilized; not
  analytically confirmed) for 15 hours, did not increase unscheduled DNA
  synthesis.25 Hasspieler et al. tested 1,1,1-trichloroethane in a DNA single-strand
  break assay and in an UDS-DNA repair assay, in a human hepatic cell line,
4 1,1,1-Trichloroethane
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<pre>    HepG2. The DNA single-strand assay was negative at 25-500 µg/µL, while the
    UDS-DNA repair assay was positive at concentrations exceeding 25 µg/µL.47
    Several studies are available for which their relevance to mutagenicity (or
    carcinogenicity) is unclear. Cell transformation assays in BALB/c-3T3 mouse
    cells, Fischer rat embryo cells or SA7/Syrian hamster embryo cells, only tested
    without metabolic activation, were all positive.48-50 1,1,1-Trichloroethane was
    also found to bind to calf thymus DNA, RNA or protein when incubated with rat
    or mouse liver microsomes, although at much lower rates/exposure levels than
    measured for 1,1,2-trichloroethane, 1,1-dichloroethane, and other haloethanes, as
    was stated by the authors.51
4.2 In vivo assays
    Three micronucleus tests in mice are available; in all three negative results have
    been observed.
        One bone marrow micronucleus assay has been conducted using male and
    female NMRI mice. Animals were administrated 1,1,1-trichloroethane at a dose
    of 100, 266, or 2,000 mg/kg bw i.p. (4 animals per dose), at 0 and 24 h. Bone
    marrow smears were prepared 30 hours after the last treatment. Control animals
    were treated with vehicle only. No significant increase in micronucleated
    polychromatic erythrocytes was found.20
        Tsuchimoto and Matter reported on the ability of 1,1,1-trichloroethane to
    induce micronucleated erythrocytes in CD-1 mice.52 Animals received two
    intraperitoneal doses of 0.008, 0.016 and 0.032 mL/kg bw (equivalent to doses of
    11, 21 and 42 mg/kg bw, assuming the administration of pure 1,1,1-
    trichloroethane), for two consecutive days. Six hours after the last dose was
    applied, the animals was killed and bone marrow smears were analysed. No
    increase in cells with micronuclei were noted. Despite the claim of the authors
    that the doses applied represent one-eighth, one-fourth and one-half of the LD50,
    the Committee notes that no data on acute toxicity via the intraperitoneal route
    are available, and the doses applied in this study appear to be far below the doses
    applied by Gocke et al. (1981).20
        A micronucleus assay with a modified test protocol was applied by Salamone
    et al. (1981), involving multiple sampling at one dose rather than a single sample
    at multiple doses.53 B6C3F1 hybrid mice were injected i.p. with 1,1,1-trichloro-
    ethane at 0 and 24 hours, at a dose which was reported as ‘80% of the LD50’ (not
    further specified). Samples were subsequently taken at 48, 72 and 96 hours after
    the last injection. A significant increase of cells with polychromatic micronuclei
    Genotoxicity                                                                        25
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<pre>    were observed after 72 hours. A confirmation test at doses of 40, 60, and 80% of
    the LD50, however, could not confirm this positive finding. The interpretation of
    this study is hampered by the fact that the actual doses were not specified.
    DNA, RNA and protein binding of 1,1,1-trichloroethane in vivo was studied in
    six male Wistar rats and twelve male BALB/c mice. Radiolabeled compound
    was injected intraperitoneally and animals were killed 22 hours later. Similar
    results were obtained for both species; binding to isolated DNA, RNA and
    proteins was reported as low in general, with a slightly higher labeling in kidney
    DNA and RNA.51
    1,1,1-Trichloroethane was included in a screen for inducing spermhead
    abnormalities in mice, as an indicator test for germ cell mutagenicity. Five male
    BALB/c mice received intraperitoneal 5 daily concentrations of 1,1,1-
    trichloroethane in a volume of 0.1, 0.25, 0.5, 1.0, 2.0 mL in corn oil for 5 weeks.
    The exact dose was not specified but reported as equivalents of the LD50; the
    highest dose was recorded as a lethal dose. No abnormal sperm morphology was
    noted.54
    Sex-linked recessive lethal mutations were not found in D. melanogaster.20
4.3 Carcinogenic mechanism of action
    For 1,1,1-trichloroethane, no general view on a possible mode of action for
    genotoxic and carcinogenic activity is published in literature.
 6  1,1,1-Trichloroethane
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<pre>Chapter 5
        Classification
5.1     Evaluation of data on carcinogenicity and genotoxicity
        Although a number of epidemiological studies is available, none of these studies
        provide basis for conclusions on the potential carcinogenic properties of 1,1,1-
        trichloroethane. In some studies associations were found, however, all of these
        studies have been compromised by methodological limitations, such as lack of
        statistical power and multiple exposures to other solvents – some of which are
        known or suspected to be carcinogens themselves.
            Animal carcinogenicity studies are available. Inhalation studies did not
        reveal evidence for carcinogenicity. For the oral route, an increased incidence of
        leukemia (mainly immunoblastic lymphoma) was noted in rats of both sexes,
        whereas another study showed no increased incidence of tumours in rats or mice.
        The Committee, however, considers both oral studies of insufficient quality to
        assess the carcinogenicity of 1,1,1-trichloroethane.
        Conflicting results have been obtained for in vitro genotoxicity testing. Both
        negative, and positive or equivocal results have been obtained in bacterial and
        mammalian assays covering either gene mutations, structural or numerical
        chromosome aberrations. In contrast, no DNA damage (recombinagenic effects,
        aneuploidy) was reported in yeast and no mutations were found in the sex-linked
        recessive Drosophila test. The high volatility of 1,1,1-trichloroethane does not
        appear to provide a sound explanation for the conflicting results that are also
        observed in enclosed systems. Conflicting results might be attributed to the
        presence of genotoxic additives, as commercially available 1,1,1-trichloroethane
        Classification                                                                     27
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<pre>    is known to contain stabilisers such as nitromethane, 1,4-dioxane and butylene
    oxide.14,17
        In vivo, no clastogenicity is observed in mice exposed to 1,1,1-
    trichloroethane.20,52,53
    As conflicting results have been obtained in vitro, and no information is available
    related to the potential to induce gene mutation in vivo, no conclusion can be
    drawn on the genotoxicity of 1,1,1-trichloroethane. It can, therefore, not be
    excluded that 1,1,1-trichloroethane possesses a low genotoxic potential.
5.2 Recommendation for classification
    The Committee is of the opinion that the available data are insufficient to
    evaluate the carcinogenic properties of 1,1,1-trichloroethane (category 3).*
    According to the classification system of the Health Council (see Annex I).
 8  1,1,1-Trichloroethane
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<pre>  References
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0 Heineman E, Cocco P, Gomez M et al. Occupational Exposure to chlorinated aliphatic hydrocarbons
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0 Gocke E, King M.-T, Eckhardt K.& Wild D. Mutagenicity fo cosmetics ingredients licensed by the
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3 Nestmann ER, Otson R, Kowbel DJ, Bothwell PD, Harrington TR. Mutagenicity in a modified
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4 Richold M and Jones E. Mutagenic activity of 42 coded compounds in the Salmonella/microsome
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6 Simmon VF, Kauhanen K, Tardiff RG. Mutagenic activity of chemicals identified in drinking water.
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7 Strobel K and Grummt T. Aliphatic and aromatic halocarbons as potential mutagens in drinking
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0 1,1,1-Trichloroethane
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<pre>8 Norpoth K, Reisch A, Heinecke A. Biostatistics of Ames-test data. In: Short-Term Test Systems for
  Detecting Carcinogens. Norpoth KH and Garner RC, eds, New York, Springer-Verlag.; 1980: 312-
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9 Roldan-Arjona T, Garcia-Pedrajas MD, Luque-Romero FL et al. An association betwen mutagenicity
  of the Ara test of Salmonella typhimurium and carcinogenicity in rodents for 16 halogenated
  aliphatic hydrocarbons. Mutagenesis 1991; 6: 199-205.
0 Skopek TR, Andon BM, Kaden DA and Thilly WG. Mutagenic activity of 42 coded compounds
  using 8-azaguanine resistance as a genetic marker in Salmonella typhimurium. In: Evaluation of
  Short-Term Tests for Carcinogens. Report of the International Collaborative Program. de Serres FJ
  and Ashby J, eds. [1], 371-375. 1981. Amsterdam Elsevier.
1 Legault R, Blaise C, Rokosh D et al. Comparative assessment of the SOS chromotest kit and the
  mutatox test with the Salmonella plate incorporation (Ames test) and fluctuation tests for screening
  genotoxic agents. Environ Toxicol Water Qual 1994; 9: 45-57.
2 Nakamura S, Oda Y.Shimada T et al. SOS-inducing activity of chemical carcinogens and mutagens in
  Salmonella typhimurium TA1535/pSK1002: examination with 151 chemicals. Mutat Res 1987; 192:
  239-246.
3 Jagannath DR, Vultaggio DM and Brusick DJ. Genetic activity of 42 coded compounds in the mitotic
  gene conversion assay using Saccharomyces cerevisiae strain D4. In: Evaluation of Short-Term Tests
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  [1], 456-467. 1981. Amsterdam Elsevier.
4 Mehta RD and Von Borstel RC. Mutagenic activity of 42 encoded compounds in the haploid yeast
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  Amsterdam Elsevier.
5 Parry JM and Sharp DC. Induction of mitotic aneuploidy in the yeast strain D6 by 42 coded
  compounds. In: Evaluation of Short-Term Tests for Carcinogens. Report of the International
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6 Sharp DC and Parry JM. Use of repair-deficient strains of yeast to assay the activity of 40 coded
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  Collaborative Program. De Serres FJ and Ashby J, eds. [1], 502-516. 1981. Amsterdam Elsevier.
7 Whittaker SG, Zimmermann FK, Dicus B et al. Detection of induced mitotic chromosome loss in
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8 Zimmerman FK and Scheel I. Induction of mitotic gene conversion in strain D7 of Saccharomyces
  cerevisiae by 42 coded chemicals. In: Evaluation of Short-Term Tests for Carcinogens. Report of the
  International Collaborative Program. De Serres FJ and Ashby J, eds. [1], 481-490. 1981. Amsterdam
  Elsevier.
  References                                                                                           31
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<pre>9 Brennan R and Schiestl RH. Chloroform and carbon tetrachloride induce intrachromosomal
  recombination and oxidative free radicals in Saccharomyces cerevisiae. Mutat Res 1998; 397: 271-
  278.
0 Crebelli R, Benigni R, Franekic J et al. Induction of chromosome malsegregation by halogenated
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  401-411.
1 Doherty AT, Ellard S, Parry EM, Parry JM. An investigation into the activation and deactivation of
  chlorinated hydrocarbons to genotoxins in metabolically competent human cells. Mutagenesis 1996;
  11(3): 247-274.
2 Galloway SM, Armstrong MJ, Reuben C. Chromosome aberrations an dsister chromatid exchanges
  in Chinese hamster ovary cells: Evaluations of 108 chemicals. Environ Mol Mutag 1987; 10 (suppl
  10): 1-175.
3 Perry PE, Thomson EJ. Evaluation of the sister chromatid exchange method in mammalian cells as a
  screening system for carcinogens. In: Evaluation of Short-Term Tests for Carcinogens. Report of the
  International Collaborative Program. De Serres FJ and Ashby J eds. [1], 560-569. 1981. Amsterdam
  Elsevier.
4 Mitchell AD, Rudd CJ and Caspary WJ. Evaluation of the L5178Y mouse lymphoma cell
  mutagenesis assay: intralaboratory results for sixty-three coded chemicals tested at SRI International.
  Environ Mol Mutag 1988; 12 (suppl 13): 37-101.
5 Myhr BC and Caspary WJ. Evaluation of the L5178Y mouse lymphoma cell mutagenesis assay:
  Intralaboratory results for sixty-three coded chemicals tested at Litton Bionetics, Inc. Environ Mol
  Mutag 1988; 12 (suppl 13): 103-194.
6 Tennant RW, Stasiewicz S and Spalding JW. Comparison of multiple parameters of rodent
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7 Hasspieler B, Haffner D, Stelljes M, Adeli K. Toxicological assessment of industrial solvents using
  human cell bioassays: assessment of short-term cytotoxicity and long-term genotoxicity potential.
  Toxicology and Industrial Health 2006; 22: 301-315.
8 Hatch GG, Mamay PD, Ayer ML et al. Chemical enhancement of viral transformation in Syrian
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  43: 1945-1950.
9 Price PJ, Hassett CM and Mansfield JI. Transforming activities of trichloroethylene and proposed
  industrial alternatives. In Vitro 1978; 14: 290-293.
0 Tu AS, Murray TA, Hatch KM et al. In vitro transformation of BALB/c-3T3 cells by chlorinated
  ethanes and ethylenes. Cancer Lett 1985; 28: 85-92.
1 Turina MP, Collaci A, Grilli S et al. Short-term tests of genotoxicity for 1,1,1-trichloroethane. Res
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2 Tsuchimoto T, Matter BE. Activity of coded compounds in the micronucleus test. In: Evaluation of
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  and Ashby J, eds. [1], 705-711. 1981. Amsterdam Elsevier.
2 1,1,1-Trichloroethane
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<pre>3 Salamone MF, Heddle JA and Katz M. Mutagenic activity of 41 compounds in the in vivo
  micronucleus assay. In: Evaluation of Short-Term Tests for Carcinogens. Report of the International
  Collaborative Program. De Serres FJ and Ashby J, eds. [1], 686-697. 1981. Amsterdam Elsevier.
4 Topham JC. Do induced sperm-head abnormalities in mice specifically identify mammalian
  mutagens rather than carcinogens? Mutat Res 1980; 74: 379-387.
5 Health Council of the Netherlands. Guideline to the classification of carcinogenic compounds. Health
  Council of the Netherlands, The Hague; 2010: publication no. A10/07E.
  References                                                                                           33
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<pre>4 1,1,1-Trichloroethane</pre>

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<pre>A Request for advice
B The Committee
C Submission letter (in English)
D Comments on the public review draft
E IARC Monograph
F Human data
G Animal data
H Genotoxicity data
  Carcinogenic classification of substances by the Committee
  Annexes
                                                             35
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<pre>6 1,1,1-Trichloroethane</pre>

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<pre>nnex A
     Request for advice
     In a letter dated October 11, 1993, ref DGA/G/TOS/93/07732A, to, the State
     Secretary of Welfare, Health and Cultural Affairs, the Minister of Social Affairs
     and Employment wrote:
     Some time ago a policy proposal has been formulated, as part of the simplification of the
     governmental advisory structure, to improve the integration of the development of recommendations
     for health based occupation standards and the development of comparable standards for the general
     population. A consequence of this policy proposal is the initiative to transfer the activities of the
     Dutch Expert Committee on Occupational Standards (DECOS) to the Health Council. DECOS has
     been established by ministerial decree of 2 June 1976. Its primary task is to recommend health based
     occupational exposure limits as the first step in the process of establishing Maximal Accepted
     Concentrations (MAC-values) for substances at the work place.
     In an addendum, the Minister detailed his request to the Health Council as
     follows:
     The Health Council should advice the Minister of Social Affairs and Employment on the hygienic
     aspects of his policy to protect workers against exposure to chemicals. Primarily, the Council should
     report on health based recommended exposure limits as a basis for (regulatory) exposure limits for air
     quality at the work place. This implies:
     •    A scientific evaluation of all relevant data on the health effects of exposure to
          substances using a criteria-document that will be made available to the Health
     Request for advice                                                                                     37
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<pre>      to a health based recommended exposure limit, or, in the case of genotoxic
      carcinogens, a ‘exposure versus tumour incidence range’ and a calculated
      concentration in air corresponding with reference tumour incidences of 10-4 and 10-6
      per year.
  •   The evaluation of documents review the basis of occupational exposure limits that
      have been recently established in other countries.
  •   Recommending classifications for substances as part of the occupational hygiene
      policy of the government. In any case this regards the list of carcinogenic substances,
      for which the classification criteria of the Directive of the European Communities of
      27 June 1967 (67/548/EEG) are used.
  •   Reporting on other subjects that will be specified at a later date.
  In his letter of 14 December 1993, ref U 6102/WP/MK/459, to the Minister of
  Social Affairs and Employment the President of the Health Council agreed to
  establish DECOS as a Committee of the Health Council. The membership of the
  Committee is given in Annex B.
8 1,1,1-Trichloroethane
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<pre>nnex B
     The Committee
     •  R.A. Woutersen, chairman
        Toxicologic Pathologist; TNO Innovation for Life, Zeist; Professor of
        Translational Toxicology, Wageningen University and Research Centre,
        Wageningen
     •  J. van Benthem
        Genetic Toxicologist, National Institute for Public Health and the
        Environment, Bilthoven
     •  P.J. Boogaard
        Toxicologist, SHELL International BV, The Hague
     •  G.J. Mulder
        Emeritus Professor of Toxicology, Leiden University, Leiden
     •  Ms M.J.M. Nivard
        Molecular Biologist and Genetic Toxicologist, Leiden University Medical
        Center, Leiden
     •  G.M.H. Swaen
        Epidemiologist, Dow Chemicals NV, Terneuzen
     •  E.J.J. van Zoelen
        Professor of Cell Biology, Radboud University Nijmegen, Nijmegen
     •  S.R. Vink, scientific secretary
        Health Council of the Netherlands, The Hague
     The Committee                                                              39
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<pre>  The Health Council and interests
  Members of Health Council Committees are appointed in a personal capacity
  because of their special expertise in the matters to be addressed. Nonetheless, it
  is precisely because of this expertise that they may also have interests. This in
  itself does not necessarily present an obstacle for membership of a Health
  Council Committee. Transparency regarding possible conflicts of interest is
  nonetheless important, both for the chairperson and members of a Committee
  and for the President of the Health Council. On being invited to join a
  Committee, members are asked to submit a form detailing the functions they
  hold and any other material and immaterial interests which could be relevant for
  the Committee’s work. It is the responsibility of the President of the Health
  Council to assess whether the interests indicated constitute grounds for non-
  appointment. An advisorship will then sometimes make it possible to exploit the
  expertise of the specialist involved. During the inaugural meeting the
  declarations issued are discussed, so that all members of the Committee are
  aware of each other’s possible interests.
0 1,1,1-Trichloroethane
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<pre>nnex C
     Submission letter (in English)
     Subject         : Submission of the advisory report 1,1,1-Trichloroethane
     Our reference : DGV/MBO/U-932342
     Your Reference : U-7258/SV/fs/246-N16/E
     Enclosed        :1
     Date            : 24 July 2012
     Dear State Secretary,
     I hereby submit the advisory report on the effects of occupational exposure to
     1,1,1-Trichloroethane.
     This advisory report is part of an extensive series in which carcinogenic
     substances are classified in accordance with European Union guidelines. This
     involves substances to which people can be exposed while pursuing their
     occupation.
         The advisory report was prepared by the Subcommittee on Classifying
     Carcinogenic Substances, a permanent subcommittee of the Health Council's
     Dutch Expert Committee on Occupational Safety (DECOS). The advisory report
     has been assessed by the Health Council's Standing Committee on Health and the
     Environment.
     Submission letter (in English)                                                 41
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<pre>  I have today sent copies of this advisory report to the State Secretary of
  Infrastructure and the Environment and to the Minister of Health, Welfare and
  Sport, for their consideration.
  Yours sincerely,
  (signed)
  Prof. H. Obertop,
  Acting President
2 1,1,1-Trichloroethane
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<pre>nnex D
     Comments on the public review draft
     A draft of the present report was released in 2012 for public review. The
     following organisations and persons have commented on the draft document:
     • Ms V. Gálvez Pérez, Instituto Nacional de Seguridad e Higiene en el Trabajo,
         Madrid, Spain
     • Mr T.J. Lentz, National Institute of Occupational Safety and Health,
         Cincinnati, the USA
     Comments on the public review draft                                            43
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<pre>4 1,1,1-Trichloroethane</pre>

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<pre>nnex E
     IARC Monograph
     VOL: 71 (1999) (p.1295)
     Summary of Data Reported and Evaluation
     Exposure data
     1,1,1-Trichloroethane is a solvent. It has been detected in waste-, ground-,
     drinking- and ambient water as well as in ambient and urban air.
     Human carcinogenicity data
     An increased risk for central nervous system and multiple myeloma was reported
     from a cohort study of workers exposed to 1,1,1-trichloroethane in Finland.
     These findings were not confirmed by two case-control studies carried out in the
     United States and Canada, while an increased risk for cancer of the lung and
     kidney was shown in the Canadian study.
     Animal carcinogenicity data
     1,1,1-Trichloroethane was tested for carcinogenicity by oral administration in
     rats in two experiments and in mice in one experiment. Although leukaemia was
     IARC Monograph                                                                   45
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<pre>  seen in both sexes of rats in one study and a few liver tumours occurred in male
  mice, the results of these studies were considered to be inadequate for evaluation.
  1,1,1-Trichloroethane was tested by inhalation in rats in two experiments and in
  mice in one experiment. No chemically related increase in tumour incidence was
  observed in either rats or mice in one adequate study. Another inhalation study
  was considered to be inadequate.
  In a multistage study for γ-glutamyltranspeptidase (γ-GT)-positive foci in the
  liver of male rats, neither single administration of 1,1,1-trichloroethane by
  gavage after a two-thirds partial hepatectomy followed by treatment with
  phenobarbital (initiation study) nor repeated administration of 1,1,1-
  trichloroethane by gavage after two-thirds partical hepatectomy and initiation
  with N-nitrosodiethylamine (promotion study) increased the number of (γ-GT)-
  positive foci.
  Other relevant data
  Absorption of 1,1,1-trichloroethane vapour is mainly through the respiratory
  tract. It is rapidly eliminated form blood. Metabolism plays a minor role in this
  process, more than 90% being eliminated unchanged, both in exposed people and
  rodents. The main metabolites are trichloroethanol, trichloroacetic acid and
  carbon dioxide.
  1,1,1-Trichloroethane is neurotoxic and hepatotoxic, following exceptionally
  high exposure concentrations of people and also in rodents. No structural damage
  has been reported in reproductive toxicity studies in rats and mice, but delayed
  development, particularly of neurological attributes, has been reported in one
  study with mice.
  1,1,1-Trichloroethane covalently bound to DNA, RNA and protein in mice and
  rats buth did not induce micronuclei or abnormal sperm head morphology in
  mice in vivo. It induced chromosomal aberrations and cell transformation in
  mammalian cell cultures and it showed inconclusive evidence of sister chromatid
  exchange induction. It did not induce unscheduled DNA synthesis or gene
  mutation in mammalian cells in vitro. 1,1,1-Trichloroethane did not cause
  mutation in plants or sex-linked mutation in Drosophila. It did not induce DNA
6 1,1,1-Trichloroethane
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<pre>damage, gene conversion, mutation or aneuploidy in yeast or genetic crossing-
over or aneuploidy in fungi, but it was mutagenic to some bacterial strains.
Evaluation
There is inadequate evidence for the carcinogenicity of 1,1,1-trichloroethane in
humans. There is inadequate evidence for the carcinogenicity of 1,1,1-
trichloroethane in experimental animals.
Overall evaluation
1,1,1-Trichloroethane is not classifiable as to its carcinogenicity to humans
(Group 3).
IARC Monograph                                                                   47
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<pre>8 1,1,1-Trichloroethane</pre>

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<pre> nnex        F
             Human studies
 tudy design and population     Exposure         Exposure         Follow- Tumour type; relative risk    Ref.
nformation                      information      duration         up      (95% CI)
Cohort; Finnish workers;        No data;         0-8y             8-17 y Cancer of the nervous system   3
 40 male and 131 female                                                   (3 cases): SIR 6.1
                                                                          (95% CI 1.25-17.7); multiple
                                                                          myeloma (2 cases): SIR 16.0
                                                                          (95% CI 1.9-57.7)
Cohort; employees working at    No data          >1y              >1 y    Multiple myeloma mortality    4
Hill Air Force Base; n = 14,457                                           (2 cases): SMR 56.6
                                                                          (95% CI 6.9-204.5)
                                                                          Multiple myeloma mortality    5
                                                                          (2 cases): SMR 13.2
                                                                          (95% CI 2.2-80.4)
Case-control; 181 cases and     Four exposure    Exposure         --      Multiple myeloma: No          6
 81 controls                    categories up to categories up to         significant increased
                                60,000 (ppm*y)   45 years of              ORs for exposure categories
                                (10-y lagged and exposure                 separately. OR for ‘ever’
                                unlagged)                                 exposed subjects 1.8
                                                                          ((95% CI 1.1-2.9)
                                                                          (primary analysis) or 2.2
                                                                          (95% CI 1.1-4.4) (reanalysis)
             Human studies                                                                                   49
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<pre>Case-control; 300 cases and         Low to high exposure Ever exposed,    --      Astrocytic brain cancer:         10
 20 controls from population in     combined              2-20 y or 21+ y         OR 1.2 (95% CI 0.9-1.8) for
  US states with prominent                                                        ever exposed; OR 1.1 (95%
workforce representation in the                                                   CI 0.7-1.7) for 2-20 years
 etroleum refining and chemical                                                   exposed; OR 1.8 (95% CI
manufacturing industries                                                          1.0-3.3) for 21+ years
                                                                                  exposed; Chi for trend
                                                                                  1.87 (p<0.05)
                                    low-medium or high 21+ y              --      astrocytic brain cancer;
                                    intensity of exposure                         OR 1.6 (95% CI 0.9-3.1)
                                                                                  for low-medium intensity
                                                                                  exposure; OR 3.7; (95% CI
                                                                                  0.7-27.9) for high intensity
                                                                                  exposure; Chi for trend 2.28
                                                                                  (p<0.05)
Case-control; 5,866 cases and       Probability of low,   No data         --      pancreatic cancer mortality;     8
 52,386 controls from               medium or high                                OR 2.9 (95% CI 1.2-7.5) for
 4 US states                        exposure                                      black males with high
                                                                                  probability of exposure (8 cases
                                                                                  exposed)
Case-control; 438 cases and         No data               No data         --      renal cell cancer (n=13);        9
 87 controls                                                                      OR 1.26 (95% CI 0.6-2.8)
Case-control; 3,730 cases and       Any level             No data         --      Lung cancer                      7
 33 controls                                                                      (French Canadians; n=7);
                                                                                  OR 3.5 (90% CI 1.0-12.0);
                                                                                  kidney cancer (whole
                                                                                  population; n=4) 2.4
                                                                                  (90% CI 1.0-6.0)
Case-control; Quebec, Canada;       Maternal exposure     No data         --      Acute lymphoblastic leukemia     11
 90 cases and 790 controls                                                        in offspring; OR 7.55
                                                                                  (95% CI 0.92-61.97)
Case-control; 14,067 employees at No data                 No data         No data No increased risk of             12
Rohr plant (control: total US white                                               esophageal cancer
 nd nonwhite population and San
Diego County population
Case-control; 14                    No data               No data         No data No increased risk of esophageal  12
esophageal cancer) and 8                                                          or stomach cancer
stomach cancer) cases, 56 and
 2 controls for esophageal and
 tomach cancer, resp.
  0           1,1,1-Trichloroethane
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<pre> nnex       G
            Animal studies
 pecies      dose         freq          sex (no./ Xpo       Xpe       no. survivors no. animals comments/       Ref.
                                        group)                                      with tumours specified
                                                                                                 tumours
nhalation studies
 ischer 344 0, 820,       6 hr/d; 5 d/w M/F (50)  24 months 24 months not           bilateral,   unilateral or 13
at           2,700 and                                                significantly benign,      unilateral and
             8,200 mg/m3                                              < control     primary      bilateral
             (0, 150, 500                                             (range        interstitial combined
             and 1,500                                                50-60%,       cell tumour  was not
             ppm)a                                                    read from     of testes:   increased
                                                                      graph)        36/50,
                                                                                    30/50,
                                                                                    38/50.
                                                                                    45/50b
B6C3F1       0, 820,      6 hr/d;       M/F (50)  24 months 24 months not           lacrimal/    adenoma and 13
mouse        2,700 and 5 d/w                                          significantly Harderian    cystadenoma
             8,200 mg/m3                                              < control     gland:       combined;
             (0, 150,                                                 (range 50- M 8/50,         historical
             500 and                                                  60%, read 8/49, 5/50,      control
             1,500 ppm)a                                              from graph) 4/50;          incidence:
                                                                                    F 3/50,      4-12%
                                                                                    1/50, 2/50,
                                                                                    7/50c
 prague-     0, 4,700 and 6 hrs/d;      M/F (96)  12 months 30 months no data       incidence of                13,14
Dawley rat 9,500 mg/m3 5 d/w                                                        neoplasms
             (0, 875 and                                                            comparable
             1,750 ppm                                                              to control
            Animal studies                                                                                         51
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<pre>Oral studies
 prague-     0 and 500 4-5 d/w         M/F (50      104 weeks    141 weeks     not           leukemia/     mainly         15
Dawley rat mg/kg bw/d                  control; 40                             significantly lymphoma:     immuno-
             in olive oil              treated)                                < control     M 3/50,       blastic
             (gavage)d                                                                       9/40,         lympho-
                                                                                             F 1/50.       sarcomas in
                                                                                             4/40 (no      the lung
                                                                                             statistical
                                                                                             analysis)
Osborne-     0, 750 or    5 d/w        M/F (20      78 weeks     110 weeks     M 0/20,       incidence     high           16
Mendel rat 1,500                       control; 50                             0/50, 0/50, and type        incidence of
             mg/kg bw/d                treated)                                F 3/20,       similar to    chronic
             in corn oil                                                       2/50,         control       murine
             (gavage)                                                          1/50                        pneumonia
                                                                                                           present in all
                                                                                                           control and
                                                                                                           treated rats
                                                                                                           (M/F) was
                                                                                                           probably
                                                                                                           cause for
                                                                                                           high
                                                                                                           incidence of
                                                                                                           early deaths
B6C3F1       0; Low       5 d/w        M/F (20      78 weeks     90 weeks      M 10/20,      incidence     high           16
mouse        dose: 2,000,              control; 50                             19/50,        and type of   incidence of
             2,500 and                 treated)                                15/50;        neoplasms     chronic
             3,000 mg/kg                                                       F 19/20,      similar to    murine
             bw/d for 10,                                                      41/50,        control       pneumonia
             10 and 58 w,                                                      30/50                       present in all
             resp.                                                                                         control and
             High dose:                                                                                    treated mice
             4,000, 5,000                                                                                  (M/F) was
             and 6,000                                                                                     probably
             mg/kg bw/d                                                                                    cause for
             for 10,                                                                                       high
             10 and 58 w,                                                                                  incidence of
             resp.                                                                                         early deaths
              (gavage)
M = male; F = female; freq = frequency; Xpo= duration of exposure; Xpe= duration of the experiment.
    production grade 1,1,1-trichloroethane was used containing 5% stabilizers: butylene oxide, t-amyl alcohol, methyl butynol,
    nitroethane, and nitromethane; <1% minor impurities
    Cochran-Armitage test; α = 0.02 (2-sided)
    Cochran-Armitage test; α = 0.05 (1-sided)
    Technical-grade 1,1,1-trichloroethane was used with maximum level of stabilizers and impurities: 3.8% 1,4-dioxane,
    0.47% 1,2-epoxybutane, 0.27% nitromethane, <1 ppm N-methylpyrrole, 100 ppm chloroform, 250 ppm carbon
    tetrachloride, 426 ppm 1,1-dichloroethane, 2.3 ppm 1,2-dichloroethane, 41.8 ppm 1,2,3-trichloroethane, 398 ppm
    1,1-dichloroethylene, 50 ppm 1,2-dichloroethylene trans, 200 ppm trichloroethylene, 475 ppm tetrachloroethylene.
 2           1,1,1-Trichloroethane
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<pre> nnex        H
             Genotoxicity data
             In vitro and in vivo genotoxicity data are presented below. If some information
             was given on restriction of the volatile compound, it is presented under exposure
             conditions. Results from references cited in IARC were copied from IARC. 2
 est system                              Exposure              Dosea           Result b            Ref.
                                         conditions            (LED or HID)
                                                                               exogenous metabolic
                                                                               activation
                                                                               without    with
n vitro
 rophase, induction, SOS response,                             666             –          –        32
trand-breaks or cross-links
 almonella typhimurium
orward mutation                                                1,000           NT         –        30
orward mutation (Ara test)                                     3,75            –          –        29
 A100, reverse mutation                  desiccator            70              +          +        26
 A100, reverse mutation                                        up to 5,000     –          –        18,21
 A100, reverse mutation                  in desiccator, vapour NG              +          +        22
                                         exposure
 A100, reverse mutation                  desiccator            144             –          (+)      20
 A100, reverse mutation                                        150             +          +        23
 A100, reverse mutation                  vapour exposure       266 • 103 mg/m3 –          –        25
             Genotoxicity data                                                                           53
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<pre>  A100, reverse mutation                                 500              +  –  27
  A100, reverse mutation                                 3,300            –  NT 31
  A104, reverse mutation                                 5                –  +  27
  A1535, reverse mutation                vapour          NG               +  +  22
  A1535, reverse mutation                                up to 5,000      –  –  18,19,21,24
  A1535, reverse mutation                desiccator      144              +  +  20
  A1535, reverse mutation                                80               +  +  23
  A1535, reverse mutation                vapour exposure 266 • 103 mg/m3  –  –  25
  A1537, reverse mutation                vapour          1,000            –  –  22
  A1537, reverse mutation                                up to 5,000      –  –  24 18,21
  A1538, reverse mutation                vapour          1,000            –  –  22
  A1538, reverse mutation                                up to 5,000      –  –  18,24
  A98, reverse mutation                  vapour          1,000            –  –  22
  A98, reverse mutation                                  134              –  NT 28
  A98, reverse mutation                                  3,300            –  NT 31
  A98, reverse mutation                                  up to 5,000      –  –  18,19,21
  A98, reverse mutation                                  5                +  +  27
  A97, reverse mutation                                  5                +  +  27
  scherichia coli WP2 uvrA                               268              NT +  28
  scherichia coli WP2 uvrA                               up to 1,000      –  –  18,19
  scherichia coli PQ37, SOS Chromotest,                  1,000            –  NT 31
DNA damage
  ibrio fischeri M169, Mutatox test, DNA                 4,800            –  NT 31
 amage
 accharomyces cerevisiae,                                750              –  –  36
 ifferential toxicity
 accharomyces cerevisiae D4,                             125              –  –  33
 ene conversion
 accharomyces cerevisiae JD1, gene                       750              –  –  36
 onversion
 accharomyces cerevisiae D7,                             2,600            NT –  38
 ene conversion
  spergillus nidulans,                   sealed tube     1,300            –  NT 40
 train P1 crossing-over
 accharomyces cerevisiae XV185-14C,                      1,488            –  –  34
everse mutation
 accharomyces cerevisiae D6,             sealed bottle   500              –  –  35
 neuploidy
 accharomyces cerevisiae D61.M,                          6,000            –  NT 37
 neuploidy
  spergillus nidulans strain P1,         sealed tube     1,300            –  NT 40
 neuploidy
Drosophila melanogaster, Basc strain,                    3,335 µg/mL feed –     20
 ex-linked recessive lethal mutations
  4            1,1,1-Trichloroethane
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<pre>Unscheduled DNA synthesis, rat primary          vapour exposure       133                  –             NT         25
 epatocytes
Human hepatic cell line, HepG2,                                       500                  –                        47
DNA single-strand breaks
Human hepatic cell line, HepG2,                                       50                   +                        47
DNA repair
Gene mutation, mouse lymphoma L5178Y                                  NG/536               –             ?          45,46
 ells, tk locus
Gene mutation, mouse lymphoma L5178Y                                  680                  –             –          44
 ells, tk locus
 ister chromatid exchange,                                            10                   NT            –          43
Chinese hamster ovary cells
 ister chromatid exchange,                      ?                     1,000                ?             ?          42
Chinese hamster ovary cells
Chromosomal aberrations,                        ?                     160                  +             –          42
Chinese hamster ovary cells
Cell transformation,                            glass incubation      4                    +             NT         50
BALB/c-3T3 cells                                chamber
Cell transformation,                                                  13                   +             NT         49
 ischer rat embryo cells
Cell transformation,                            vapour exposure       11 • 103 mg/m3       +             NT         48
 A7/Syrian hamster embryo cells
Binding (covalent) to calf thymus DNA,                                7.6                  NT            +          51
at/mouse RNA or protein
n vivo
Micronucleus test, NMRI mouse bone marrow                             2x 2,000 ip          –                        20
Micronucleus test, B6C3F1 mouse bone                                  2x 67 ip             –                        53
marrow
Micronucleus test, CD-1 mouse bone marrow                             2x 43 ip             –                        52
Binding (covalent) to DNA, RNA or protein,                            1.2 ip               + (DNA(+))               51
male Wistar rat and BALB/c mouse liver,
 idney, lung and stomach
 perm morphology, mice                                                5x 1,340 ip          –                        54
     LED = lowest effective dose; HID = highest ineffective dose; in vitro tests: µg/mL; in vivo tests: mg/kg bw/d;
     NG = not given; ip = intraperitoneal
     + = positive; (+) = weakly positive; – = negative; NT = not tested; ? = inconclusive
               Genotoxicity data                                                                                          55
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<pre>6 1,1,1-Trichloroethane</pre>

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<pre> nnex       I
            Carcinogenic classification of
            substances by the Committee
            The Committee expresses its conclusions in the form of standard phrases:
Category     Judgement of the Committee (GRGHS)                                   Comparable with EU Category
                                                                                  67/548/EEC          EC No 1272/2008
                                                                                  before              as from
                                                                                  12/16/2008          12/16/2008
 A           The compound is known to be carcinogenic to humans.                  1                   1A
             • It acts by a stochastic genotoxic mechanism.
             • It acts by a non-stochastic genotoxic mechanism.
             • It acts by a non-genotoxic mechanism.
             • Its potential genotoxicity has been insufficiently investigated.
                Therefore, it is unclear whether the compound is genotoxic.
 B           The compound is presumed to be as carcinogenic to humans.            2                   1B
             • It acts by a stochastic genotoxic mechanism.
             • It acts by a non-stochastic genotoxic mechanism.
             • It acts by a non-genotoxic mechanism.
             • Its potential genotoxicity has been insufficiently investigated.
                Therefore, it is unclear whether the compound is genotoxic.
             The compound is suspected to be carcinogenic to man.                 3                   2
3)           The available data are insufficient to evaluate the carcinogenic     Not applicable      Not applicable
             properties of the compound.
4)           The compound is probably not carcinogenic to man.                    Not applicable      Not applicable
 ource: Health Council of the Netherlands. Guidline to the classification of carcinogenic compounds.
 he Hague: Health Council of the Netherlands, 2010; publication no. A10/07E.55
            Carcinogenic classification of substances by the Committee                                                57
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<pre>8 1,1,1-Trichloroethane</pre>

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<br><br>