<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>Tetrahydrofuran
     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 Tetrahydrofuran
Uw kenmerk            : DGV/MBO/U-932342
Ons kenmerk           : U-7437/JR/fs/246-G17
Bijlagen              :1
Datum                 : 23 november 2012
Geachte staatssecretaris,
Graag bied ik u hierbij het advies aan over de gevolgen van beroepsmatige blootstelling aan
tetrahydrofuraan.
Dit advies maakt deel uit van een uitgebreide reeks waarin kankerverwekkende stoffen
worden geclassificeerd volgens richtlijnen van de Europese Unie. Het gaat om stoffen
waaraan mensen tijdens de beroepsmatige uitoefening kunnen worden blootgesteld.
Dit advies is opgesteld door een vaste subcommissie van de Commissie Gezondheid en
beroepsmatige blootstelling aan stoffen (GBBS), de Subcommissie Classificatie van
carcinogene stoffen. Het advies is getoetst door de Beraadsgroep Gezondheid en omgeving
van de Gezondheidsraad.
Ik heb het advies vandaag ter kennisname toegezonden aan de staatssecretaris van
Infrastructuur en Milieu en aan de minister van Volksgezondheid, Welzijn en Sport.
Met vriendelijke groet,
prof. dr. W.A. van Gool,
voorzitter
Bezoekadres                                                     Postadres
Parnassusplein 5                                                Postbus 16052
2 5 11 V X D e n        Haag                                    2500 BB Den     Haag
E - m a il : jo l a n d a . r i jn k e l s @g r. n l            w w w. g r. n l
Te l e f o o n ( 0 7 0 ) 3 4 0 6 6 3 1
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<pre></pre>

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<pre>Tetrahydrofuran
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. 2012/23, The Hague, November 23, 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, 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. Tetrahydrofuran. Evaluation of the
carcinogenicity and genotoxicity. The Hague: Health Council of the Netherlands,
2012; publication no. 2012/23.
all rights reserved
ISBN: 978-90-5549-916-8
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<pre>   Contents
   Samenvatting 9
   Executive summary 11
   Scope 13
.1 Background 13
.2 Committee and procedures 13
.3 Data 14
   Tetrahydrofuran 15
.1 Identity, and physico-chemical properties 15
.2 IARC conclusion 16
   Carcinogenicity 17
.1 Observations in humans 17
.2 Carcinogenicity studies in animals 17
   Mode of action 21
.1 Genotoxic mode of action 21
.2 Non-genotoxic mode of action 22
.3 Animal carcinogenicity and its relevance for humans 24
   Contents                                               7
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<pre>    Classification 29
 .1 Evaluation and conclusion 29
 .2 Recommendation for classification 30
    References 31
    Annexes 33
A   Request for advice 35
B   The Committee 37
C   The submission letter 39
D   Comments on the public review draft 41
E   Classification of substances with respect to carcinogenicity 43
    Tetrahydrofuran
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<pre>Samenvatting
Op verzoek van de minister van Sociale Zaken en Werkgelegenheid evalueert en
beoordeelt de Gezondheidsraad de kankerverwekkende eigenschappen van stof-
fen waaraan mensen tijdens het uitoefenen van hun beroep kunnen worden bloot-
gesteld. De evaluatie en beoordeling worden verricht door de subcommissie
Classificatie van Carcinogene Stoffen van de Commissie Gezondheid en
Beroepsmatige blootstelling aan stoffen van de raad, hierna kortweg aangeduid
als de commissie. In het voorliggende advies neemt de commissie tetrahydro-
furaan onder de loep. De stof wordt onder andere gebruikt: bij de fabricage van
artikelen voor verpakkingen, transport en opslag van voedsel; als oplosmiddel;
en als chemisch intermediair bij polymerisatie reacties.
Naar het oordeel van de commissie zijn de gegevens niet voldoende om de
kankerverwekkende eigenschappen van tetrahydrofuraan te evalueren
(categorie 3).*
Volgens het classificatiesysteem van de Gezondheidsraad (zie bijlage E).
Samenvatting                                                                    9
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<pre>Executive summary
At request of the Minister of Social Affairs and Employment, the Health Council
of the Netherlands evaluates and judges the carcinogenic properties of
substances to which workers are occupationally exposed. The evaluation is
performed by the subcommittee on Classifying Carcinogenic Substances of the
Dutch Expert Committee on Occupational Safety of the Health Council,
hereafter called the Committee. In this report, the Committee evaluates
tetrahydrofuran. The substance is used: in the manufacture of articles for
packaging, transporting, and storing foods; as a solvent; and, as an intermediate
in polymerisation processes.
According to the judgement of the Committee, the available data are insufficient
to evaluate the carcinogenic properties of tetrahydrofuran (category 3).*
According to the classification system of the Health Council (see Annex E).
Executive summary                                                                 11
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<pre>2 Tetrahydrofuran</pre>

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<pre> hapter 1
        Scope
1.1     Background
        In the Netherlands a special policy is in force with respect to occupational use
        and exposure to carcinogenic substances. Regarding this policy, the Minister of
        Social Affairs and Employment has asked the Health Council of the Netherlands
        to evaluate the carcinogenic properties of substances, and to propose a
        classification (see Annex A). In addition to classifying substances, the Health
        Council also assesses the genotoxic properties of the substance in question. The
        assessment and the proposal for a classification are expressed in the form of
        standard sentences (see Annex E)
        This report contains the evaluation of the carcinogenicity and genotoxicity of
        tetrahydrofuran.
1.2     Committee and procedures
        The evaluation is performed by the subcommittee on Classifying Carcinogenic
        Substances of the Dutch Expert Committee on Occupational Safety of the Health
        Council, hereafter called the Committee. The members of the Committee are
        listed in Annex B. The submission letter (in English) can be found in Annex C.
             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
    tetrahydrofuran, such an IARC-monograph is not available.
         Published data were retrieved from the online databases Medline, Toxline,
    and Chemical Abstracts. The last online search was performed in October 2012.
    The relevant data were included in this report.
 4  Tetrahydrofuran
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<pre> hapter 2
        Tetrahydrofuran
2.1     Identity, and physico-chemical properties
        Tetrahydrofuran is used: as a medium for Grignard and metal hydride reactions;
        in the synthesis of butyrolactone, succinic acid, and 1,4-butanediol diacetate; in
        the manufacture of articles for packaging, transporting, and storing foods; as a
        solvent for dyes and lacquers; and as chemical intermediate in polymerisation
        solvent for fat oils, unvulcanised rubber, resins, and plastics. Tetrahydrofuran is
        also an indirect additive when it is in the contact surface of articles intended for
        use in food processing.
        The identity, and the physico-chemical properties are shown below.
        Chemical name                :   Tetrahydrofuran
        CAS registry number          :   109-99-9
        EINECS number                :   203-726-8
        Synonyms                     :   Tetramethylene oxide; tetraidrofurano; tetrahydrofuranne;
                                         tetrahydrofuraan; oxolane; oxacyclopentane; furanidine;
                                         cyclotetramethylene oxide; butylene oxide
        Appearance                   :   Colourless volatile liquid, with characteristic odour
        Chemical formula             :   C4 H 8 O
        Tetrahydrofuran                                                                            15
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<pre>    Structure                 :
                                        O
    Molecular weight          :   72.1
    Boiling point             :   66ºC
    Melting point             :   -108.5ºC
    Vapour pressure           :   114 mm Hg at 20ºC; 204 mm Hg at 30ºC
    Vapour density (air = 1)  :   2.5
    Solubility                :   Soluble in water (30% at 25ºC), ethyl alcohol, and ethyl ether
    Conversion factor         :   1mg/m3 = 0.34 ppm
    EU classification         :   Highly flammable (R11)
                                  May form explosive peroxides (R19).
                                  Irritating to eyes and respiratory system (R36/37).
2.2 IARC conclusion
    Tetrahydrofuran has not been evaluated by IARC.
 6  Tetrahydrofuran
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<pre> hapter 3
        Carcinogenicity
3.1     Observations in humans
        No human studies addressing the carcinogenicity of tetrahydrofuran have been
        retrieved from public literature.
3.2     Carcinogenicity studies in animals
        The National Toxicology Program (NTP) performed carcinogenicity studies
        using rats and mice.1,2 So far known this is the only long-term carcinogenicity
        study reported in the public literature. The results are discussed below.
        Rats. Groups of F344/N rats (N=50/group/sex) inhaled tetrahydrofuran at
        concentrations of 0 (vehicle control), 200, 600, or 1,800 ppm, for six hours per
        day, five days per week for a total of 105 weeks. Survival and mean body
        weights of all dosed groups were comparable to that of the vehicle controls. No
        clinical findings or non-neoplastic lesions related to exposure were observed in
        male or female rats.
            Regarding neoplastic lesions, tumour development was observed in the
        kidneys of male rats (see Table 1). However, group-wise comparisons revealed a
        non-significant increase, although a positive trend was observed, and the number
        of animals with tumours in the two highest exposure groups exceeded the
        historical range for vehicle controls. Furthermore, all males suffered from
        Carcinogenicity                                                                  17
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<pre>  Table 1 Tumour development in the kidneys of male F344 rats (NTP-study).1,2
  Number of animals with lesion                 Control 200 ppm           600 ppm 1,800 ppm
  Number of animals examined                    50         50             50      50
  Renal tubule, adenoma                           1          1             4       3
  Renal tubule, carcinoma                         0          0             0       2
  Renal tubule tumours, combined                  1          1             4       5
  Renal tubule, hyperplasia                       5          5             6       7
  Chronic progressive nephropathy (CPN)         48         50             50      50
  Historical control range reported: 0-4%, with a mean rate of 0.9 ± 1.3%.
  chronic progressive nephropathy without any treatment-related differences in
  severity. No signs of tumour development were observed in female rats, and in
  other organs in male rats.
  Mice. Groups of B6C3F1 mice (N=50/group/sex) inhaled tetrahydrofuran at
  concentrations of 0 (vehicle control), 200, 600, or 1,800 ppm, for six hours per
  day, five days per week for a total of 105 weeks.1,2 Throughout the study, the
  mean body weights of all dosed groups were similar to those of vehicle controls.
  However, after week 36, the survival of male mice in the highest dose group was
  significantly less compared to the vehicle controls. Also, the same group suffered
  from a state of narcosis during, and up to one hour after the exposure periods.
  This resulted in prolonged wetting of the preputial fur, which probably has
  caused ascending urogenital tract bacterial infection. Finally, this may have led
  to a moribund state and death. No exposure-related non-neoplastic lesions were
  observed in male of female mice.
  Signs of neoplastic lesions were observed in the liver only. In the highest group
  of females, the increase of hepatocellular adenomas combined with carcinomas
  was statistically significantly higher compared to the vehicle controls (see
  Table 2). Hepatocellular tumours (adenomas and carcinomas) were also found in
  males (vehicle control, 35/50 (70%); 200 ppm, 31/50; 600 ppm, 30/50; and,
  1,800 ppm, 18/50). However, there was a high spontaneous incidence in male
  controls (historical controls, 37.8 ± 12.5%, range 11 - 60%). Furthermore, the
  NTP explained the low liver tumour incidence in the group exposed to 1,800
  ppm, to a lower survival in this group. These two factors precluded any
  conclusion on the carcinogenicity in male mice.
8 Tetrahydrofuran
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<pre>Table 2 Tumour development in the liver of female B6C3F1 mice (NTP-study).1,2
Number of animals with lesion                 control   200 ppm    600 ppm    1,800 ppm
Number of animals examined                    50        50         50         48
Adenoma                                       10        14         13         19
Adenoma, multiple                              2         3          5         12
Carcinoma                                      4         6          9         10
Carcinoma, multiple                            2         4          1          6
Adenoma or carcinoma combinedaa               17        24         26         41
Eosinophilic focus                             7         9          7         11
Necrosis                                       3         0          0          7
a   Historical control range incidence: 21.3 ± 11.9%, range 3-54%.
Carcinogenicity                                                                         19
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<pre> hapter 4
        Mode of action
4.1     Genotoxic mode of action
4.1.1   Gene mutation tests
        In vitro
        In two independent Ames assays, tetrahydrofuran was tested in concentrations of
        up to 10,000 µg/plate in Salmonella typhimurium strains TA98, TA100, TA1535,
        and TA1537, with and without a metabolic activation system. In both assays,
        tetrahydrofuran was not mutagenic.2
        In vivo
        No induction of sex-linked recessive lethal mutations was noted in male germ
        cells of Drosophila melanogaster. The flies were administered tetrahydrofuran
        by feeding or injection doses of 10,000, 40,000, or 125,000 ppm.2
        Mode of action                                                                  21
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<pre>4.1.2 Gytogenetic tests
      In vitro
      At doses up to 5 mg/mL with and without a metabolic activation system,
      tetrahydrofuran did not induce sister chromatid exchanges or chromosome
      aberrations in cultured Chinese hamster ovary cells.2
      In vivo
      Tetrahydrofuran did not induce sister chromatid exchanges in bone marrow cells
      of mice given a single intraperitoneal injection of 500 to 2,500 mg/kg bw
      (23-hour exposure), and 500 to 2,000 mg/kg bw (42-hour exposure).2 In addition,
      in mice given 500, 1,000 or 2,000 mg tetrahydrofuran/kg bw, the compound did
      not induce chromosome aberrations in mouse bone marrow cells (sample times
      17- or 36-hours).2
          In male and female mice, the frequency of tetrahydrofuran-induced
      micronucleated polychromatic, and normochromatic erythrocytes, was
      investigated (at the end of a 14-week period; exposure was for six hours a day,
      five days per week).2 In female mice, inhalation of doses of 600, 1,800 or 5,000
      ppm, did not significantly increase the number of micronucleated erythrocytes.
      In male mice, a small increase of micronucle-ated normochromatic erythrocytes
      was noted at the mid dose only. The Committee considers the outcome of this
      study inconclusive, because the test was not performed according to the current
      guidelines.
4.1.3 DNA-adduct formation
      Hermida et al. (2006) showed that tetrahydrofuran has the potential to form
      adducts with 2’-deoxyguanosine, in the presence of a metabolic activation
      system, and NADPH.3 To the Committee, the relevance of the finding is unclear,
      because the conditions were biologically not relevant.
4.2   Non-genotoxic mode of action
      Three short-term animal studies have been performed to elucidate possible non-
      genotoxic mechanisms of action of tetrahydrofuran in the kidneys of male rats,
 2    Tetrahydrofuran
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<pre>and in the liver of female mice. The studies described below all used the same
experimental design, and animal species, as was carried out by the NTP.
     NTP performed fourteen-week duration studies in rats and mice, with a same
design as in the two-year duration study.2 The animals (N=10/group/sex/species)
were exposed to tetrahydrofuran at air concentrations of 0 (control), 66, 200, 600
or 5,000 ppm, for six hours per day, five days per week, for fourteen weeks.
     Histopathology on kidney tissue of male and female rats did not reveal signs
of tissue degeneration or pre-neoplastic lesions. In female rats, absolute and
relative liver weights were significantly increased in rats exposed to 5,000 ppm
compared to controls. No other effects were observed in the kidneys or liver.
     Significant increases in absolute and relative liver weights were observed in
male mice exposed to 600 ppm and greater, and in female mice exposed to 1,800
ppm and greater. In male and female mice exposed to 5,000 ppm, a significant
increase in incidence of minimal to mild centrilobular cytomegaly of the liver
was observed compared to controls. No such significant effects were observed in
the other exposure groups. Also no other effects in the liver were observed, nor
any effect in the kidneys.
     Gamer et al. (2002) reported on tetrahydrofuran-induced cell proliferation
and enzyme induction in male rat kidney and female mouse liver.4 Male F344
rats (N=6/group), and female B6C3F1 mice (N=10/group) inhaled
tetrahydrofuran at concentrations of 0 (vehicle control), 600, 1,800 or 5,400 mg/
m3 (0, 200, 600 and 1,800 ppm, respectively) for six hours a day, for five
consecutive days, either for one week (five treatments) or for four weeks (twenty
treatments). Also, the reversibility of treatment-related changes was studied in
both animal species, which were exposed for five days, and then sacrificed three
weeks after the last exposure. Male rat kidney tissue, and female mouse liver
tissue were sampled for analyses on α2-microglobulin accumulation (rat kidney
tissue only), cell proliferation, apoptosis and metabolic enzyme determination.
     After five and twenty treatments, the rats showed a statistically significant
dose-related α2-microglobulin accumulation in the renal cortex. No signs of
reversibility were observed after the three-week recovery period. In rats exposed
to 1,800 ppm for five treatments (without recovery), the α2-microglobulin
accumulation in the renal cortex was accompanied with increased apoptosis and
cell proliferation. No exposure-related apoptosis and cell proliferation was
observed in rats exposed to 1,800 ppm for twenty treatments, five treatments
with recovery, or in rats exposed to lower exposure levels. Morphological
examination did reveal degeneration or necrosis. A slight increase in hyaline
droplet accumulation was observed in males exposed to 1,800 ppm for twenty
Mode of action                                                                     23
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<pre>      treatments, but not in other groups. Tetrahydrofuran did not induce metabolic
      enzymes.
           In female B6C3F1 mice, a statistically significant increase in cell
      proliferation was observed only in mice inhaling 1,800 ppm for five treatments
      (all zones), and in zone 3 (central vein region) after twenty treatments. This was
      accompanied with an increased mitotic index, but not with increased apoptosis.
      There were no morphological signs of cell degeneration or necrosis. The level
      and activity of metabolic enzymes were statistically significantly increased in
      mice exposed to 1,800 ppm for five treatments, but not in other groups.
           Van Ravenzwaay et al. (2003) exposed female B6C3F1 mice (N=18/group) to
      tetrahydrofuran at air concentrations of 0 (control), 1,800 or 5,000 ppm, for six
      hours per day for five days.5 The animals were killed on the day of last exposure.
      Thereafter, they determined metabolic enzyme amount and activity, and
      performed histochemical analysis (morphology and cell proliferation) on liver
      tissues. Treatment with tetrahydrofuran at 5,000 ppm increased significantly the
      level and activity of metabolic enzymes. Furthermore, at this exposure level, cell
      proliferation was statistically significantly increased compared to controls. No
      such effects occurred in the group exposed to 1,800 ppm. Tetrahydrofuran did
      not affect subcellular morphology. The investigators also pretreated groups with
      a drug metabolism enzyme inhibitor. The inhibitor clearly blocked enzyme
      activity, whereas histochemical analysis of tissues in these groups (at 5,000 ppm)
      revealed the presence of significant cell proliferation. Therefore, the authors
      suggested that cell proliferation was caused by tetrahydrofuran itself, and not by
      its (oxidative) metabolites.
4.3   Animal carcinogenicity and its relevance for humans
      In the literature, it is under debate whether the tetrahydrofuran-induced tumours
      in the male rat kidney, and in the female mouse liver, are of relevance for
      humans.6-9 The state of the art, and the opinion of the Committee are given
      below.
4.3.1 Male rat kidney tumours
      Alpha-2u globulin accumulation
      Renal tumours in male rats, which are associated with alpha-2u globulin
      accumulation via renal nephropathy, are considered not relevant for humans.4,6,7
 4    Tetrahydrofuran
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<pre>Humans as well as female rats and mice do not synthesize alpha-2u globulin.
Alpha-2u globulin accumulation is characterised by:6,9
    Hyaline droplets. In the two-year NTP-study, the presence of hyaline droplets
in renal proximal tubule cells was observed in the kidneys of control animals,
and in rats exposed to 1,800 ppm tetrahydrofuran (by the authors called protein
droplets).2 However the severity did not differ between the groups. The NTP also
performed a fourteen-week inhalation study (see Section 4.2).2 In the highest
exposed group (5,000 ppm) a slight increase in hyaline droplets was observed
compared to control animals, but again, the severity of these droplets did not
differ between the two groups. In a third study, Gamer et al. (2002) found only a
slight non-significant increase of hyaline droplets in proximal tubular cells of
male rats exposed to 1,800 ppm tetrahydrofuran for twenty treatments compared
to control animals (see Section 4.2).4
    Presence of alpha-2u globulin in hyaline droplets. Immunohistochemical
analyses by Gamer et al. (2002) demonstrated a statistically significant exposure-
related increase in alpha-2u globulin levels in the renal cortex of male rats, which
were exposed to tetrahydrofuran for five or twenty treatments (see Section 4.2).4
Only in the highest exposed group (1,800 ppm) this was accompanied by a slight
increase in hyaline droplets.
    Alpha-2u globulin specific nephropathological lesions. No evidence for
alpha-2u globulin specific lesions, or cell degeneration, in the kidneys have been
found in any of the three studies.2,4
    In summary, hyaline droplets and the presence of alpha-2u globulin in those
droplets have been demonstrated in tetrahydrofuran-exposed animals. For alpha-
2u globulin levels, the increase was significant, but differences of hyaline droplet
accumulation and severity between exposed and control animals, were minimal.
No signs of alpha-2u globulin specific lesions or cell degeneration have been
observed.
Chronic Progressive Nephropathy (CPN)
Another suggestion is that the development of renal tumours was preceded by
advanced chronic progressive nephropathy (CPN). CPN is considered a
spontaneous age-related disease that occurs in high incidences in certain
common strains of rats only (including Fischer 344 strains).8 It is, therefore,
considered a rodent-specific entity, having no relevance for humans.
    In the two-year NTP-study, both the incidence and the severity of CPN did
not differ among the groups, including the control group. Almost all rats were
affected. The renal tissues of the NTP-study were re-evaluated by others.9-12
Mode of action                                                                       25
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<pre>      Within the CPN affected renal tissue, foci of atypical (focal) tubule hyperplasia
      were observed. These preneoplastic lesions could have contributed to the
      development of renal tumours. However the incidence of combined
      preneoplastic and neoplastic lesions did not differ between the exposed animals
      and the control animals.10
      Overall, the Committee considers it clear that the tumours found in exposed and
      non-exposed male rats could be related to these two mechanisms. Since neither
      alpha-2u globulin accumulation nor CPN occurs in humans, and no genotoxic or
      non-genotoxic mode of action(s) could be attributed to the development of renal
      tumours in male rats, the Committee considers the findings in male rats not
      relevant in assessing the carcinogenic potential of tetrahydrofuran in humans.
4.3.2 Female mouse liver tumours
      The relevance of chemically-induced liver tumours in mice has long been
      questioned.7,13,14 The reason for this is that mouse cancer models frequently
      develop spontaneous hepatocellular tumours at high rates. A typical pattern
      observed is that due to differences in sex hormones, the rates in male mice are
      higher than in female mice.14 In particular when a high rate is observed in one
      sex only, some investigators consider the findings not relevant for humans. On
      the other hand, the Committee considers liver tumours in mice relevant for
      humans when the induction of tumours can be explained by a specific
      carcinogenic mechanism, such as genotoxicity, and/or the promotion of tumour
      development in early or late stages.7,9
          In evaluating the mode of action, the two-year NTP-study has a main
      limitation in that data on male mice cannot be judged, because of the lower
      survival rate in the highest dosed-group. This was most likely due to the presence
      of a bacterial infection. So, it cannot be ruled out that tetrahydrofuran might have
      induced liver tumours in male mice as well, if there was no infection at all.
      However, the Committee is aware that male and female rats, which were also
      exposed to tetrahydrofuran in the same study, did not show any sign of the
      development of liver tumours.
          Regarding genotoxicity, genotoxicity assays were negative (see Section 4.1).
      Also, the principal metabolites of tetrahydrofuran, gamma-butyrolactone and
      gamma-hydroxybutyric acid, did not show signs of carcinogenicity and
      genotoxicity.7,15
          In the literature it is suggested that exposure to tetrahydrofuran may have
      resulted in liver tumours by inducing cell proliferation, which might have led to
 6    Tetrahydrofuran
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<pre>promotion in the growth of pre-initiated cells.4,7,9 Increased cell proliferation was
clearly observed in female mice of the highest-exposed group (1,800 ppm; after
five treatments) in the short-term study by Gamer et al. (2002; see Section 4.2).4,5
However, after twenty treatments the increase was non-significant. Furthermore,
in the same study, and in the NTP-studies, no clear signs of increased cell
degeneration or necrosis were observed.2,4 This missing link between cell
proliferation and cell degeneration indicates that the induction of cell
proliferation cannot be associated with the liver tumours that developed in
exposed female mice.
    Overall, the Committee concludes that there are strong indications (i.e.,
species specific susceptibility for liver tumours, and lack of a clear genotoxic
mode of action) that the liver tumours found in female mice were of no relevance
for humans.
Mode of action                                                                        27
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<pre> hapter 5
        Classification
5.1     Evaluation and conclusion
        No data on the carcinogenicity of tetrahydrofuran in humans are available.
            In animals one carcinogenicity inhalation study has been performed using
        rats and mice. In male rats, a slight but statistically non-significant increase in
        incidence of renal tubule adenomas and carcinomas (combined) was observed at
        1,800 ppm; in female mice exposed to the same exposure level, a clear increase
        in incidence of liver adenomas and carcinomas (combined) was reported.
        Tetrahydrofuran did not induce tumours at other sites in the body, nor in the
        opposite sex.
            Regarding the kidney tumours in male rats, the Committee concludes that
        these are not relevant for humans, since the most likely mechanisms that induced
        these tumours are sex and species specific (alpha-2u globulin accumulation and
        chronic progressive nephropathy), which do not occur in humans. Also, the
        Committee concludes that the liver tumours in female mice are of no relevance
        for humans, because of the high species susceptibility for this type of tumours,
        and the absence of tumours at other sites of the body in combination with the
        lack of genotoxic potential of tetrahydrofuran. Overall, there is little or no animal
        data supporting an association between exposure to tetrahydrofuran and cancer.
        Classification                                                                        29
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<pre>5.2 Recommendation for classification
    According to the judgement of the Committee, the available data are insufficient
    to evaluate the carcinogenic properties of tetrahydrofuran (category 3).*
    According to the classification system of the Health Council (see Annex E).
 0  Tetrahydrofuran
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<pre>References
Chhabra RS, Herbert RA, Roycroft JH, Chou B, Miller RA, Renne RA. Carcinogenesis studies of
tetrahydrofuran vapors in rats and mice. Toxicol Sci 1998; 41(2): 183-188.
National Toxicology program. Toxicology and carcinogenesis studies of tetrahydrofuran (CAS No.
109-99-9) in F344/N rats and B6C3F1 mice (inhalation studies). National Toxicology Program, US,
NTP technical Report 475; 1998.
Hermida SA, Possari EP, Souza DB, de AC, I, Gomes OF, Di MP et al. 2’-deoxyguanosine,
2’-deoxycytidine, and 2'-deoxyadenosine adducts resulting from the reaction of tetrahydrofuran with
DNA bases. Chem Res Toxicol 2006; 19(7): 927-936.
Gamer AO, Jaeckh R, Leibold E, Kaufmann W, Gembardt C, Bahnemann R et al. Investigations on
cell proliferation and enzyme induction in male rat kidney and female mouse liver caused by
tetrahydrofuran. Toxicol Sci 2002; 70(1): 140-149.
van Ravenzwaay B., Gamer AO, Leibold E, Kaufmann W. Effect of cytochrome P-450 inhibition on
tetrahydrofuran-induced hepatocellular proliferation in female mice. Arch Toxicol 2003; 77(8): 459-
464.
Doi AM, Hill G, Seely J, Hailey JR, Kissling G, Bucher JR. alpha 2u-globulin nephropathy and renal
tumors in national toxicology program studies. Toxicol Pathol 2007; 35(4): 533-540.
Fenner-Crisp PA, Mayes ME, David RM. Assessing the human carcinogenic potential of
tetrahydrofuran: I. Mode of action and human relevance analysis of the male rat kidney tumor. Regul
Toxicol Pharmacol 2011; 60(1): 20-39.
Hard GC, Khan KN. A contemporary overview of chronic progressive nephropathy in the laboratory
rat, and its significance for human risk assessment. Toxicol Pathol 2004; 32(2): 171-180.
References                                                                                          31
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<pre>  U.S.Environmental Protection Agency. Toxicological review of tetrahydrofuran (CAS no. 109-99-9).
  In support of summary information on the Integrated Risk Information System (IRIS). U.S. EPA,
  Washington DC, EPA/635/R-11/006F; 2012.
0 Bruner RH, Greaves P, Hard GC, Regan KS, Ward JM, David RM. Histopathologic changes in the
  kidneys of male F344 rats from a 2-year inhalation carcinogenicity study of tetrahydrofuran: a
  pathology working group review and re-evaluation. Regul Toxicol Pharmacol 2010; 58(1): 100-105.
1 Hard GC, Seely JC. Recommendations for the interpretation of renal tubule proliferative lesions
  occurring in rat kidneys with advanced chronic progressive nephropathy (CPN). Toxicol Pathol 2005;
  33(6): 641-649.
2 Lock EA, Hard GC. Chemically induced renal tubule tumors in the laboratory rat and mouse: review
  of the NCI/NTP database and categorization of renal carcinogens based on mechanistic information.
  Crit Rev Toxicol 2004; 34(3): 211-299.
3 Alden CL, Smith PF, Piper CE, Brej L. A critical appraisal of the value of the mouse cancer bioassay
  in safety assessment. Toxicol Pathol 1996; 24(6): 722-725.
4 Peychal SE, Bilger A, Pitot HC, Drinkwater NR. Predominant modifier of extreme liver cancer
  susceptibility in C57BR/cdJ female mice localized to 6 Mb on chromosome 17. Carcinogenesis 2009;
  30(5): 879-885.
5 Health Council of the Netherlands. Gamma-butyrolactone, health-based recommended occupational
  exposure limit. Health Council of the Netherlands, The Hague, publication No. 2008/13OSH; 2008.
6 Health Council of the Netherlands. Guideline to the classification of carcinogenic compounds. Guide
  for classifying compounds in terms of their carcinogenic properties, and for assessing their
  genotoxicity. Health Council, The Hague, The Netherlands, Report No. A10/07E; 2010.
2 Tetrahydrofuran
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<pre>A Request for advice
B The Committee
C The submission letter
D Comments on the public review draft
E Classification of substances with respect to carcinogenicity
  Annexes
                                                               33
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<pre>4 Tetrahydrofuran</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 Council as part of a specific request
     Request for advice                                                                                        35
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<pre>      for advice. If possible this evaluation should lead to a health based recommended exposure limit,
      or, in the case of genotoxic carcinogens, a ‘exposure versus tumour incidence range’ and a
      calculated concentration in air corresponding with reference tumour incidences of 10-4 and 10-6
      per year.
  •   The evaluation of documents review the basis of occupational exposure limits that have been
      recently established in other countries.
  •   Recommending classifications for substances as part of the occupational hygiene policy of the
      government. In any case this regards the list of carcinogenic substances, for which the
      classification criteria of the Directive of the European Communities of 27 June 1967 (67/548/
      EEG) are used.
  •   Reporting on other subjects that will be specified at a later date.
  In his letter of 14 December 1993, ref U 6102/WP/MK/459, to the Minister of
  Social Affairs and Employment the President of the Health Council agreed to
  establish DECOS as a Committee of the Health Council. The membership of the
  Committee is given in annex B.
6 Tetrahydrofuran
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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
     •  J.M. Rijnkels, scientific secretary
        Health Council, The Hague
     The Committee                                                              37
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<pre>  The first draft of the present advisory report was prepared by K. Jenken, TNO
  Quality of Life, by contract with the Dutch Health Council.
  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.
8 Tetrahydrofuran
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<pre>nnex C
     The submission letter
     Subject           : Submission of the advisory report Tetrahydrofuran
     Your Reference    : DGV/MBO/U-932342
     Our reference     : U-7437/JR/fs/246-G17
     Enclosed          :1
     Date              : November 23, 2012
     Dear State Secretary,
     I hereby submit the advisory report on the effects of occupational exposure to
     Tetrahydrofuran.
     This advisory report is part of an extensive series in which carcinogenic
     substances are classified in accordance with European Union guidelines. This
     involves substances to which people can be exposed while pursuing their
     occupation.
         The advisory report was prepared by the Subcommittee on the Classification
     of Carcinogenic Substances, a permanent subcommittee of the Health Council’s
     utch Expert Committee on Occupational Safety. The advisory report as been
     assessed by the Health Council’s Standing Committee on Health and the
     Environment.
     The submission letter                                                          39
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<pre>  I have today sent copies of this advisory report to the State Secretary of
  Infrastructure and the Environment and to the Minister of Health, Welfare and
  Sport, for their consideration.
  Yours sincerely,
  (signed)
  Professor W.A. van Gool,
  President
0 Tetrahydrofuran
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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 organisation has commented on the draft document:
     • Mr. T.J. Lentz, National Institute for Occupational Safety and Health, USA.
     Comments on the public review draft                                           41
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<pre>2 Tetrahydrofuran</pre>

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<pre> nnex       E
            Classification of substances with
            respect to carcinogenicity
            The Committee expresses its conclusions in the form of standard phrases:
 ategory    Judgement of the committee (GRGHS)                                           Comparable with EU Category
                                                                                         67/584/EEC     EC No 1272/2008
                                                                                         (before        (as from
                                                                                         12/16/2008)    12/16/2008)
A           The compound is known to be carcinogenic to man.                             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, the mechanism of action is not known.
B           The compound is presumed to be carcinogenic to man.                          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, the mechanism of action is not known.
            The compound is suspected to be carcinogenic to man.                         3              2
3)          The available data are insufficient to evaluate the carcinogenic             Not applicable Not applicable
            properties of the compound.
4)          The compound is probably not carcinogenic to man.                            Not applicable Not applicable
ource: Health Council of the Netherlands. Guideline to the classification of carcinogenic compounds. The Hague: Health
 ouncil, 2010; publication no. A10/07E.16
            Classification of substances with respect to carcinogenicity                                               43
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<pre>4 Tetrahydrofuran</pre>

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<br><br>