<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>2,4,5-Trimethylaniline
Evaluation of the carcinogenicity and genotoxicity
</pre>

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

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

<pre></pre>

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

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

<pre>Gezondheidsraad                                          Vo o r z i t t e r
Health Council of the Netherlands
Aan de minister van Sociale Zaken en Werkgelegenheid
Onderwerp               : Aanbieding advies 2,4,5-Trimethylaniline
Uw kenmerk              : DGV/MBO/U-932542
Ons kenmerk             : U-5138/JR/pg/246-K12
Bijlagen                :1
Datum                   : 1 april 2008
Geachte minister,
Graag bied ik u hierbij het advies aan over de kankerverwekkendheid van 2,4,5-trimethyla-
niline. Het maakt deel uit van een uitgebreide reeks waarin kankerverwekkende stoffen
worden geclassificeerd volgens richtlijnen van de Europese Unie. Het gaat om stoffen waar-
aan mensen tijdens de beroepsmatige uitoefening kunnen worden blootgesteld.
     Het advies is opgesteld door een vaste subcommissie van de Commissie Gezondheid en
beroepsmatige blootstelling aan stoffen (GBBS), de Subcommissie Classificatie van carci-
nogene stoffen. Het advies is voorgelegd aan de Commissie GBBS en vervolgens getoetst
door de Beraadsgroep Gezondheid en omgeving van de Gezondheidsraad.
Ik heb dit advies vandaag ter kennisname toegezonden aan de minister van Volksgezond-
heid, Welzijn en Sport en de minister van Volkshuisvesting, Ruimtelijke Ordening en
Milieubeheer.
Hoogachtend,
prof. dr. J.A. Knottnerus
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 6 6 3 1                                      Te l e f a x ( 0 7 0 ) 3 4 0 7 5 2 3
E - m a i l : j o l a n d a . r i j n k e l s @ g r. n l                    w w w. g r. n l
</pre>

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

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

<pre></pre>

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

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

<pre>2,4,5-Trimethyhlaniline
Evaluation of the carcinogenicity and genotoxicity
Subcommittee on the classification of carcinogenic substances of the
Dutch Expert Committee on Occupational Standards,
a committee of the Health Council of the Netherlands
to:
the Minister of Social Affairs and Employment
No. 2008/01OSH, The Hague, April 1, 2008
</pre>

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

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

<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...” (Section
22, Health Act).
     The Health Council receives most requests for advice from the Ministers of
Health, Welfare & Sport, Housing, Spatial Planning & the Environment, Social
Affairs & Employment, and Agriculture, Nature & Food Quality. The Council
can publish advisory reports on its own initiative. It usually does this in order to
ask attention for developments or trends that are thought to be relevant to gov-
ernment 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. 2,4,5-Trimethyhlaniline; Evaluation of the
carcinogenicity and genotoxicity. The Hague: Health Council of the Netherlands,
2008; publication no. 2008/01OSH.
all rights reserved
ISBN: 978-90-5549-686-0
</pre>

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

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

<pre>    Contents
    Samenvatting 9
    Executive summary 11
1   Scope 13
1.1 Background 13
1.2 Committee and procedures 13
1.3 Data 14
2   General information 15
2.1 Identity and physico-chemical properties 15
2.2 IARC classification 16
3   Carcinogenicity 17
3.1 Observations in humans 17
3.2 Carcinogenicity studies in animals 17
4   Mutagenicity and genotoxicity 21
4.1 In vitro assays 21
4.2 In vivo assays 21
4.3 Additional information on carcinogenic mechanism 22
    Contents                                            7
</pre>

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

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

<pre>5   Classification 23
5.1 Evaluation of data on carcinogenicity and genotoxicity 23
5.2 Recommendation for classification 24
    References 25
    Annexes 27
A   Request for advice 29
B   The committee 31
C   Comments on the public review draft 33
D   IARC Monograph 35
E   Carcinogenic classification of substances by the committee 37
F   Guideline 93/21/EEG of the European Union 39
8   2,4,5-Trimethylaniline
</pre>

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

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

<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 2,4,5-trime-
thylaniline onder de loep. De stof werd onder andere gebruikt bij de productie
van kleurstoffen en geneesmiddelen.
Op basis van de beschikbare gegevens leidt de commissie af dat 2,4,5-trimethy-
laniline beschouwd moet worden als kankerverwekkend voor de mens. Dit is ver-
gelijkbaar met een classificatie in categorie 2 volgens de richtlijnen van de
Europese Unie. De commissie is verder van mening dat de stof een stochastisch
genotoxisch werkingsmechanisme heeft.
Samenvatting                                                                   9
</pre>

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

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

<pre>10 2,4,5-Trimethyhlaniline</pre>

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

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

<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 sub-
stances to which workers are occupationally exposed. The evaluation is per-
formed by the subcommittee on Classifying Carcinogenic Substances of the
Dutch Expert Committee on Occupational Standards of the Health Council, here-
after called the committee. In this report, the committee evaluated 2,4,5-trimeth-
ylaniline. The agent has been used as an intermediate for dyestuffs and
pharmaceuticals.
Based on the available information, the committee is of the opinion that 2,4,5-tri-
methylaniline should be considered as carcinogenic to humans. This recommen-
dation is comparable to the EU classification in category 2. The committee is
furthermore of the opinion that 2,4,5-trimethylaniline acts by a stochastic geno-
toxic mechanism.
Executive summary                                                                   11
</pre>

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

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

<pre>12 2,4,5-Trimethyhlaniline</pre>

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

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

<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 classifica-
        tion (see Annex A). The assessment and the proposal for a classification are
        expressed in the form of standard sentences (see Annex E). The criteria used for
        classification are partly based on an EU-directive (see Annex F). In addition to
        classifying substances, the Health Council also assesses the genotoxic properties
        of the substance in question.
        This report contains the evaluation of the carcinogenicity of 2,4,5-trimethyl-
        aniline.
1.2     Committee and procedures
        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. The first draft was prepared by I.A. van de Gevel and M.I.
        Willems, from the Department of Occupational Toxicology of the TNO Nutrition
        Scope                                                                               13
</pre>

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

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

<pre>    and Food Research, by contract with the Ministry of Social Affairs and Employ-
    ment.
         In 2007 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
    listed in Annex C. 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 sci-
    entific 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 genotox-
    icity of the substance in question. In the case of 2,4,5-trimethylaniline, such an
    IARC-monograph is available, of which the summary and conclusion of IARC is
    inserted in Annex D.
         More recently published data were retrieved from the online databases Med-
    line, Toxline, Chemical Abstracts, and RTECS. The last updated online search
    was in June 2007. The new relevant data were included in this report.
14  2,4,5-Trimethyhlaniline
</pre>

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

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

<pre>Chapter 2
        General information
2.1     Identity and physico-chemical properties
        2,4,5-Trimethylaniline has been used as an intermediate for dyestuffs (red dye
        Ponceau 3R), and pharmaceuticals.1 Below is given the identity and some of its
        physical and chemical properties.
        Chemical name            :   Benzenamine, 2,4,5-trimethyl
        CAS registry number      :   137-17-7
        EINECS number            :   205-282-0
        IUPAC name               :  2,4,5-trimethylaniline
        Synonyms                 :  1-amino-2,4,5-trimethylbenzene; pseudocumidine; 1,2,4-trime-
                                     thyl-5-aminobenzene; 2,4,5-trimethylbenzenamine; psi-cumi-
                                     dine; NCI-C02299
        Description              :   white to light tan crystalline solid
        Molecular formula        :   C9H13N
        Structure                :
        Molecular weight         :   135.2
        Melting point            :   62-65 °C
        Boiling point            :   234-235 °C
        General information                                                                      15
</pre>

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

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

<pre>    Solubility                   : Highly soluble in water; soluble in ethanol
    Relative vapour density      : 3.76
    Vapour pressure              : 0.13 kPa at 68.4 °C; 1.3 kPa at 109.0 °C
    Stability                    : Stable under ordinary conditions
    Conversion factors           : 1 ppm= 5.61 mg/m3
    (20 °C)                        1 mg/m3 = 0.18 ppm
    EU risk and safety phrases   : R45: may cause cancer
                                   R23/24/25: toxic by inhalation, in contact with skin, and if swal-
                                   lowed
                                   R51/53: toxic to aquatic organisms, may cause long-term
                                   adverse effects in the aquatic environment
                                   S53: avoid exposure – obtain special instructions before use
                                   S45: in case of accident or when you feel unwell, seek medical
                                   advise immediately (show the label where possible)
                                   S61: avoid release to the environment. Refer to special instruc-
                                   tions/safety data sheets
    EU classification            : Carcinogenic category 2
2.2 IARC classification
    In 1982, IARC concluded that there is limited evidence for the carcinogenicity of
    2,4,5-trimethylaniline in animals, and that no data were available from studies in
    humans.1 In 1987, IARC classified the agent in group 3, indicating that it was not
    classifiable as to its carcinogenicity to humans. 2
16  2,4,5-Trimethyhlaniline
</pre>

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

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

<pre>Chapter 3
        Carcinogenicity
3.1     Observations in humans
        No data were available on the carcinogenicity of 2,4,5-trimethylaniline in
        humans.
3.2     Carcinogenicity studies in animals
        Two series of carcinogenicity studies have been performed in rats and mice,
        which were fed 2,4,5-trimethylaniline-enriched diets.
            In the study by Weisburger et al. (1978) male CD rats, and male and female
        CD-1 mice were given diets containing 1,000 or 2,000 ppm 2,4-5-trimethyla-
        niline (as the hydrochloride) for 78 weeks, with a further observation period of
        26 (rats) and 13 (mice) weeks on plain diet.3 The dose of 2,000 ppm was consid-
        ered the maximum tolerated dose. An additional group of 25 animals per species
        per sex served as matched untreated control. Also a pooled untreated control
        group was used to evaluate the results. Only animals that survived six months or
        more were examined.
            In rats, subcutaneous fibromas and fibrosarcomas, and liver tumours were
        found. The incidences for matched controls, pooled controls, low- and high dose
        groups are shown in Table 3.1. Overall, no treatment-related increases in tumour
        incidences were observed. Although the increase in tumours in the low-dose
        Carcinogenicity                                                                  17
</pre>

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

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

<pre>             group was statistically significantly increased compared to pooled controls, no
             such significant increases were observed in the high-dose group.
                  In contrast, in both male and females mice, treatment-related increases of
             tumour incidences were observed for lung and liver tumours (see Table 3.1). In
             some mice also vascular tumours were observed, but these could not be related to
             treatment.
                  The committee noted the poor reporting of the study design and results of
             both the rat and mouse study. This plus the low survival rate in the mouse study
             led to the conclusion of the Working Group of IARC that the mouse study was
             inadequate for evaluation.1 It is unclear to the committee why IARC discarded in
             particular the mouse study, since survival rates and the number of animals exam-
             ined between the rat and mouse studies did not differ appreciable. Overall,
             despite the poor reporting, the committee considers the results of the Weisburger
             studies suggestive for carcinogenic activity of 2,4,5-trimethylaniline.
                  The second large carcinogenicity study was performed by the National Cancer
             Institute (NCI) of the United States.4 Male and female F344 rats and B6C3F1
             mice received 200 or 800 ppm (rats), and 50 or 100 ppm (mice) 2,4,5-trimethyla-
             niline (free amine) in the diet for 101 weeks. Plain diets were given to matched
             controls. Survival and tumour incidence rates are given in Table 3.2 (rats) and
             Table 3.3 (mice).
Table 3.1 Tumour incidences of rats and mice receiving 2,4,5-trimethylaniline-enriched diets.3
Dose in feed                                       0 ppm             0 ppm              1,000 ppm 2,000 ppm
                                                  (matched control) (pooled control)
CD rats (males)
  no. of animals at start of study                 25                111                25        25
  liver tumours                                   2/22                2/111             3/17**§   2/25
  skin tumours                                    4/22               18/111             6/17*§    1/25 (lipoma)
CD1 mice (males)
  no. of animals at start of study                 25                100                25        25
  liver tumours                                   3/18                7/99               9/14**   19/21**
  lung tumours                                    5/18               24/99              11/14**   10/21*§
  vascular tumours                                0/18                5/99               3/14      3/21
CD1 mice (females)
  no. of animals at start of study                 25                102                25        25
  liver tumours                                   0/20                1/102              6/15**   14/22**
  lung tumours                                    6/20               32/102             11/15**   12/22*§
  vascular tumours                                0/20                9/102              3/15      3/22
* p<0.05; ** p<0.025; § compared to pooled controls.
18           2,4,5-Trimethyhlaniline
</pre>

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

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

<pre>Table 3.2 Tumour incidences of rats receiving 2,4,5-trimethylaniline-enriched diets.4
Dose in feed                             0 ppm              200 ppm            800 ppm
                                         (matched control)
F344 rats (males)
no. of animals at start of study         20                 50                 50
survival (percentage)                    80                 74                 86
lung: adenomas/adenocarcinomas           1/20 (1 carc)      0/49               7/50 (2 carc)
liver: hepatocellular carcinomas         0/19               3/50               11/50*
       neoplastic nodules                1/19               3/50               11/50***
       bile-duct carcinomas              0/19               0/50               4/50
F344 rats (females)
no. of animals at start of study         20                 50                 50
survival (percentage)                    70                 84                 84
lung: adenomas/adenocarcinomas           0/20               3/43 (2 carc       11/50* (2 carc)
liver: hepatocellular carcinomas         0/20               0/49               9/50**
       neoplastic nodules                0/20               12/49              20/50***
       bile-duct carcinomas              0/19               0/49               1/50
* p<0.02; ** p<0.039; *** p<0.05; carc= adenocarcinoma
Table 3.3 Tumour incidences of mice receiving 2,4,5-trimethylaniline-enriched diets.4
Dose in feed                             0 ppm              200 ppm            800 ppm
                                         (matched control)
B6C3F1 mice (males)
no. of animals at start of study         20                 50                 50
survival (percentage)                    80                 86                 76
lung: adenomas/adenocarcinomas           4/20 (4 carc)      9/50 (9 carc)      1/50 (1 carc)
liver: hepatocellular carcinomas         5/20               26/50**            27/50*
       hyperplastic nodules              1/20               3/50               7/50
       bile-duct carcinomas              0/20               2/50               2/51
Vasculature: hemangiosarcoma             2/20               3/50               6/50
B6C3F1 mice (females)
no. of animals at start of study         20                 50                 50
survival (percentage)                    85                 78                 90
lung: adenomas/adenocarcinomas           0/19               5/49 (4 carc)      6/48*** (6 carc)
liver: hepatocellular carcinomas         0/20               18/49*             40/50*
       hyperplastic nodules              0/20               4/49               13/50
       bile-duct carcinomas              0/20               0/49               0/50
Vasculature: hemangiosarcoma             1/20               11/49***           7/50
* p<0.02; ** p<0.03; *** p<0.05; carc= adenocarcinoma
Carcinogenicity                                                                                 19
</pre>

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

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

<pre>       Statistically significant dose-related increases in tumour incidences were
   observed for liver and lung tumours in male and female rats, and for liver
   tumours in male and female mice. Overall, the committee is of the opinion that
   the NCI studies point to carcinogenic activity of 2,4,5-trimethylaniline in both
   rats and mice.
20 2,4,5-Trimethyhlaniline
</pre>

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

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

<pre>Chapter 4
        Mutagenicity and genotoxicity
4.1     In vitro assays
        2,4,5-Trimethylaniline induced reverse mutations in the conventional Ames test
        in Salmonella typhimurium strains TA98 and TA100, in the presence of an exog-
        enous metabolic system.1,5,6 It, furthermore, induced gene mutations at the hprt
        locus of mammalian fibroblasts at a concentration of 50 μg/mL.7
             In Chinese hamster V79 cells, exposure to 2,4,5-trimethylaniline at concen-
        trations of up to 10 mM for 2 or 4 hours did not induce DNA strand breaks.6
        In Chinese hamster ovary cells, the agent increased the frequency of sister chro-
        matid exchanges (SCE) and chromosomal aberrations in the presence and
        absence (SCE only) of an exogenous metabolic system (maximum concentration
        was 5 mg/mL for 2 hours).8
4.2     In vivo assays
        Kugler-Steigmeier et al. (1988, 1989) tested the genotoxic potential of 2,4,5-tri-
        methylaniline in the conventional wing spot test using Drosophila melanogaster
        flies.5,7 This test detects somatic mutations and recombinations. The agent
        increased the frequency of small single spots, whereas the frequency of large sin-
        gle spots and twin spots did not differ significantly from untreated controls. The
        exposure was for 24 or 48 hours to various concentrations (up to 20 mM).
        Mutagenicity and genotoxicity                                                      21
</pre>

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

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

<pre>4.3 Additional information on carcinogenic mechanism
    In the literature attention is given to structure-activity comparisons among aro-
    matic amines in general.9,10 As a result the American Environmental Protection
    Agency indicated a ‘high-moderate’ concern for carcinogenicity to 2,4,5-trime-
    thylaniline.
        The possible genotoxic mechanism of 2,4,5-trimethylaniline is not clarified
    yet. Based on their results, Kugler-Steigmeier et al. suggested that mutagenic
    activity is dependent on metabolic activation.5,7 At least other aromatic amines,
    which have been more extensively studied, are known to cause cancer by a geno-
    toxic mechanism.9
22  2,4,5-Trimethyhlaniline
</pre>

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

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

<pre>Chapter 5
        Classification
5.1     Evaluation of data on carcinogenicity and genotoxicity
        No data on the genotoxicity and carcinogenicity of 2,4,5-trimethylaniline in
        humans were available, nor were there any data available on inhalation exposure
        in animals.
            In two independent long-term carcinogenicity studies, 2,4,5-trimethylaniline
        administered in the diet of rats and mice resulted in treatment-related liver and
        lung tumour development in part of the animals. However, in one rat group no
        treatment-related tumour development was observed. Although the committee
        noted the poor reporting of one of these studies, it is of the opinion that the data
        indicate sufficient evidence for the carcinogenicity of 2,4,5,-trimethylaniline in
        animals.
            Furthermore, the agent showed to be mutagenic in bacterial mutagenicity
        assays and in assays using Drosophila melanogaster flies. It also showed clasto-
        genic effects in vitro in mammalian cells. Based on these results the committee
        considers 2,4,5-trimethylaniline a genotoxic carcinogen that acts by a stochastic
        mechanism.
            The committee did not find indications that the observations in animals, and
        the proposed carcinogenic mechanism would not occur in humans.
        Classification                                                                       23
</pre>

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

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

<pre>5.2 Recommendation for classification
    Based on the available information, the committee is of the opinion that 2,4,5-tri-
    methylaniline should be considered as carcinogenic to humans. This recommen-
    dation is comparable to the EU classification in category 2. The committee is
    furthermore of the opinion that 2,4,5-trimethylaniline acts by a stochastic geno-
    toxic mechanism.
24  2,4,5-Trimethyhlaniline
</pre>

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

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

<pre>  References
1 International Agency for Research on Cancer. 2,4,5- and 2,4,6-Trimethylaniline and their
  hydrochlorides. IARC Monographs on the evaluation of carcinogenic risk on humans, Lyon, France,
  Volume 27: pp177-188; 1982.
2 International Agency for Research on Cancer. Overall evaluations of carcinogenicity: an updating of
  IARC monographs volumes 1 to 42. IARC monographs on the evaluation of carcinogenic risk to
  humans, Lyon, France, Supplement 7; 1987.
3 Weisburger EK, Russfield AB, Homburger F, Weisburger JH, Boger E, Van Dongen CG et. al.
  Testing of twenty-one environmental aromatic amines or derivatives for long-term toxicity or
  carcinogenicity. J Environ Pathol Toxicol 1978; 2(2): 325-356.
4 National Cancer Institute. Bioassay of 2,4,5-trimethylaniline for possible carcinogenicity.
  Natl.Cancer Inst, Bethesda, Maryland, USA.Carcinogenesis Technical Report Series No. 160: 1979.
5 Kugler-Steigmeier ME, Friederich U, Graf U, Lutz WK, Maier P, Schlatter C. Genotoxicity of aniline
  derivatives in various short-term tests. Mutat Res 1989; 211(2): 279-289.
6 Zimmer D, Mazurek J, Petzold G, Bhuyan BK. Bacterial mutagenicity and mammalian cell DNA
  damage by several substituted anilines. Mutat Res 1980; 77(4): 317-326.
7 Kugler-Steigmeier ME, Friederich U, Graf U, Maier P, Schlatter C. Testing of 2,4,5- and 2,4,6-
  trimethylaniline in the Salmonella assay, in mammalian cell cultures, and in Drosophila
  melanogaster, and comparison of the results with carcinogenicity data. Arch Toxicol Suppl 1988; 12:
  337-340.
8 Loveday KS, Anderson BE, Resnick MA, Zeiger E. Chromosome aberration and sister chromatid
  exchange tests in Chinese hamster ovary cells in vitro. V: Results with 46 chemicals. Environ Mol
  Mutagen 1990; 16(4): 272-303.
  References                                                                                          25
</pre>

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

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

<pre>9  California Environmental Protection Agency. Evidence on the carcinogenicity of 2,4,5-
   trimethylaniline and its strong acid salts (draft). California EPA, Office of Environmental Health
   Hazard Assessment, Sacramento, USA; 1997.
10 Crabtree HC, Hart D, Thomas MC, Witham BH, McKenzie IG, Smith CP. Carcinogenic ranking of
   aromatic amines and nitro compounds. Mutat Res 1991; 264(4): 155-162.
26 2,4,5-Trimethyhlaniline
</pre>

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

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

<pre>A Request for advice
B The committee
C Comments on the public review draft
D IARC Monograph
E Carcinogenic classification of substances by the committee
F Guideline 93/21/EEG of the European Union
  Annexes
                                                             27
</pre>

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

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

<pre>28 2,4,5-Trimethyhlaniline</pre>

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

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

<pre>Annex A
      Request for advice
      In a letter dated October 11, 1993, ref DGA/G/TOS/93/07732A, to, the State
      Secretary of Welfare, Health and Cultural Affairs, the Minister of Social Affairs
      and Employment wrote:
      Some time ago a policy proposal has been formulated, as part of the simplification of the governmen-
      tal advisory structure, to improve the integration of the development of recommendations for health
      based occupation standards and the development of comparable standards for the general population.
      A consequence of this policy proposal is the initiative to transfer the activities of the Dutch Expert
      Committee on Occupational Standards (DECOS) to the Health Council. DECOS has been established
      by ministerial decree of 2 June 1976. Its primary task is to recommend health based occupational
      exposure limits as the first step in the process of establishing Maximal Accepted Concentrations
      (MAC-values) for substances at the work place.
      In an addendum, the Minister detailed his request to the Health Council as fol-
      lows:
      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                                                                                        29
</pre>

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

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

<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 calcu-
       lated 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 classifica-
       tion 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.
30 2,4,5-Trimethyhlaniline
</pre>

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

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

<pre>Annex B
      The committee
      •   G..J. Mulder, chairman
          emeritus professor of toxicology, Leiden University, Leiden
      •   P.J. Boogaard
          toxicologist, SHELL International BV, The Hague
      •   Ms. M.J.M. Nivard
          molecular biologist and genetic toxicologist, Leiden University Medical Cen-
          ter, Leiden
      •   G.M.H. Swaen
          epidemiologist, Dow Chemicals NV, Terneuzen
      •   R.A. Woutersen
          toxicologic pathologist, TNO Quality of Life, Zeist
      •   A.A. van Zeeland
          professor of molecular radiation dosimetry and radiation mutagenesis, Uni-
          versity Medical Center, Leiden
      •   E.J.J. van Zoelen
          professor of cell biology, Radboud University Nijmegen, Nijmegen
      •   J.M. Rijnkels, scientific secretary
          Health Council of the Netherlands, The Hague
      The committee consulted an additional expert, Prof. dr. G. Mohn, working at
      Department of Radiation Genetics and Chemical Mutagenesis of the University
      of Leiden, with respect to the genotoxic data.
      The committee                                                                    31
</pre>

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

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

<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 Coun-
   cil Committee. Transparency regarding possible conflicts of interest is nonethe-
   less important, both for the President 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 mate-
   rial 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 establishment meeting the declarations issued are dis-
   cussed, so that all members of the Committee are aware of each other’s possible
   interests.
32 2,4,5-Trimethyhlaniline
</pre>

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

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

<pre>Annex C
      Comments on the public review draft
      A draft of the present report was released in 2007 for public review. The follow-
      ing organisations and persons have commented on the draft document:
      • E. González-Fernández, Ministerio de Trabajo y Asuntos Sociales, Spain;
      • R.D. Zumwalde, National Institute for Occupational Safety and Health, the
          USA.
      Comments on the public review draft                                               33
</pre>

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

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

<pre>34 2,4,5-Trimethyhlaniline</pre>

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

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

<pre>Annex D
      IARC Monograph
      Vol.: 27 (1982) (p. 177)1
      2,4,5-Trimethylaniline
      CAS No.: 137-17-7
      Chem. Abstr. Name: Benzenamine, 2,4,5-trimethyl-
      Summary of Data Reported and Evaluation
      Experimental data
      2,4,5-Trimethylaniline and its hydrochloride were tested in two experiments in
      mice and in two experiments in rats by dietary administration. In one experiment
      in mice, 2,4,5-trimethylaniline produced an increased incidence of hepatocellular
      carcinomas in female mice. The other experiment in mice was considered inade-
      quate for an evaluation. In one experiment in rats it produced an increased inci-
      dence of liver carcinomas and lung adenomas. In the other experiment in rats no
      significantly increased incidence of tumours was observed.
          2,4,5-Trimethylaniline was mutagenic to Salmonella typhimurium with meta-
      bolic activation. The available data were inadequate to evaluate the mutagenicity
      of 2,4,6-trimethylaniline.
      IARC Monograph                                                                    35
</pre>

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

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

<pre>   Human data
   2,4,5-Trimethylaniline has been produced commercially in the past. No case
   report or epidemiological study was available to the Working Group.
   Evaluation
   There is limited evidence for the carcinogenicity of 2,4,5-trimethylaniline in
   experimental animals. No evaluation of the carcinogenicity of 2,4,5-trimethyla-
   niline to humans could be made.
   Subsequent evaluation: Suppl. 7 (1987) (p. 73: Group 3)
36 2,4,5-Trimethyhlaniline
</pre>

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

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

<pre>Annex         E
              Carcinogenic classification of
              substances by the committee
The committee expresses its conclusions in the form of standard phrases:
Judgment of the committee                                                                       Comparable with EU class
This compound is known to be carcinogenic to humans                                             1
•   It is stochastic or non-stochastic genotoxic
•   It is non-genotoxic
•   Its potential genotoxicity has been insufficiently investigated. Therefore, it is unclear
    whether it is genotoxic
This compound should be regarded as carcinogenic to humans                                      2
•   It is stochastic or non-stochastic genotoxic
•   It is non-genotoxic
•   Its potential genotoxicity has been insufficiently investigated. Therefore, it is unclear
    whether it is genotoxic
This compound is a suspected human carcinogen.                                                  3
•   This compound has been extensively investigated. Although there is insufficient evidence    (A)
    for a carcinogenic effect to warrant a classification as ‘known to be carcinogenic to
    humans’ or as ‘should be regarded as carcinogenic to humans’, they indicate that there is
    cause for concern.
•   This compound has been insufficiently investigated. While the available data do not war-    (B)
    rant a classification as ‘known to be carcinogenic to humans’ or as ‘should be regarded as
    carcinogenic to humans’, they indicate that there is a cause for concern.
This compound cannot be classified                                                              not classifiable
•   There is a lack of carcinogenicity and genotoxicity data.
•   Its carcinogenicity is extensively investigated. The data indicate sufficient evidence sug-
    gesting lack of carcinogenicity.
              Carcinogenic classification of substances by the committee                                             37
</pre>

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

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

<pre>38 2,4,5-Trimethyhlaniline</pre>

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

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

<pre>Annex F
      Guideline 93/21/EEG of the European
      Union
      4.2            Criteria for classification, indication of danger, choice of risk phrases
      4.2.1          Carcinogenic substances
      For the purpose of classification and labelling, and having regard to the current state of knowledge,
      such substances are divided into three categories:
      Category 1:
      Substances known to be carcinogenic to man.
      There is sufficient evidence to establish a causal association between human exposure to a substance
      and the development of cancer.
      Category 2:
      Substances which should be regarded as if they are carcinogenic to man.
      There is sufficient evidence to provide a strong presumption that human exposure to a substance may
      result in the development of cancer, generally on the basis of:
      •    appropriate long-term animal studies
      •    other relevant information.
      Guideline 93/21/EEG of the European Union                                                             39
</pre>

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

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

<pre>   Category 3:
   Substances which cause concern for man owing to possible carcinogenic effects but in
   respect of which the available information is not adequate for making a satisfactory assess-
   ment.
   There is some evidence from appropriate animal studies, but this is insufficient to place the substance
   in Category 2.
   4.2.1.1       The following symbols and specific risk phrases apply:
   Category 1 and 2:
   T; R45 May cause cancer
   However for substances and preparations which present a carcinogenic risk only when inhaled, for
   example, as dust, vapour or fumes, (other routes of exposure e.g. by swallowing or in contact with
   skin do not present any carcinogenic risk), the following symbol and specific risk phrase should be
   used:
   T; R49 May cause cancer by inhalation
   Category 3:
   Xn; R40 Possible risk of irreversible effects
   4.2.1.2       Comments regarding the categorisation of carcinogenic substances
   The placing of a substance into Category 1 is done on the basis of epidemiological data; placing into
   Categories 2 and 3 is based primarily on animal experiments.
   For classification as a Category 2 carcinogen either positive results in two animal species should be
   available or clear positive evidence in one species; together with supporting evidence such as geno-
   toxicity data, metabolic or biochemical studies, induction of benign tumours, structural relationship
   with other known carcinogens, or data from epidemiological studies suggesting an association.
40 2,4,5-Trimethyhlaniline
</pre>

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

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

<pre>Category 3 actually comprises 2 sub-categories:
a    substances which are well investigated but for which the evidence of a tumour-inducing effect is
     insufficient for classification in Category 2. Additional experiments would not be expected to
     yield further relevant information with respect to classification.
b    substances which are insufficiently investigated. The available data are inadequate, but they
     raise concern for man. This classification is provisional; further experiments are necessary
     before a final decision can be made.
For a distinction between Categories 2 and 3 the arguments listed below are relevant which reduce
the significance of experimental tumour induction in view of possible human exposure. These argu-
ments, especially in combination, would lead in most cases to classification in Category 3, even
though tumours have been induced in animals:
•    carcinogenic effects only at very high levels exceeding the 'maximal tolerated dose'. The maxi-
     mal tolerated dose is characterized by toxic effects which, although not yet reducing lifespan, go
     along with physical changes such as about 10% retardation in weight gain;
•    appearance of tumours, especially at high dose levels, only in particular organs of certain species
     is known to be susceptible to a high spontaneous tumour formation;
•    appearance of tumours, only at the site of application, in very sensitive test systems (e.g. i.p. or
     s.c. application of certain locally active compounds);
•    if the particular target is not relevant to man;
•    lack of genotoxicity in short-term tests in vivo and in vitro;
•    existence of a secondary mechanism of action with the implication of a practical threshold above
     a certain dose level (e.g. hormonal effects on target organs or on mechanisms of physiological
     regulation, chronic stimulation of cell proliferation;
•    existence of a species - specific mechanism of tumour formation (e.g. by specific metabolic
     pathways) irrelevant for man.
For a distinction between Category 3 and no classification arguments are relevant which exclude a
concern for man:
•    a substance should not be classified in any of the categories if the mechanism of experimental
     tumour formation is clearly identified, with good evidence that this process cannot be extrapo-
     lated to man;
•    if the only available tumour data are liver tumours in certain sensitive strains of mice, without
     any other supplementary evidence, the substance may not be classified in any of the categories;
•    particular attention should be paid to cases where the only available tumour data are the occur-
     rence of neoplasms at sites and in strains where they are well known to occur spontaneously with
     a high incidence.
Guideline 93/21/EEG of the European Union                                                                 41
</pre>

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

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

<pre>42 2,4,5-Trimethyhlaniline</pre>

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

<br><br>