<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>Strong inorganic acid mists containing
sulphuric acid
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<pre>Gezondheidsraad
Health Council of the Netherlands
Aan de Staatssecretaris van Sociale Zaken en Werkgelegenheid
Postbus 90801
2509 LV DEN HAAG
Onderwerp          : Aanbieding advies ‘zwavelzuurnevels’
Uw kenmerk         : DGV/BMO-U-932542
Ons kenmerk        : U-454/JR/RA/459-K39
Bijlagen           :1
Datum              : 15 april 2003
Mijnheer de Staatssecretaris,
Bij brief van 3 december 1993, nr DGV/BMO-U-932542, verzocht de Staatssecretaris van
Welzijn, Volksgezondheid en Cultuur namens de Minister van Sociale Zaken en Werkgelegenheid
de Gezondheidsraad om gezondheidskundige advieswaarden af te leiden ten behoeve van de
bescherming van beroepsmatig aan stoffen blootgestelde personen.
      In dat kader bied ik u hierbij een advies aan over de kankerverwekkende eigenschappen van
sterke anorganische zure nevels die zwavelzuur bevatten. Dit advies is opgesteld door de
Commissie WGD van de Gezondheidsraad en beoordeeld door de Beraadsgroep Gezondheid en
Omgeving.
      Ik heb dit advies vandaag ter kennisname toegezonden aan de Minister van Volksgezondheid,
Welzijn en Sport en de Minister van Volkshuisvesting, Ruimtelijke Ordening en Milieu.
Hoogachtend,
prof. dr JA Knottnerus
Bezoekadres                                                            Postadres
Parnassusplein 5                                                       Postbus 16052
2511 VX Den Haag                                                       2500 BB Den Haag
Telefoon (070) 340 6631                                                Telefax (070) 340 75 23
E-mail: jolanda rijnkels@gr.nl                                         www.gr.nl
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<pre>Strong inorganic acid mists containing
sulphuric acid
Evaluation of the carcinogenicity and genotoxicity
Dutch Expert Committee on Occupational Standards,
a committee of the Health Council of the Netherlands
to:
the Minister and State Secretary of Social Affairs and Employment
No. 2003/07OSH, The Hague, April 15, 2003
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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...” (Section 21, 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 Preservation & Fisheries. 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.
Preferred citation:
Health Council of the Netherlands: Strong inorganic acid mists containing sulphuric
acid; Evaluation of the carcinogenicity and genotoxicity. The Hague: Health Council of
the Netherlands, 2003; publication no. 2003/07OSH.
all rights reserved
ISBN: 90-5549-475-5
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<pre>    Inhoud
    Samenvatting 7
    Executive summary 8
1   Scope 9
1.1 Background 9
1.2 Committee and procedures 9
1.3 Data 10
2   Strong inorganic acid mists containing sulphuric acid 11
2.1 Introduction 11
2.2 IARC conclusion 12
2.3 Human data 12
2.4 Animal data 15
2.5 Mutagenicity and genotoxicity 18
2.6 Evaluation 19
2.7 Recommendation for classification 20
    References 21
    Inhoud                                                   5
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<pre>  Annexes 23
A Request for advice 24
B The committee 26
C Comments on the public review draft 28
D IARC Monograph 29
E Classification of substances with respect to carcinogenicity 32
F Guideline 93/21/EEG of the European Union 33
  Inhoud                                                          6
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<pre>  Samenvatting
  Op verzoek van de Minister van Sociale Zaken en Werkgelegenheid beoordeelt de
  Gezondheidsraad de kankerverwekkende eigenschappen van stoffen waaraan mensen
  tijdens de beroepsuitoefening kunnen worden blootgesteld. In het voorliggende rapport
  neemt de Commissie WGD van de Raad, die deze beoordelingen verricht, anorganische
  zure nevels die zwavelzuur bevatten onder de loep. De commissie heeft haar oordeel
  gegoten in door de Europese Unie aangegeven termen.
  De commissie concludeert dat anorganische zure nevels die zwavelzuur bevatten,
  kankerverwekkend zijn voor de mens (vergelijkbaar met EU categorie 1). Deze
  kankerverwekkende zure nevels zijn volgens de commissie niet-stochastisch
  genotoxisch*.
* Dit betekent dat een gezondheidskundige advieswaarde kan worden afgeleid, gebruikmakend van een methode die
  rekening houdt met een drempelwaarde. Een dergelijke advieswaarde wordt niet afgeleid voor genotoxische
  kankerverwekkende stoffen. In dit laatste geval schat de commissie het extra kankerrisico middels een lineaire
  extrapolatiemethode.
  Samenvatting                                                                                                   7
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<pre>  Executive summary
  At request of the Minister of Social Affairs and Employment, the Health Council of the
  Netherlands evaluates the carcinogenic properties of substances at the workplace and
  proposes a classification with reference to the EU-directive. The Dutch Expert
  Committee on Occupational Standards performs this evaluation. The present report
  contains an evaluation by the committee on the carcinogenicity of strong inorganic acid
  mists containing sulphuric acid.
  The committee concludes that strong inorganic acid mists containing sulphuric acid are
  known to be carcinogenic to humans (comparable with EU category 1). These inorganic
  acid mists act by a non-stochastic genotoxic mechanism*.
* This means that an occupational exposure limit can be derived using a threshold model. Such an exposure limit cannot be
  derived for genotoxic carcinogens. In the latter case, the committee estimates additional lifetime cancer risks using a
  linear extrapolation model as a default method.
  Executive summary                                                                                                       8
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<pre>Chapter 1
        Scope
1.1     Background
        In the Netherlands a special policy is in force with respect to occupational use and
        exposure to carcinogenic substances. The Minister of Social Affairs and Employment
        has asked the Health Council of the Netherlands to study the carcinogenic properties of
        substances and to propose a classification with reference to an EU-directive (annex A
        and F). This task is carried out by the Council’s Dutch Expert Committee on
        Occupational Standards, hereafter called the committee.
             The evaluation of the carcinogenicity of a substance is based on IARC* evaluations.
        The original publications are not reviewed and evaluated in the text of the report, but the
        overall conclusion of the IARC on the carcinogenic properties is included (annex D).
             In addition to classifying substances with respect to their possible carcinogenicity
        according to the EU Guidelines, the committee also assesses the genotoxic properties of
        the substances in question. The committee expresses its conclusions in the form of
        standard sentences (annex E).
1.2     Committee and procedures
        The present report contains an evaluation by the committee of the carcinogenicity of
        strong inorganic acid mists containing sulphuric acid. The members of the committee
*       International Agency for Research on Cancer.
        Scope                                                                                       9
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<pre>    are listed in annex B. The committee consulted two additional experts, Prof dr G Mohn
    and dr M Nivard, both working at Department of Radiation Genetics and Chemical
    Mutagenesis of the University of Leiden, with respect to the genotoxic data. The first
    draft of this report was prepared by M Willems, from the TNO Nutrition and Food
    Research in Zeist, by contract with the Ministry of Social Affairs and Employment.
         In 2000, 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 of the carcinogenicity of strong inorganic acid mists containing
    sulphuric acid has been based on an IARC evaluation (IARC92). Where relevant, the
    original publications cited by IARC were reviewed and evaluated in the text.
         In addition, literature has been retrieved from the CD ROMs of Toxline, and
    Medline, covering the period 1985 to December 2002.
    Scope                                                                                       10
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<pre>Chapter 2
        Strong inorganic acid mists containing
        sulphuric acid
2.1     Introduction
        Chemical name            :   sulphuric acid
        CAS registry number      :   7664-93-9
        EINECS number            :   231-639-5
        Synonyms                 :   oil of vitriol, sulfuric acid, spirit of sulphur, battery acid, dipping acid,
                                     electrolyte acid, fertilizer acid, hydrogen sulphate, matting acid,
                                     Nordhausen acid.
        Appearance               :   colourless (pure) to dark brown, oily, hygroscopic liquid, with no
                                     odour.
        Occurrence               :   sulphuric acid is a liquid that is present in air primarily as aerosol
                                     (mists) under normal working conditions; the compound may also be
                                     present as vapour.
        Use                      :   as a raw material in the manufacture of synthetic fertilizers, nitrate
                                     explosives, dyes, other acids, parchment paper, glue, purification of
                                     petroleum, and pickling of metal. It is used in refining of mineral and
                                     vegetable oils, as an electrolyte of lead-acid storage batteries, and in
                                     laboratories for qualitative and quantitative analyses.
        Chemical formula         :   H2SO4
        Molecular weight         :   98.08 g/mol
        Boiling point            :   315-338 oC; decomposes at 340 oC into sulphur trioxide and water.
        Melting point            :   10 oC (anhydrous acid)
        Vapour pressure          :   < 0.04 kPa at 20 oC; 0.13 kPa at 146 oC
        Vapour density (air = 1) :   3.4
        Solubility               :   miscible with water and alcohol
        Strong inorganic acid mists containing sulphuric acid                                                      11
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<pre>      Conversion factor            :  1 ppm = 2.7 mg/m3
                                      1 mg/m3 = 0.37 ppm
      EU Classification          C:   corrosive substance.
      (100% solution)
                               R35:   causes severe burns.
                               S1/2:  keep locked up and out of reach of children.
                               S26:   in case of contact with eyes rinse immediately with plenty of water and
                                      seek medical advice.
                               S30:   never add water to this product.
                               S45:   In case of accident or if you feel unwell, seek medical advice
                                      immediately (show the label where possible).
      See Kri93, Mer89, IPC00
2.2   IARC conclusion
      In 1992, IARC concluded that there was sufficient evidence that occupational exposure
      to strong inorganic acid mists containing sulphuric acid is carcinogenic to humans and
      classified the compound in Group 1 (IARC92). The conclusion of IARC was solely
      based on human data.
2.3   Human data
2.3.1 IARC data
      IARC evaluated numerous epidemiological studies. Only those studies, which are
      relevant for the present evaluation, are described below. In all these studies, mists of
      sulphuric acid were the predominant exposure, but in none of these studies atmospheric
      levels were presented.
           In a cohort study of US chemical workers in an isopropanol manufacture, using the
      strong-acid method with sulphuric acid, a highly significant excess risk for cancer of the
      paranasal sinuses was observed, when compared to US proportional mortality rates
      (Weil et al., 1952).
           In one large cohort study, undertaken by the US National Institute for Occupational
      Safety and Health (NIOSH), Beaumont et al. (1987)*, Steenland and Beaumont (1989)*
      and Steenland et al. (1988)* reported on the mortality patterns of 1,165 male
      steelworkers exposed to sulphuric acid and other acid mists in three steel-pickling
      operations. Of those workers, 722 had been exposed only to sulphuric acid. The
*     See IARC evaluation from 1992 (IARC92).
      Strong inorganic acid mists containing sulphuric acid                                                   12
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<pre>      investigators found a highly significant excess risk for laryngeal and lung cancer. The
      risk calculations were adjusted for smoking.
           Soskolne et al. (1984)* performed a nested case-control study of workers at a
      refinery and chemical plant in the United States. Fifty incident cases were compared
      with 175 matched controls. The odds ratios (OR) for cancer, especially laryngeal cancer,
      were increased for workers with exposure to sulphuric acid compared with controls
      (laryngeal cancer: moderate exposure level, OR 4.6 (95% CI 0.83-25.35); high exposure
      level, OR 13.4 (95% CI 2.08-85.99). The ratios were adjusted for the effects of tobacco,
      previous history of ear, nose and throat diseases and alcoholism.
           The same investigators performed a population-based case-control study in Canada
      (Soskolne et al., 1992)*, in which 183 incident males cases of laryngeal cancer and 183
      matched control cases were compared for exposure to sulphuric acid. Retrospective
      assessment of exposure to sulphuric acid was based on job period, occupation, job title,
      and employer for each job held by a subject. Omitting exposures in the five years prior
      to diagnosis, the investigators found a significant dose-response effect, with an odds
      ratio of 2.52 (95% CI 0.80-7.91) for short duration-low exposure through 6.87 (95% CI
      1.00-47.06) for long duration-higher exposure. The results were controlled for tobacco
      and alcohol use.
           Siemiatycki (1991)* performed another population-based case-control study and
      included cases of eleven types of histologically confirmed cancer, involving 3,730
      cancer patients and 533 population controls. Thirteen percent of the entire study
      population were occupationally exposed to inorganic acid solutions (hydrochloric,
      sulphuric and nitric acids). In this group, there were two significant associations: a
      relative risk (RR) of 2.0 for oat-cell carcinoma of the lung (33 cases; 90% CI 1.3-2.9)
      and a RR of 1.7 for cancer of the kidney (32 cases; 90% CI 1.2-2.4). Some evidence for
      an association with exposure to sulphuric acid was found for lung cancer. No excess
      cancer of oesophagus, stomach, colon, rectum, pancreas, prostate or bladder, skin
      melanoma or non-Hodgkin’s lymphoma were found.
           IARC considered the studies in workers involved in the manufacture of phosphate
      fertilizers, lead batteries, sulphuric acid, and nitric acid to be less informative (IARC92,
      Ano92).
2.3.2 Additional data
      After the IARC evaluation two case studies have been published. Houghton and White
      (Hou94) reported of a 65-year-old electric forklift truck driver, who developed an
      invasive squamous cell carcinoma in the left vocal fold in the larynx. The man did not
      smoke, drank alcohol only occasionally and had not been exposed to asbestos.
      Strong inorganic acid mists containing sulphuric acid                                        13
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<pre>According to the authors, the cancer was caused to exposure to sulphuric acid fumes
emanating from poorly maintained lead batteries above the driver’s seat.
     In another case study, a cluster is presented of three patients with nasopharyngeal
carcinoma. All three patients worked in the same building of a telecommunications
conveyance station in southern Taiwan with long-term exposure to sulphuric acid
vapour concentrations as high as 0.18 mg/m3. The patients had spent more time in the
room where the sulphuric acid concentration was the highest compared with 19 healthy
workers, working elsewhere in the same building. The authors claimed that the patients
were not exposed to any other known environmental chemicals. Therefore, the authors
suggested that exposure to sulphuric acid vapour may be highly associated with the
development of nasopharyngeal carcinomas (Ho99).
In 1996, Coggon et al. (Cog96) presented the results of a cohort and a nested case-
control study of upper aerodigestive tumours in men employed since 1950 at two battery
plants and two steel works in the United Kingdom. The cohort included 2,678 men with
definite exposure to acid mists (mainly sulphuric acid, but also hydrochloric acid), 367
with possible exposure and 1,356 who were not exposed. Mortality was compared with
that of the national population. Cases of upper aerodigestive cancer were identified from
death certificates and cancer registration. At the end of 1993, 93% of the men were
traced, including 1,277 who had died. Among the men definitely exposed to acid mists,
overall mortality was less than in the national population (SMR (standardised mortality
ratio) 0.92, 95% CI 0.85-0.98), as was mortality from all cancers (SMR 0.92, 95% CI
0.79-1.05) and specifically from laryngeal cancer (SMR 0.48, 95% CI 0.01-2.70). A
total of fifteen fatal cases of upper aerodigestive cancer were identified during the
follow-up. When these cases were compared with controls, the excess risk was
moderately increased in those who had worked for at least five years in jobs with
exposure to acid mists (sulphuric acid or hydrochloric acid) (odds ratio 2.0, 95% CI 0.4-
10). In 1997, Hathaway (Hat97) commented on the way the data in the previous study
were presented, and concluded that the data were of limited use and produced no
evidence that sulphuric acid mists may cause upper aerodigestive cancer.
     In 1997, Steenland (Ste97) presented an extension of a previous follow-up study
(see IARC92: publications of Steenland and/or Beaumont) for ten years (up to the end of
October 1994) of a cohort of men exposed to acid mists in the steel industry in the US.
The cohort consisted of 1,013 men with an average exposure of 9.2 years and with the
average years of first and last exposure being 1949 and 1960, respectively. The primary
exposure was to sulphuric acid mists although part of the cohort was exposed to other
acid mists. Data were obtained from mailed questionnaires and telephone interviews.
Fourteen cases of laryngeal cancer (six of them were still alive as of the follow-up date)
were observed in the cohort while 6.4 were expected (based on US rates and adjustment
Strong inorganic acid mists containing sulphuric acid                                      14
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<pre>      for tobacco and alcohol consumption). Except for one whose smoking status was
      unknown, all of these cases were current or former smokers. Seven out of these fourteen
      cases were daily exposed to sulphuric acid only, four to sulphuric and other acids, and
      three to other acids only; ten cases were exposed to sulphuric acid (Ste97).
           Cocco et al. (Coc99) conducted a case-control study, based on the death certificates
      concerning gastric cancer of several million deaths in 24 states of the United States. No
      excess risk was associated with sulphuric acid exposure at the workplace (odds ratio
      0.99 (95% CI 0.95-1.03), adjusted for all other exposures (inorganic dust, metals and
      nitrosamines)) and by marital and socio-economic status, and metropolitan residence).
           In a review considering essentially the same data base as presented by IARC,
      Sathiakumar et al. (Sat97) concluded that despite several limitations (imprecise results,
      not adjusted for confounding factors as smoking, alcohol, and other chemical
      compounds) the results indicate, in aggregate, a moderate association between inorganic
      mists containing sulphuric acid and larynx cancer and that the data suggest a dose-
      response relationship. The biological plausibility and the possible mechanism of action
      could not be ascertained. Furthermore, the authors concluded that there was limited
      evidence to support a causal relationship between exposure to inorganic mists
      containing sulphuric acid and lung cancer. Also the data were inadequate to draw
      conclusions regarding the association between exposure to these mists and nasal cancer.
      Greim and Reuter (Gre01) used the available carcinogenicity data to propose a new
      classification of carcinogenic chemicals by the German MAK commission. The authors
      assume that the laryngeal cancer seen in man is a result of severe local irritation caused
      by high concentrations of sulphuric acid aerosols and the associated increase in
      regenerative cell proliferation. Therefore, sulphuric acid is classified in Category 4
      (Substances with carcinogenic potential for which genotoxicity plays no or at most a
      minor part. No significant contribution to human cancer risk is expected provided the
      MAK and BAT* values are observed).
2.4   Animal data
2.4.1 IARC data
      No data were available to the IARC Working Group.
*     MAK, Maximale Arbeitsplatz-Konzentration (maximum workplace concentration); BAT, Biologischer Arbeitsstoff-
      Toleranz-Wert (biological tolerance value for occupational exposures).
      Strong inorganic acid mists containing sulphuric acid                                                       15
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<pre>2.4.2 Additional data
      In the review of Swenberg and Beauchamp a large unpublished initiation-promotion and
      cocarcinogenesis study by the US Environmental Protection Agency (Laskin and
      Sellakumar, 1978, see Swe97) was discussed. Male Syrian golden hamsters (n= 60/
      group) were exposed to 100 mg/m3 sulphuric acid mist by inhalation, for 6 hours a day
      and 5 days a week for the animal’s lifespan. The groups were also exposed to a single
      (10 or 40 mg) or multiple (1 or 4 mg, 15 times) tracheal intubations of benzo(a)pyrene
      (BP) before or at the same time with the exposure of sulphuric acid. Control groups
      included air and colony control, a group exposed to sulphuric acid only, and groups
      treated with BP only. Laryngeal and tracheal epithelial hyperplasia was increased in
      hamsters exposed to sulphuric acid with and without BP intubation in the initiation-
      promotion experiment. No consistent differences associated with exposure to sulphuric
      acid were observed in the cocarcinogenesis experiment. There were no quantitative data
      on mortality or actual lifespan presented. However, in the initiation-promotion
      experiment, there were no obvious differences between the experimental groups. For the
      cocarcinogenesis experiment, it was reported that cumulative mortality was highest in
      the groups receiving BP with or without sulphuric acid. No data on body weight (gain)
      were presented. No neoplasms of the respiratory tract were found in any of the
      experimental groups exposed to sulphuric acid alone (i.e. in a total of 240 animals).
           In the initiation-promotion part of this study, three benign laryngeal and tracheal
      tumours and two lung carcinomas were found in hamsters intubated once with 40 mg BP
      while one tracheal polyp was seen in the 40 mg BP plus sulphuric acid group. Following
      a single intubation with 10 mg BP, there was one hamster with an adenoma and a
      squamous cell carcinoma of the lung and another with a lung adenocarcinoma, while
      there was one animal with a lung adenocarcinoma when additionally exposed to
      sulphuric acid.
           In the cocarcinogenesis part, no consistent differences were found in benign or
      malignant tumours in BP-exposed animals that were associated with sulphuric acid
      exposure. Multiple intubations of 4 mg BP caused an incidence in neoplasms of 48/60
      while an incidence of 43/60 was found in animals receiving the combined BP-sulphuric
      acid treatment. In these groups, numbers of benign tumours were equal, but there were
      more carcinomas in the group receiving BP only. Multiple treatments with 1 mg BP
      resulted in neoplasms in 7/60 animals. A similar treatment combined with exposure to
      sulphuric acid resulted in a tumour incidence of 15/60. Seven additional benign tumours
      accounted for this increase in tumours in the sulphuric acid-exposed group. There were
      no differences in the time at which the tumours appeared in the two groups. Swenberg
      and Beauchamp concluded that this study, conducted at high exposure levels of
      Strong inorganic acid mists containing sulphuric acid                                    16
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<pre>sulphuric acid, did not show any evidence for carcinogenic activity and equivocal
evidence for cocarcinogenic or promoting activity. The committee noted that in this
study no general toxic effects were observed, despite the high exposure to sulphuric acid
mist, and concludes that the hamster might be a rather insensitive experimental animal
in assessing carcinogenicity.
     Ichinose and Sagai (Ich92) reported on the promoting and cocarcinogenic effects of
sulphuric acid. Male Wistar rats were given a single intraperitoneal injection of N-bis(2-
hydroxypropyl)nitrosamine (BHPN) at a dose of 0.5 g/kg body weight, prior to the
inhalatory exposure to a mixture of 0.4 ppm nitrogen dioxide and 1 mg/m3 sulphuric
acid for 13 months. Following exposure, the animals were maintained in a clean room
for another 11 months. As a result of the mixed exposure (BHPN plus nitrogen dioxide
plus sulphuric acid) 3 out of the 36 animals developed lung tumours. No lung tumours
occurred in the group exposed to nitrogen dioxide plus sulphuric acid only (n=36) and in
the untreated controls (n=35). The numbers of lung tumours did not significantly differ
among the groups. The committee is of the opinion that the presented data do not allow
a conclusion on the carcinogenic effects of sulphuric acid.
     More recently, Uleckiené and Griciuté (Ule97) used Wistar rats and CBAxC57B1
mice of both sexes, to study the carcinogenic effects of sulphuric acid in a long-term
study. The rats (n=30/group/sex) were exposed to maximal tolerated doses of sulphuric
acid by intratracheal installation (0.3 mL 0.6%, twice a month for 12 months) or by
gastric intubation (0.5 mL 0.6%, once a week for life); one untreated group served as
control (n=30/sex). Other groups were administered benzo(a)pyrene by intratracheal
installation (twice a month for two months, total dose 20 mg) with or without sulphuric
acid exposure to determine cocarcinogenesis. Mice (n=22-30/group/sex) received
sulphuric acid water solutions by gastric intubation (0.2 mL 0.2%, once a week for life),
urethane by intraperitoneal injections (twice a week, 10 injections, total dose 100mg) or
a combination of these two compounds; one untreated group served as control (n=30
males and 27 females). The animals were observed for their entire life. Sulphuric acid
increased the overall tumour morbidity in rats and mice. The majority of the tumours
appeared in organs at the site at which sulphuric acid was installed (intratracheal
installation, trachea and lungs; gastric intubation, oesophagus and forestomach)
showing that it is a local acting carcinogen. The authors, furthermore, consider sulphuric
acid to be a weak chemical carcinogen, because i) tumours that appeared in the
respiratory tract were not numerous, ii) there were almost no malignant tumours in the
first year of study, and iii) not all differences were statistically significant. The
investigators also consider the compound to be a moderate cocarcinogen when
administered with benzo(a)pyrene. According to the committee, the data are too limited
to make this conclusion. Overall, the committee considers the study of Uleckiené and
Strong inorganic acid mists containing sulphuric acid                                      17
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<pre>      Criciuté insufficient for evaluating the carcinogenic activity of sulphuric acid mists,
      because it does not meet international criteria for assessing carcinogenicity.
           Swenberg and Beauchamp (Swe97) presented in their review also the results of a
      number of studies (using monkeys, dogs, rabbits, guinea pigs) focusing on the toxicity
      of air pollutants including sulphur dioxide, sulphuric acid, and ozone. Although these
      studies were concluded to suffer from a number of flaws with respect to duration,
      number of animals, and organs/tissues examined, they did not show preneoplastic or
      carcinogenic effects.
           In a 28 day sub-acute inhalation study, female Alpk:APfSD (Wistar-derived) rats
      (n=10/group) were exposed to aerosols of sulphuric acid at concentrations of 0 (control),
      0.3, 1.38 and 5.5 mg/m3 for 5 days per week, for a period of either 5 days or 28 days.
      The major treatment related effect was squamous metaplasia of the larynx. The severity
      of the metaplasia was related to exposure duration and concentration; at 0.3 mg/m3
      sulphuric acid aerosol only minimal metaplastic change was observed after 28 days in a
      few animals. No effects were observed in the nasal passage or lungs (Kil02).
           Overall, Swenberg and Beauchamp (Swe97) evaluated most of the carcinogenicity
      studies with animals in great detail. In addition, Greim and Reuter (Gre01) used the
      available carcinogenicity animal data to propose a new classification of carcinogenic
      chemicals by the German MAK commission. In both reviews, the authors concluded
      that all the carcinogenic studies are comprised by inadequate quality control and
      reporting. Overall, from the literature, it is proposed that sulphuric acid may be a tumour
      promoter through the mechanism of chronic tissue irritation.
2.5   Mutagenicity and genotoxicity
2.5.1 IARC data
      IARC did not find data on the genetic and related effects of exposure to sulphuric acid
      mists in experimental in vitro systems; however, IARC evaluated some studies on the
      effects of the reduction of pH values (< 7: range between 3 and 6.7) by the strong acid.
           Singer and Grunberger (1983)* reported that low pH enhances the level of
      depurination of isolated DNA.
           Low pH did not affect the frequency of point mutations in various bacteria strains,
      yeast and fungi, but it induced gene conversion in S. cerevisiae, chromosomal
      aberrations in Vicia faba root tips and mitotic abnormalities in sea urchin.
           Brusick (1986)* and Morita et al. (1989)* reported that low pH induced
      chromosomal aberrations in Chinese hamster ovary cells (pH ≤ 5.5). No chromosomal
*     See IARC evaluation from 1992 (IARC92).
      Strong inorganic acid mists containing sulphuric acid                                       18
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<pre>      effects, however, were observed in rat lymphocytes. Exposure to low pH did not result
      in mutations in mouse lymphoma L5178Y cells (Cifone et al., 1987)*. In all the studies
      with mammalian cells, the presence of S9 significantly enhanced the effects.
2.5.2 Additional data
      Based on the same data as evaluated by IARC, Swenberg and Beauchamp (Swe97)
      suggest that the most likely mechanisms of carcinogenicity by inorganic acid mists is
      related to the ability to reduce pH, which influences chromosomal integrity.
           Also in a review by Soskolne et al. (Sos89), the pH as a modulator of mitotic
      activity and cell differentiation by sulphuric acid mist exposure was discussed. Based on
      the available data at that time, the authors expected that a decrease of pH in the
      extracellular matrix might cause structural/functional alterations in the mitotic
      apparatus, thus resulting in spindle damage and non-disjunction, and may affect gene
      expression and alter cell differentiation. They recommended further research to get more
      insight in the genetic toxicity from acidification.
           No additional studies of localized pH or in vivo genotoxic effects of strong inorganic
      acid mists containing sulphuric acid are known to the committee.
2.6   Evaluation
      The epidemiological data, evaluated by the committee, showed an association between
      exposure to strong inorganic acid mists containing sulphuric acid and laryngeal cancer.
      Life-style factors, such as tobacco and alcohol consumption, and other exposures were,
      according to the committee, only of minor influence on the association between
      exposure to strong inorganic acid mists and laryngeal cancer. Also the committee noted
      that the association with laryngeal cancer was found in various industries and
      occupations in which workers may be exposed to strong inorganic acid mists containing
      sulphuric acid. Based on these data, the committee concludes that exposure to strong
      inorganic acid mists containing sulphuric acid can cause laryngeal cancer.
      Data from carcinogenicity studies on sulphuric acid in experimental animals are
      inadequate. In a large lifetime study in hamsters, the carcinogenicity of 100 mg/m3
      sulphuric acid mist was evaluated, as well as its ability to act as a promoter or co-
      carcinogen for benzo(a)pyrene. No evidence for carcinogenic potential was shown.
      Although an increase in papillomas was noticed in the benzo(a)pyrene plus sulphuric
      acid group, the cocarcinogenic or promoting potential was considered equivocal.
      Strong inorganic acid mists containing sulphuric acid                                       19
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<pre>         In other animal studies with among others dogs and monkeys, no evidence for
    carcinogenicity of sulphuric acid was found. These studies suffer, however, from a
    number of flaws as to duration, number of animals, organs/tissues examined, etcetera.
    The committee did not find evidence that strong inorganic acid mists containing
    sulphuric acid causes mutations in DNA. In vitro data do indicate that sulphuric acid
    mists are clastinogenic.
    Based on the in vitro mutagenicity and genotoxicity data, the committee considers
    sulphuric acid mist as a non-stochastic genotoxic agent. Most likely, a reduction of the
    pH is one of the biological mechanisms, by which strong inorganic acid mists containing
    sulphuric acid exerts its carcinogenic effect.
2.7 Recommendation for classification
    The committee concludes that strong inorganic acid mists containing sulphuric acid are
    known to be carcinogenic to humans (comparable with EU category 1). The committee
    is of the opinion that these acid mists act as non-stochastic genotoxic carcinogens.*
*   This means that an occupational exposure limit can be derived using a threshold model. Such an exposure limit cannot be
    derived for genotoxic carcinogens. In the latter case, the committee estimates additional lifetime cancer risks using a
    linear extrapolation model as a default method.
    Strong inorganic acid mists containing sulphuric acid                                                                   20
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<pre>       References
Ano92  Anonymus. Carcinogenicity of occupational exposures to mists and vapors from strong inorganic mists,
       including sulfuric acid, and hydrochloric acid. Meeting of the IARC working group on the evaluation of
       carcinogenic risks to humans from occupational exposures to mists and vapors from strong inorganic acids
       and other industrial chemicals. Scand J Work Environ Health, 1992; 18:329-32.
Coc99  Cocco P, Ward MH and Dosemeci M. Risk for stomach cancer associated with 12 workplace hazards:
       analysis of death certificates from 24 states of the United States with the aid of job exposure matrices.
       Occup Environ Med, 1999; 56: 781-787.
Cog96  Coggon D, Pannett B and Wield G. Upper aerodigestive cancer in battery manufacturers and tell workers
       exposed to mineral acid mists. Occup Environ Med, 1996; 53: 445-449.
Gre01  Greim H and Reuter U. Classification of carcinogenic chemicals in the work area by the German MAK
       Commission: current examples for the new categories. Toxicology, 2001; 166: 11-23.
Hat97  Hathaway JA. Comment on ‘Upper aerodigestive cancer in battery manufacturers and steel workers
       exposed to mineral acid mists’ published by Coggon et al. (see Cog96). Occup Environ Med, 1997; 54: 141-
       142.
Ho99   Ho C-K, Lo WCH, Huang P-H, Wu M-T, Christiani DC and Lin C-T. Suspected nasopharyngeal carcinoma
       in three workers with long term exposure to sulphuric acid vapour. Occup Environ Med, 1999; 56: 426-428.
Hou94  Houghton DJ, White PS. The carcinogenic risk of exposure to sulphuric acid fumes from lead acid batteries.
       J Laryngol Otol, 1994; 108: 881-2.
IARC92 International Agency for Research on Cancer (IARC). Occupational exposures to mists and vapours from
       sulfuric acid and other strong inorganic acids. In: Occupational exposures to mists and vapours from strong
       organic acids and other industrial chemicals. Lyon, France: IARC, 1992: 41-130 (IARC monographs on the
       evaluation of carcinogenic risks to humans; Vol 54).
       References                                                                                                  21
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<pre>Ich92 Ichinose T and Sagai M. Combined exposure to NO2, O3 and H2SO4-aerosol and lung tumor formation in
      rats. Toxicology, 1992; 74: 173-184.
IPC00 International Program on Chemical Safety. international Occupational Safety and Health Information
      Centre. Sulfuric acid (ICSC: 0362). 2000. Http://www.ilo.org/
Kil02 Kilgour JD, Foster J, Soames A, Farrar DG and Hext PM. Responses in the respiratory tract of rats
      following exposure to sulphuric acid aerosols for 5 or 28 days. J Appl Toxicol, 2002: 22: 387-395.
Kri93 Kristensen P. Inorganic acid aerosols. In: Criteria documents from the Nordic Expert Group 1992. Beije B
      and Lundberg P (eds). Arbete och Hälsa, 1993:1: 7-54
Mer89 The Merck Index. An encyclopedia of chemicals, drugs, and biologicals. Budavari S end O’Neil J (eds),
      eleventh edition, Merck & Co., Inc., Rahway (NJ), USA, 1989.
Sat97 Sathiakumar N, Delzell E, Amoateng-Adjepong Y, et al. Epidemiologic evidence on the relationship
      between mists containing sulfuric acid and respiratory cancer. Crit Rev Toxicol, 1997; 27: 233-51.
Sos89 Soskolne CL, Pagano G, Cipollaro M, Beaumont JJ and Giordano GG. Epidemiologic and toxicologic
      evidence for chronic health effects and the underlying biologic mechanisms involved in sub-lethal
      exposures to acidic pollutants. Achives Environ Health, 1989; 44: 180-191.
Ste97 Steenland K. Laryngeal cancer incidence among workers exposed to acid mists (United States). Cancer
      Causes Control, 1997; 8: 34-8.
Swe97 Swenberg JA, Beauchamp RO Jr. A review of the chronic toxicity, carcinogenicity and possible
      mechanisms of action in inorganic mists in animals. Crit Rev Toxicol, 1997; 27: 253-9.
Ule97 Uleckiené S and Griciuté L. Carcinogenicity of sulfuric acid in rats and mice. Pathol Oncol Res, 1997; 3:
      38-43.
      References                                                                                                22
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<pre>A Request for advice
B The committee
C Comments on the public review draft
D IARC Monograph
E Classification of substances with respect to carcinogenicity
F Guideline 93/21/EEG of the European Union
  Annexes
                                                               23
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<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 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 crite-
            ria-document that will be made available to the Health Council as part of a specific request for advice.
            If possible this evaluation should lead to a health based recommended exposure limit, or, in the case of
      Request for advice                                                                                                24
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<pre>    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 govern-
    ment. 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.
Request for advice                                                                                               25
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<pre>Annex B
      The committee
      •  GJ Mulder, chairman
         professor of toxicology; Leiden University, Leiden
      •  RB Beems
         toxicologic pathologist; National Institute of Public Health and the Environment,
         Bilthoven
      •  LJNGM Bloemen
         epidemiologist; DOW benelux NV, Terneuzen
      •  PJ Boogaard
         toxicologist; SHELL International BV, The Hague
      •  PJ Borm
         toxicologist; Heinrich Heine Universität Düsseldorf (Germany)
      •  JJAM Brokamp, advisor
         Social and Economic Council, The Hague
      •  DJJ Heederik
         epidemiologist; IRAS, University of Utrecht, Utrecht
      •  AAJP Mulder, advisor
         Ministry of Social Affairs and Employment, The Hague
      •  TM Pal
         occupational physician; Dutch Centre for Occupational Diseases, Amsterdam
      •  IM Rietjens
         professor of toxicology; Wageningen University, Wageningen.
      The committee                                                                        26
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<pre>•   H Roelfzema, advisor
    Ministry of Health, Welfare and Sport, The Hague
•   T Smid
    occupational hygienist; KLM Health Safety & Environment, Schiphol and professor
    of working conditions, Free University, Amsterdam
•   GMH Swaen
    epidemiologist; Maastricht University, Maastricht
•   RA Woutersen
    toxicologic pathologist; TNO Nutrition and Food Research, Zeist
•   P Wulp
    occupational physician; Labour Inspectorate, Groningen
•   ASAM van der Burght, scientific secretary
    Health Council of the Netherlands, The Hague
•   JM Rijnkels, scientific secretary
    Health Council of the Netherlands, The Hague
The committee consulted two additional experts, Prof dr G Mohn and dr M Nivard, both
working at Department of Radiation Genetics and Chemical Mutagenesis of the
University of Leiden, with respect to the genotoxic data.
The first draft of the present advisory report was prepared by MI Willems, from the
Department of Occupational Toxicology of the TNO Nutrition and Food Research, by
contract with the Ministry of Social Affairs and Employment.
Secretarial assistance was provided by mrs R Aksel-Gauri.
Lay-out: mrs J van Kan.
The committee                                                                        27
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<pre>Annex C
      Comments on the public review draft
      A draft of the present report was released in 2000 for public review. The following
      organisations and persons have commented on the draft document:
      • Mr A Aalto, Ministry of Social Affairs and Health, Finland;
      • Mr C Braun, Akzo Nobel, The Netherlands;
      • Mr T Fry, Health and Safety Executive, United kingdom.
      Comments on the public review draft                                                 28
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<pre>Annex D
      IARC Monograph
      Occupational exposures to mists and vapours from strong organic acids and other
      industrial chemicals (Volume 54, 1992)
                           5. Summary of Data Reported and Evaluation
      5.1 Exposure data
           Strong inorganic acids may be present in the work environment as mists, vapours or
      gases. The most prevalent acids are sulfuric, hydrochloric, nitric and phosphoric acids,
      which may be present in a wide variety of industries, including the extraction,
      fabrication and finishing of metal, fertilizer production, battery manufacture and various
      segments of the petroleum, chemical and petrochemical industries. Millions of workers
      worldwide are estimated to be potentially exposed to these acids.
           Sulfuric acid is the most widely used of the strong inorganic acids. Average
      exposures to sulfuric acid mists in pickling, electroplating and other acid treatment of
      metals are frequently above 0.5 mg/m3, while lower levels are usually found in the
      manufacture of lead-acid batteries and in phosphate fertilizer production. Exposure to
      sulfuric acid also occurs during its manufacture and during the production of
      isopropanol, synthetic ethanol and detergents. Hydrochloric acid is used in industries
      that involve acid treatment of metals, where occupational exposure levels to
      hydrochloric acid mists and gas are frequently above 1 mg/m3. Exposures to
      hydrochloric acid may also occur during its synthesis and use in various industrial
      processes. Pickling and other acid treatments of metal may entail occupational
      IARC Monograph                                                                             29
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<pre>exposures to nitric and phosphoric acids, but these occur less frequently than exposures
to sulfuric and hydrochloric acids. Exposure to nitric acid also occurs during its
manufacture and exposure to phosphoric acid in phosphate fertilizer production.
5.2 Human carcinogenicity data
    An early study of isopropanol manufacture in the USA using the strong-acid process
demonstrated an excess of nasal sinus cancer. Studies of one US cohort of workers in
pickling operations within the steel industry showed excesses of laryngeal and lung
cancer after smoking and other potential confounding variables had been controlled for.
A Swedish study of a cohort of workers in steel pickling also showed an excess risk for
laryngeal cancer. A nested case-control study of workers in a US petrochemical plant
showed an elevated risk for laryngeal cancer among workers exposed to sulfuric acid.
Of two population-based case-control studies in Canada, one of laryngeal cancer
showed an increased risk for exposure to sulfuric acid, and one of lung cancer suggested
an excess risk; the latter also suggested a risk associated with exposure to mixed
inorganic acids. In all these studies, sulfuric acid mists were the commonest exposure,
and positive exposure-response relationships were seen in two of the studies.
    Additional supporting evidence was provided by one cohort study in the soap
manufacturing industry in Italy, which showed an increased risk for laryngeal cancer.
Studies of three US cohorts and one Swedish cohort in the phosphate fertilizer
manufacturing industry showed excess lung cancer, but there was potential confounding
from exposure to radon decay products in some cohorts.
5.3 Animal carcinogenicity data
    No data were available to the Working Group.
5.4 Other relevant data
    Acid mists containing particles with a diameter of up to a few micrometers will be
deposited in both the upper and lower airways. They are irritating to mucous epithelia,
they cause dental erosion, and they produce acute effects in the lungs (symptoms and
changes in pulmonary function). Asthmatics appear to be at particular risk for
pulmonary effects.
    Significant increases in the incidences of sister chromatid exchange, micronucleus
formation and chromosomal aberrations in peripheral lymphocytes were observed in a
single study of workers engaged in the manufacture of sulfuric acid.
    The studies reviewed examined the effects of pH values < 7 specifically. In cultured
mammalian cells at pH 6.7 or below, cell transformation, gene mutation and
chromosomal aberrations were induced. Mitotic abnormalities were induced in sea
urchins and clastogenic effects in plants. Gene conversion was induced in yeast cells.
IARC Monograph                                                                           30
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<pre>No point mutation was observed in fungi, yeast or bacteria. Acid pH caused
depurination of isolated DNA.
5.5 Evaluation
    There is sufficient evidence that occupational exposure to strong-inorganic-acid
mists containing sulfuric acid is carcinogenic.
Overall evaluation
    Occupational exposure to strong-inorganic-acid mists containing sulfuric acid is
carcinogenic to humans (Group 1).
IARC Monograph                                                                       31
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<pre>Annex          E
               Classification of substances with respect
               to carcinogenicity
The committee expresses its conclusions in the form of standard phrases:
Judgement of the committee                                                                              Comparable with EU class
This compound is known to be carcinogenic to humans                                                     1
     • It is 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 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 of a    (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 warrant a    (B)
       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
               Classification of substances with respect to carcinogenicity                                                   32
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<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                                                                    33
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<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 assessment.
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 genotoxicity
data, metabolic or biochemical studies, induction of benign tumours, structural relationship with other
known carcinogens, or data from epidemiological studies suggesting an association.
Category 3 actually comprises 2 sub-categories:
a    substances which are well investigated but for which the evidence of a tumour-inducing effect is insuf-
     ficient for classification in Category 2. Additional experiments would not be expected to yield further
     relevant information with respect to classification.
Guideline 93/21/EEG of the European Union                                                                     34
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<pre>b    substances which are insufficiently investigated. The available data are inadequate, but they raise con-
     cern for man. This classification is provisional; further experiments are necessary before a final deci-
     sion 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 arguments,
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 maximal tol-
     erated 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 cer-
     tain 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 extrapolated 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 occurrence of
     neoplasms at sites and in strains where they are well known to occur spontaneously with a high inci-
     dence.
Guideline 93/21/EEG of the European Union                                                                      35
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<br><br>