<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>Picric acid
(CAS No: 88-89-1)
Health-based Reassessment of Administrative
Occupational Exposure Limits
Committee on Updating of Occupational Exposure Limits,
a committee of the Health Council of the Netherlands
No. 2000/15OSH/052, The Hague, 31 October 2002
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<pre>Preferred citation:
Health Council of the Netherlands: Committee on Updating of Occupational
Exposure Limits. Picric acid; Health-based Reassessment of Administrative
Occupational Exposure Limits. The Hague: Health Council of the Netherlands,
2002; 2000/15OSH/052.
all rights reserved
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<pre>1     Introduction
      The present document contains the assessment of the health hazard of picric
      acid by the Committee on Updating of Occupational Exposure Limits, a
      committee of the Health Council of the Netherlands. The first draft of this
      document was prepared by AAE Wibowo, Ph.D. and MM Verberk, Ph.D.
      (Coronel Institute of the Academic Medical Center, Amsterdam, the
      Netherlands).
           Literature was retrieved from the databases Medline, Embase, and Chemical
      Abstracts starting from 1966, 1988, and 1970, respectively. HSEline, Cisdoc,
      Mhidas, and NIOSHTIC (covering the period 1985/87 until 1998) as well as
      Poltox (Toxline, Cambridge Scient. Abstr., and FSTA; covering the period
      1990-1995), data bases available on CD-ROM, were also consulted. The
      following key words were used: picric acid, 2,4,6-trinitrophenol, and 88-89-1.
           Data considered to be critical were evaluated by reviewing the original
      publications. The final literature search was carried out in May 1998.
           In September 2001, the President of the Health Council released a draft of
      the document for public review. The committee received no comments.
2     Identity
       name                    :    picric acid
       synonyms                :    2,4,6-trinitrophenol; trinitrophenol;
                                    2-hydroxy-1,3,5-trinitrobenzene; carbazotic acid; picronitric
                                    acid; phenol trinitrate; nitroxanthic acid
       molecular formula       :    C6H3N3O7
       structural formula
       CAS number              :    88-89-1
052-3 Picric acid
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<pre>3     Physical and chemical properties
       molecular weight         :    229.1
       boiling point            :    explodes above 300oC
       melting point            :    122-123oC
       flash point              :    150oC (closed cup)
       vapour pressure          :    at 20oC: <0.01 kPa
       solubility in water      :    slightly soluble
       Log Poctanol/water       :    1.33
       conversion factors       :    not applicable
       (20oC, 101.3 kPa)
      Data from ACG99, NLM01.
      Picric acid consists of colourless to pale yellow, odourless, intensely bitter
      crystals. Apart from heating, it may explosively decompose on shock or
      concussion or friction (NLM01).
4     Uses
      Picric acid is used in explosives, matches, in leather industry, electric batteries,
      etching copper, manufacture of coloured glass and textile mordant, as a
      laboratory chemical, and as medicinal ointment. (ACG99, NLM01).
5     Biotransformation and kinetics
      Wyman et al. studied the kinetics of picric acid in male rats (Fischer 344; n=4)
      by oral or intravenous administration of doses of 14C-labelled picric acid of 100
      and 50 mg/kg bw, respectively. Following intravenous injection, the amount of
      radioactivity excreted in urine and faeces was approximately 60 and 9% of the
      dose administered, respectively, during the first 24 hours, and increased to
      approximately 86 and 17%, respectively, after 48 hours. After an initial blood
      distribution period of 2 hours, radioactivity was eliminated following first-order
      kinetics with an elimination rate constant (kel) of 0.052 h-1 and a plasma half-life
      of 13.4 h. Following oral administration, absorption of picric acid from the gut
      into the blood continually increased during a period of one hour, which was
      followed by elimination from the blood in a biphasic fashion. Comparison of
052-4 Health-based Recommended Occupational Exposure Limits
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<pre>      oral and intravenous blood elimination curves showed a quite limited
      bioavailability following oral administration with a large amount of picric acid
      remaining in the gut (gut absorption coefficient: ka = 0.069 h-1). Analysis of the
      distribution of radioactivity 24 hours after oral administration showed that, apart
      from the gut (contents + wall), urine, and faeces (containing ca. 26, 51, and 6%
      of the radioactivity administered, respectively), the blood was the principal
      depot (ca. 6%). Retention in the blood is, in part, the result of binding to plasma
      protein. Of the tissues assayed, the highest concentrations of radioactivity (per
      gram tissue) were found in (in decreasing order) the spleen, kidneys, liver,
      lungs, and testes. The lowest concentrations of radioactivity were found in the
      brain and adipose tissues. The radiolabel excreted in the urine during the first 24
      hours following oral dosing consisted of 60% unchanged parent compound,
      19% picramic acid (2-amino-4,6-dinitrophenol), 15% N-acetylisopicramic acid,
      4.7% N-acetylpicramic acid, and 2.4% (3) unidentified metabolites (Wym92).
6     Effects and mechanism of action
      Human data
      Referring to literature published in the period 1900-1960, Grant stated that dusts
      or fumes of picric acid had caused irritation of the eyes, and that this may be
      aggravated by sensitisation. Accidental squirt of a picric acid solution in the eye
      may cause corneal injury. He further stated that ingestion of picric acid may
      induce strange visual effects. Experimental ingestion of 300 mg of picric acid
      was reported to cause a transient yellowish appearance in the subjects. Although
      this dose was thought to be too small to cause this kind of effects, larger,
      systemic toxicity-inducing amounts were said to colour all tissues yellow,
      including the conjunctiva and aqueous humor, and to cause yellow-tinted vision
      (Gra86).
          Human data from several industrial, case, and experimental reports on skin
      effects from contact with solutions, cremes, and dusts containing picric acid or
      picrates, as reviewed by the German Commission for the Investigation of Health
      Hazards of Chemical Compounds in the Work Area (Gre99), indicate that picric
      acid has a sensitising potential.
          Apart from skin sensitisation, effects on the nose (bleeding; swelling and
      excoriation of mucosa; yellow discoloration of vestibules), skin (staining) and
      hair (discoloration), and palpable cervical glands were reported in (some of the)
      71 male and female employees engaged in working with explosives in a factory
052-5 Picric acid
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<pre>      in the US, for 1 to 15 months. The concentrations of ammonium picrate at the
      sites of ‘milling’ and ‘preforming’ ranged from 0.009 to 0.19 mg/m3 (Sun45).
      Harris et al. reported an outbreak of haematuria involving many of the
      personnel aboard US warships stationed in Japan. All evidence indicated that it
      was caused by picric acid, which was dumped in large quantities near an
      anchorage. It contaminated the harbour water and, consequently upon
      distillation of the sea water, the fresh water supply used by the personnel
      (Har46). NIOSH stated that ingestion of 2000 to 5000 mg of picric acid may
      induce — amongst others — headache, vertigo, nausea, diarrhoea, haematuria,
      and albuminuria. ‘High’ doses (not specified) would cause destruction of
      erythrocytes, haemorrhagic nephritis, hepatitis, yellow colouring of all tissues
      (including conjunctiva and aqueous humor), and yellow-tinted vision (NIO81).
      Animal data
      A solution of picric acid injected into the corneal stroma of the eyes of rabbits
      was stated to cause injury even when this solution was neutralised to a pH range
      of 7 to 9 (Gra86).
          Several studies in guinea pigs, as reviewed by the German Commission for
      the Investigation of Health Hazards of Chemical Compounds in the Work Area
      (Gre99), showed that picric acid has a sensitising potential.
      From giving male and female Fischer 344 rats (n=3/sex/dose) single oral
      (gavage) doses of picric acid (in water) ranging from 50 to 800 mg/kg bw,
      Wyman et al. determined LD50 values of 290 and 200 mg/kg bw in males and
      females, respectively (observation time: 14 days). In a separate experiment in
      male animals, blood gas analysis showed severe acidosis to be the cause of
      death (Wym92). Single oral doses of 120 and 500 mg/kg bw were reported to
      be lethal in rabbits and cats, respectively. Dogs died from respiratory paralysis
      at a single subcutaneous injection of 100-125 mg/kg bw. Autopsy showed
      yellow staining of the subcutaneous fat, lungs, intestines, blood vessels,
      swelling of the liver, and glomerulitis. Doses of 50 mg/kg bw caused transitory
      kidney changes (NRC82). Senezuk et al. reported that picric acid did not induce
      methaemoglobinaemia in Wistar rats after a single injection of 0.4 mM/kg bw
      (92 mg/kg bw) (Sen76).
      To study possible systemic effects, Sunderman et al. performed an experiment
      in which 4 rabbits and 8 guinea pigs had been placed inside a factory building
052-6 Health-based Recommended Occupational Exposure Limits
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<pre>      where milling and preforming operations were taking place. In this
      environment, the levels of exposure to ammonium picrate dusts were monitored
      to range from 0.009 to 0.19 mg/m3. The dimensions of the dust particles were
      not reported, they were probably total dusts. Some of the animals were killed
      after a 6-week exposure period and the rest after a 1-year exposure period.
      Histological examination of 2 rabbits after a 6-week exposure period showed
      glycogen infiltration and periductal fibrosis of the liver. Guinea pigs that died 3
      weeks after exposure revealed low grade subacute inflammation of the nasal
      mucosa. Some hyaline degeneration occurred in the heart tissues, and the lungs
      were somewhat congested (Sun45). The committee faces problems in
      interpreting this study: it is not clear whether the effects were induced by
      exposure to a mixture or to a single agent. Moreover, the unaccounted
      dimensions of the dust particles, the large range of exposure levels, and possible
      exposure by oral intake and skin contact hamper an assessment.
      There are conflicting reports on the mutagenicity of picric acid. Whong and
      Edwards reported that picric acid was not mutagenic in the S. typhimurium
      plate-incorporation assay, with or without metabolic activation, in strains
      TA1535, TA100, TA1537, TA1538, and TA98 (Who84), while Kawai et al.
      found positive results in a pre-incubation assay using strains TA98 and TA100
      both in the absence and presence of induced rat liver S9 (no other strains were
      tested) (Kaw87). In other tests in which strains TA1535, TA100, TA1537,
      TA1538, and TA98 were used, results were mainly positive when tested in the
      presence of a metabolic activation system in the frame-shift strains TA98,
      TA1535, and TA1538 while results were negative when tested without
      metabolic activation (Goc81, Haw83, Won77, Wym79). Picramic acid
      (2-amino-4,6-dinitrophenol), a metabolite of picric acid, induced both base pair
      substitution and frame shift-type mutations, only without activation by the rat
      liver preparation (Won77, Wym79). Testing in E. coli strain B/Sd-4 (probably
      without metabolic activation), resulted in mutagenic responses (Dem51).
          Picric acid did not induce chromosome aberrations in the root tips from
      bulbs of Allium cepa (Lev48).
          Both positive and negative results were obtained upon testing in D.
      melanogaster. Picric acid was found mutagenic in explanted gonads of D.
      melanogaster (Had49). After bathing eggs in aqueous solutions of picric acid,
      no sex-linked lethals were found (Aue47), but in a review, this study was
      considered to be inadequately performed since less than 1000 chromosomes
      were tested (Lee83). Woodruff et al. reported that picric acid was found
052-7 Picric acid
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<pre>      negative by 3 laboratories after feeding picric acid to males in the sex-linked
      recessive lethal mutation assay using D. melanogaster. Following injection,
      clearly negative (at 400 ppm), clearly positive (at 1500 ppm), and less clear-cut
      results (using a combination of 1000 and 1500 ppm) were obtained in the
      respective laboratories. Combining the data from these 3 laboratories, picric
      acid was concluded to be positive. Following injection, the results in the
      reciprocal translocation test were negative (Woo85). Gocke et al. found a
      statistically significant (p<0.05) increase in the frequency of sex-linked
      dominant lethals after feeding (1.25 mM) picric acid (Goc81).
          In vivo, 2 oral or intraperitoneal doses (administered with a 24-hour interval)
      of up to 458 and 91.6 mg/kg bw, respectively, did not cause an increase in the
      frequency of micronuclei in polychromatic erythrocytes obtained from bone
      marrow of mice (NMRI; n=2/sex/group) sacrificed 30 hours after receiving the
      final dose (Goc81). However, the committee considers this study inadequate
      since only 4 animals were exposed per dose and only one time point of
      evaluation was used.
      The committee did not find data on long-term toxicity, carcinogenicity, and
      reproduction toxicity.
7     Existing guidelines
      The current administrative occupational exposure limit (MAC) for picric acid in
      the Netherlands is 0.1 mg/m3, 8-hour TWA, with a ‘skin’ notation (SZW01).
          Existing occupational exposure limits for picric acid in some European
      countries and the USA are summarised in the annex.
8     Assessment on health hazard
      Twenty-four hours following intravenous injection to rats, 60 and 12% of the
      radioactivity administered were excreted in urine and faeces, respectively. After
      an initial blood distribution period of 2 hours, radioactivity was eliminated
      following first-order kinetics with a plasma half-life of 13.4 h. Following oral
      administration, bioavailability was quite limited with ca. 26% of the
      radioactivity administered remaining in the gut 24 hours after dosing. When
      orally dosed, picric acid and its metabolites picramic acid, N-acetylisopicramic
      acid, and N-acetylpicramic acid accounted for ca. 60, 19, 15, and 5% of the
      radioactivity excreted in the first 24-hour urine.
052-8 Health-based Recommended Occupational Exposure Limits
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<pre>       There are very few human and experimental animals data available on the
       effects of exposure to picric acid. Data from human industrial, case, and
       experimental reports which were confirmed by guinea pig studies showed that
       picric acid is a skin sensitising compound.
           The committee did not find adequate data on the toxic effects of picric acid
       following exposure by inhalation or on the effects following repeated exposure
       (including carcinogenicity and reproduction toxicity).
           Based on oral LD50 values of 200 and 290 mg/kg bw in rats, the committee
       considers picric acid as harmful when ingested. Effects observed were, amongst
       others, acidosis, yellow staining of tissues, swelling of the liver, and
       glomerulitis.
           Picric acid was mutagenic in bacteria and in Drosophila. However, since the
       committee did not find adequate mutagenicity and genotoxicity data from in
       vitro assays in mammalian cell systems and in vivo assays, it cannot draw a
       definite conclusion on the (potential) mutagenicity/genotoxicity of picric acid.
       The committee considers the toxicological database on picric acid too poor to
       justify recommendation of a health-based occupational exposure limit.
       The committee concludes that there is insufficient information to comment on
       the level of the present MAC-value.
       References
ACG99  American Conference of Governmental Industrial Hygienists (ACGIH). Picric acid. In: TLVs® and
       other occupational exposure values - 1999. [CD-ROM]. Cincinnati OH, USA: ACGIH®, 1999.
ACG02a American Conference of Governmental Industrial Hygienists (ACGIH). Guide to occupational
       exposure values - 2002. Cincinnati OH, USA: ACGIH®, Inc, 2002: 106.
ACG02b American Conference of Governmental Industrial Hygienists (ACGIH). 2002 TLVs® and BEIs®.
       Threshold Limit Values for chemical substances and fysical agents. Biological Exposure Indices.
       Cincinnati OH, USA: ACGIH®, Inc, 2002: 49.
Arb00a Arbejdstilsynet. Grænseværdier for stoffer og materialer. Copenhagen, Denmark: Arbejdstilsynet,
       2000; At-vejledning C.0.1.
Arb00b Arbetarskyddstyrelsen. Hygieniska gränsvärden och åtgärder mot luftföroreningar. Solna, Sweden:
       National Board of Occupational Safety and Health, 2000; Ordinance AFS 2000/3.
Aue47  Auerbach C, Robson JM. XXXIII. Tests of chemical substances for mutagenic action. Proc Royal
       Soc Edinburgh 1947; 62B: 284-91.
052-9  Picric acid
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<pre>CEC00  Commission of the European Communities (CEC). Commission Directive 2000/39/EC of 8 June
       2000 establishing a first list of indicative occupational exposure limit values in implementation of
       Council Directive 98/24/EC on the protection of the health and safety of workers from the risks
       related to chemical agents at work. Official Journal of the European Communities 2000; L142
       (16/06/2000): 47-50.
Dem51  Demerec M, Bertani G, Flint J. A survey of chemicals for mutagenic action on E. coli. Amer Nat
       1951; 85: 119-36.
DFG02  Deutsche Forschungsgemeinschaft (DFG): Senatskommission zur Prüfung gesundheitsschädlicher
       Arbeitsstoffe. MAK- und BAT-Werte-Liste 2002. Maximale Arbeitsplatzkonzentrationen und
       Biologische Arbeitsstofftoleranzwerte. Weinheim, FRG: Wiley-VCH, 2002: 112 (rep no 38).
Goc81  Gocke E, King MT, Eckhardt K, et al. Mutagenicity of cosmetic ingredients licensed by the
       European communities. Mutat Res 1981; 90: 91-109.
Gra86  Grant WM (ed). Picric acid. In: Toxicology of the eye. 3rd ed. Springfield IL, USA: Charles C
       Thomas Publ, 1986: 737-8.
Gre99  Greim H (ed). 2,4,6-Trinitrophenol (Pikrinsäure). In: Gesundheidsschädliche Arbeitsstoffe.
       Toxikologisch-arbeitsmedizinische Begründungen von MAK-Werte (Maximale Arbeit-
       splatz-Konzentrationen). 1st-29th ed. Weinheim, FRG: Wiley-VCH, 1999.
Had49  Hadorn E, Rosin S, Bertani G. Ergebnisse der Mutationsversuche mit chemischer Behandlung von
       Drosophila-Ovarien in vitro. Hereditas 1949; suppl: 256-66.
Har46  Harris AH, Binkley OF, Chenoweth BM Jr. Hematuria due to picric acid poisening at a naval
       anchorage in Japan. Am J Public Health 1946; 36: 727-33.
Haw83  Haworth S, Lawlor T, Mortelmans K, et al. Salmonella mutagenicity test results for 250 chemicals.
       Environ Mutagen 1983; suppl 1: 3-142.
HSE02  Health and Safety Executive (HSE). EH40/2002. Occupational Exposure Limits 2002. Sudbury
       (Suffolk), England: HSE Books, 2002: 24.
Kaw87  Kawai A, Goto S, Matsumoto Y, et al. Mutagenicity of aliphatic and aromatic nitro compounds.
       Sangyyo Igaku (Jpn J Ind Health) 1987; 29: 34-54.
Lee83  Lee WR, Abrahamson S, Valencia R, et al. The sex-linked recessive lethal test for mutagenesis in
       Drosophila melanogaster. A report of the US Environmental Protection Agency Gene-Tox Program.
       Mutat Res 1983; 123: 183-279.
Lev48  Levan A, Tjio JH. Induction of chromosome fragmentation by phenols. Hereditas 1948; 34: 453-84.
NIO81  US National Institute for Occupational Safety and Health. Occupational health guideline for picric
       acid. In: Mackison FW, Stricoff RS, Patridge LJ Jr, eds. Occupational health guidelines for chemical
       hazards. Washington DC, USA: US Government Printing Office, 1981; DHHS/NIOSH pub no
       81-123 (available from the National Technical Information Service, Springfield VA, USA; order no:
       PB83-154609).
052-10 Health-based Recommended Occupational Exposure Limits
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<pre>NLM01  US National Library of Medicine, ed (NLM). Picric acid. In: Hazardous Substances Data Bank.
       http://toxnet.nlm.nih.gov (last update picric acid file: February 8, 2000; last review date file:
       September 23, 1999).
NRC82  National Research Council (NRC). Toxicity of selected organic contaminants in drinking water.
       Washington DC, USA: NRC, 1982: 202-89 (Drinking water and health; vol 4).
Sen76  Senezuk W, Jodynis J, Rogal H. Effect of chemical structure of selected aromatic compounds on
       methemoglobin-genic properties. Bromat Chem Toksykol 1976; 9: 289-94.
Sun45  Sunderman FW, Weidman FD, Batson OV. Studies of the effects of ammonium picrate on man and
       certain experimental animals. J Ind Hyg Toxicol 1945; 27: 241-8.
SZW02  Ministerie van Sociale Zaken en Werkgelegenheid (SZW). Nationale MAC-lijst 2002. The Hague,
       the Netherlands: Sdu, Servicecentrum Uitgevers, 2002: 38.
TRG00  TRGS 900: Grenzwerte in der Luft am Arbeitsplatz; Technische Regeln für Gefahrstoffe. BArbBl
       2000; 2.
Who84  Whong WZ, Edwards GS. Genotoxic activity of nitroaromatic explosives and related compounds in
       Salmonella typhimurium. Mutat Res 1984; 136: 209-15.
Won77  Won WD. Picric acid and its biodegradation prodcuts as mutagens. Abstr Annual Meeting Am Soc
       Microbiol 1977; 77: 276.
Woo85  Woodruff RC, Mason JM, Valencia R, et al. Chemical mutagenesis testing in Drosophila. V. Results
       of 53 coded compounds tested for the National Toxicology Program. Environ Mutagen 1985; 7:
       677-702.
Wym79  Wyman JF, Guard HE, Won WD, et al. Conversion of 2,4,6-trinitrophenol to a mutagen by
       Pseudomonas aeroginosa. Appl Environ Microbiol 1979; 37: 222-6.
Wym92  Wyman JF, Serve MP, Hobson DW, et al. Acute toxicity, distribution and metabolism of
       2,4,6-trinitrophenol (picric acid) in Fischer 344 rats. J Toxicol Environ Health 1992; 37: 313-27.
052-11 Picric acid
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<pre>              Annex
Occupational exposure limits for picric acid in various countries.
country                              occupational                time-weighted        type of            notea          referenceb
- organisation                       exposure limit              average              exposure limit
                                     ppm         mg/m3
the Netherlands
- Ministry of Social Affairs         -           0.1             8h                   administrative     S              SZW02
and Employment
Germany
- AGS                                -           0.1c            8h                                      S              TRG00
                                     -           0.1c            15 min
- DFG MAK-Kommission                 -           -                                                       S, sens, d     DFG02
Great Britain
- HSE                                -           0.1             8h                   OES                               HSE02
                                     -           0.3             15 min               STEL
Sweden                               -           -                                                                      Arb00b
Denmark                              -           0.1             8h                                      S              Arb00a
USA
- ACGIH                              -           0.1             8h                   TLV                               ACG02b
- OSHA                               -           0.1             8h                   PEL                S              ACG02a
- NIOSH                              -           0.1             10 h                 REL                S              ACG02a
                                     -           0.3             15 min               STEL
European Union
- SCOEL                              -           -                                                                      CEC00
a
      S = skin notation, which means that skin absorption may contribute considerably to body burden; sens = substance can
      cause sensitisation.
b
      Reference to the most recent official publication of occupational exposure limits.
c
      Measured as the inhalable fraction of the aerosol.
d
      Classified in carcinogenicity category 3B, i.e., listed among substances for which in vitro or animals studies have
      yielded evidence of carcinogenic efects that is not sufficient for classification in one of the other categories. Further
      studies are required before a final decision can be made. A MAK value can be established provided no genotoxic
      effects have been detected.
052-12        Health-based Recommended Occupational Exposure Limits
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