<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-Chloro-6-(trichloromethyl)pyridine
      (nitrapyrin)
      (CAS reg no: 1929-82-4)
      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/032, The Hague, 7 March 2002
032-1
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<pre>      Preferred citation:
      Health Council of the Netherlands: Committee on Updating of Occupational
      Exposure Limits. 2-Chloro-6-(trichloromethyl)pyridine (nitrapyrin);
      Health-based Reassessment of Administrative Occupational Exposure Limits.
      The Hague: Health Council of the Netherlands, 2002; 2000/15OSH/032.
      all rights reserved
032-2
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<pre>1     Introduction
      The present document contains the assessment of the health hazard of
      2-chloro-6-(trichloromethyl)pyridine 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 mrs MA
      Maclaine Pont, M.Sc. (Wageningen University, Wageningen, the Netherlands).
           Literature was retrieved from the data bases Medline, Toxline, and
      Chemical Abstracts, covering the periods 1981 until May 2000, 1966 until
      May 2000, and 1937 until March 2000, respectively, and using the following
      key words: nitrapyrin, chloropicolinic, 6-chloropicolinic acid,
      2-chloro-6-(trichloromethyl)pyridine, 1929-82-4, and 4684-94-0. Data
      considered to be critical were evaluated by reviewing the original publications.
      The final search has been carried out in December 1999.
           In July 2001, the President of the Health Council released a draft of the
      document for public review. The committee received no comments.
2     Identity
       name                      :    2-chloro-6-(trichloromethyl)pyridine
       synonyms                  :    nitrapyrin; α,α,α, 6-tetrachloro-2-picoline
       molecular formula         :    C6H3NCl4
       structural formula        :
       CAS reg no                :    1929-82-4
      Data from ACG99, How92.
032-3 2-Chloro-6-(trichloromethyl)pyridine (nitrapyrin)
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<pre>3     Physical and chemical properties
       molecular weight                     :      230.9
       boiling point                        :      at 1.4 kPa: 136-137oC
       melting point                        :      62-63oC
       vapour pressure                      :      at 23oC: 0.4 Pa
       solubility in water                  :      insoluble
       Log Poctanol/water                   :      3.41 (experimental); 3.35 (estimated)
       conversion factors                   :      not applicable
       (20oC, 101.3 kPa)
      Data from ACG99, Ric96, http://esc.syrres.com.
      2-Chloro-6-(trichloromethyl)pyridine is a white crystalline solid with a mildly
      sweet odour (ACG99).
4     Uses
      2-Chloro-6-(trichloromethyl)pyridine is used as a fertiliser additive to control
      nitrification and to prevent loss of nitrogen in soil (ACG99).
5     Biotransformation and kinetics
      2-chloro-6-(trichloromethyl)pyridine
      After oral administration of 14C-2-chloro-6-(trichloromethyl)pyridine to one
      female dog, at least 80% of the radioactivity was excreted via the urine as
      N-(6-chloropicolinoyl)glycine. No half-life time was given (Red66). After
      feeding 2-chloro-6-(trichloromethyl)pyridine spiked with
      14
         C-2-chloro-6-(trichloromethyl)pyridine at 100 mg/kg diet for a number of
      days to rats, mainly 6-chloropicolinic acid and to a lesser extent
      N-(6-chloropicolinoyl)glycine were excreted. There are no quantitative data
      (Red67).
           The committee concluded that the main metabolite of
      2-chloro-6-(trichloromethyl)pyridine is 6-chloropicolinic acid, and that,
      depending on the species, a certain percentage is conjugated to glycine.
032-4 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      6-chloropicolinic acid
      After oral administration of 14C-chloropicolinic acid to rats, approximately
      98% of the dose was excreted via the urine within 48 hours, with 1.5% and
      1.3% eliminated via the faeces and expired air, respectively. The parent
      compound and its glycine conjugate accounted for 100% of the 14C eliminated
      via the urine during the first 8 hours following administration. The half-life for
      elimination of chloropicolinic acid from the body was calculated to be 2.4
      hours, and the half-life for clearance of 14C from the blood was 1.1 hour
      (Ram74).
          After 28 days of feeding 6-chloropicolinic acid to cattle at 100 mg/kg diet
      the compound could not be detected in fat and, therefore, does not accumulate
      in body tissues (Ken80).
          6-Chloropicolinic acid was fed to cows first at 1 mg/kg food for 14 days,
      then at 10 mg/kg for 14 days, and finally at 100 mg/kg for 21 days. No residues
      were found in milk and cream (detection level 0.02 mg/kg). Since the cows ate
      16.3 kg of feed daily, the intake of 6-chloropicolinic acid was calculated to be
      3.4 mg/kg bw at the high dose level (Jen71). Also from this study, it can be
      concluded that the compound does not accumulate in fat.
          Also in young pigs, no residues were detected in muscle, fat, or liver after
      feeding them with 10, 30, or 300 mg 6-chloropicolinic acid per kg food for 30
      days. At the highest dose level, the kidneys contained 0.09-0.3 mg of the
      compound/kg organ tissue (Mul76).
6     Effects and mechanism of action
      Human data
      The committee did not find human data on the effects of exposure to
      2-chloro-6-(trichloromethyl)pyridine.
      Animal data
      Acute toxicity
032-5 2-Chloro-6-(trichloromethyl)pyridine (nitrapyrin)
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<pre>      2-chloro-6-(trichloromethyl)pyridine
      The following acute lethal toxicity data have been found for
      2-chloro-6-(trichloromethyl)pyridine (Lew00, Mul76):
          LD50 oral rat: 940, 1070, 1230 mg/kg bw
          LD50 oral mouse: 710 mg/kg bw
          LD50 oral rabbit: 713 mg/kg bw
          LD50 dermal rabbit: 850 mg/kg bw.
      6-chloropicolinic acid,
      The following acute lethal toxicity data have been found for 6-chloropicolinic
      acid:
          LD50 oral: male rats: 2830 mg/kg bw, female rats: 2180 mg/kg bw (Mul76).
          LD50 oral: male mice: 1835 mg/kg bw, female mice: 1089 mg/kg bw
      (Dow86).
      Repeated dose toxicity/carcinogenicity
      2-chloro-6-(trichloromethyl)pyridine
      A 94-day dietary feeding study in rats and dogs indicate a low order of chronic
      toxicity of 2-chloro-6-(trichloromethyl)pyridine. The following parameters
      were assessed: general appearance and behaviour, growth, food consumption,
      final body and organ weights, mortality, haematological, serum urea nitrogen
      and alkaline phosphatase determination, and gross and microscopic
      examination of tissues and organs. No adverse effects were observed in rats
      and dogs on daily level of 300 and 600 mg/kg diet, respectively. These levels
      correspond to a daily ingestion rate of 15 mg/kg bw for both species
      (unpublished studies from Dow Chemical Company from 1963, 1967, 1969,
      1971, 1972, and 1974, summarised in Mul76 and ACG99).
          2-Chloro-6-(trichloromethyl)pyridine was fed to groups of male and
      female rats at concentrations of 0, 30, 100, 300 or 1000 mg/kg diet, for 2
      years. These dietary levels correspond with a daily ingestion of approximately
      1.5, 5, 15, and 50 mg/kg bw. In the male rats fed 1000 mg/kg diet, a
      statistically significant reduction in mean body weight was recorded at 12
      months, but decreases in body weight were not significant at 18 and 24 months.
032-6 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      In the female rats fed 30-1000 mg/kg diet, an increased incidence of bile duct
      hyperplasia was found (ACG99, no other details were available).
      6-chloropicolinic acid
      In 2-year feeding studies with 6-chloropicolinic acid, no adverse effects were
      observed in rats and dogs at 300 and 2000 mg/kg diet, respectively, in both the
      90-day and 2-year feeding studies. These dietary levels correspond to a daily
      ingestion of 15 and 50 mg/kg bw for rats and dogs, respectively (studies from
      1967 and 1970, summarised in Mul76, made available to the EPA in 1992).
          Some data are available of a 2-year feeding study in mice. Groups of 70
      male and 70 female B6C3F1 mice received doses of 6-chloropicolinic acid of
      0, 100, 300, or 900 mg /kg bw/d. Ten mice per sex and per dose group were
      scheduled for interim sacrifices: one after 6 monhts and one after 12 months.
      The rest of the mice were scheduled for sacrifice after 24 months. Parameters
      examined included in-life body weight, feed consumption, palpation and
      clinical observations, mortality rates, clinical chemistry, haematology, final
      body and organ weights, gross pathology and histopathology. In the male
      animals of the high-dose group, body weights were decreased throughout most
      of the study and there were renal lesions evident at all sacrifices and consisting
      of a total or near-total loss of the normal vacuolation present in proximal
      tubular epithelial cells. In the female mice of this group, there was increased
      incidence of hepatocellular carcinomas of 12%. This increase did not show a
      statistical trend and was not significant in pairwise comparisons. It was slightly
      outside the control range (0 - 8%) found in mice in previous studies in the
      same laboratory, but within the range of control incidences (0 - 15%) for other
      laboratories using the B6C3F1 mouse. In addition, the incidence of total liver
      tumours in female mice of the 900 mg/kg-group was within historical control
      ranges of the same laboratory and was not statistically significant. The authors
      concluded that the biologic significance of this equivocal increase in
      hepatocellular carcinomas was questionable and may be a reflection of normal
      variability since there were no indications of a hepatotoxic effects. The authors
      concluded that 300 mg/kg bw is a NOAEL for male and female mice when
      given via the food during 2 years (Dow86). The committee noticed that
      detailed data on the study were lacking: although the study contained many
      tables, they were not present in the copy made available to the committee, and
      the committee did not succeed in retrieving them. The document did not
      contain information on the bile duct, whereas this was the target organ in
032-7 2-Chloro-6-(trichloromethyl)pyridine (nitrapyrin)
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<pre>      female rats after oral dosing of 2-chloro-6-(trichloromethyl)pyridine (i.e., the
      parent compound). In this mouse study, the gall bladders were collected and
      preserved at necropsy. Therefore, presumably the gallbladders have been
      investigated and probably no effects have been found.
      Mutagenicity and genotoxicity
      2-Chloro-6-(trichloromethyl)pyridine was - in some cases weakly - positive
      when tested in S. typhimurium strains TA97, TA98, and TA100 with rat or
      hamster liver metabolic activation but negative when tested without metabolic
      activation. Testing with and without similar metabolic activation systems,
      results were negative in S. typhimurium strain TA1535 as well (Zei88).
          The committee did not find data on other mutagenicity/genotoxicity tests
      and concluded that the mutagenic and genotoxic properties of
      2-chloro-6-(trichloromethyl)pyridine should be investigated further.
      Reproduction toxicity
      2-chloro-6-(trichloromethyl)pyridine
      Groups of pregnant Fischer 344 rats received daily oral doses of 0, 5, 15, or
      50 mg 2-chloro-6-(trichloromethyl)pyridine/kg bw on gestation days 6-15.
      The high dose produced slight histological changes in the livers of pregnant
      females. There were no statistically significant differences in any of the
      reproductive or teratogenicity parameters (Ber88). The committee concluded
      that 2-chloro-6-(trichloromethyl)pyridine is not a reproductive toxicant in rats
      at dose levels up to 50 mg/kg bw/d, when given during organogenesis.
          Groups of pregnant New Zealand white rabbits received daily oral doses of
      0, 3, 10, or 30 mg 2-chloro-6-(trichloromethyl)pyridine/kg bw on gestation
      days 6-18. A significant depression in maternal weight gain and increased
      absolute and relative liver weights were observed at the high dose. At the low
      dose, the resorption rate was increased (p<0.05), but as these values fell within
      the range of the incidence of resorptions in historical control groups, and as
      the response was not dose-related, the apparent increase was not considered
      treatment-related by the authors. Treatment-related effects were limited to an
      increase in crooked hyoid bones at the high dose (p<0.05), with no effects
      observed in the lower treatment groups (Ber88). The committee concluded that
      when orally given during organogenesis, 2-chloro-6-(trichloromethyl)pyridine
032-8 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      was not teratogenic in rabbits but that it induced fetotoxicity at a maternally
      toxic dose of 30 mg/kg bw.
      6-chloropicolinic acid
      No adverse effects were seen on fertility, gestation, viability, lactation, body
      weights at weaning and mating and examination of fetuses for teratological
      effects in rats fed doses of 6-chloropicolinic acid up to 1000 mg/kg diet (the
      highest dose tested) in a 3-generation study with 2 litters per generation
      (unpublished study from 1967, summarised in Mul76).
7     Existing guidelines
      The current adminstrative occupational exposure limit (MAC) for
      2-chloro-6-(trichloromethyl)pyridine in the Netherlands is 10 mg/m3, 8-hour
      TWA.
          Existing occupational exposure limits for nitrapyrin in some European
      countries and in the USA are summarised in the annex.
8     Assessment of health hazard
      After oral dosing, 2-chloro-6-(trichloromethyl)pyridine is rapidly excreted via
      the urine as 6-chloropicolinic acid. Studies with 6-chloropicolinic acid also
      show its rapid excretion in rats and the absence of accumulation in body tissues
      of cattle and young pigs.
          From acute oral and dermal lethality data in rats and rabbits, respectively,
      the committee considers 2-chloro-6-(trichloromethyl)pyridine to be harmful
      if swallowed and when in contact with skin.
          In a 94-day feeding study with 2-chloro-6-(trichloromethyl)pyridine, no
      effects were observed in rats and dogs given 15 mg/kg bw (ACG99, Mul76). In
      a 2-year feeding study with 2-chloro-6-(trichloromethyl)pyridine, an increased
      incidence of bile duct hyperplasia was found in female rats given 1.5 mg/kg bw
      (ACG99). However, 6-chloropicolinic acid, its major metabolite, did not
      induce this effect in rats and dogs given up to 15 and 50 mg/kg bw for 2 years,
      respectively, (Mul76), and probably also not in mice given up to 900 mg/kg bw
      for 2 years (Dow86). Therefore, the committee is of the opinion that the bile
      duct hyperplasia in female rats might be an incidental finding and is of
      questionable relevance. Apart from a questionable increased incidence of
032-9 2-Chloro-6-(trichloromethyl)pyridine (nitrapyrin)
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<pre>       hepatocellular carcinomas in female mice fed doses of 6-chloropicolinic acid
       of 900 mg/kg bw, for 2 years, no increases in the incidences of any tumour
       were reported following long-term oral administration of
       2-chloro-6-(trichloromethyl)pyridine and 6-chloropicolinic acid.
             2-Chloro-6-(trichloromethyl)pyridine was mutagenic when tested in an in
       vitro bacterial system (S. typhimurium). No other information on the potential
       mutagenicity/genotoxicity was available.
             2-Chloro-6-(trichloromethyl)pyridine (and 6-chloropicolinic acid) showed
       no reproduction toxicity after feeding pregnant rats and rabbits during
       organogenesis (Ber88).
       The committee considers the toxicological data base on
       2-chloro-6-(trichloromethyl)pyridine too poor to justify recommendation of a
       health-based occupational exposure limit.
       The committee concludes that there is insufficient information to comment on
       the present MAC level.
       References
ACG99  American Conference of Governmental Industrial Hygienists (ACGIH). Nitrapyrin. In: TLVs ® and
       other occupational exposure values - 1999. [CD-ROM]. Cincinnati OH, USA: ACGIH®, Inc, 1999.
ACG00  American Conference of Governmental Industrial Hygienists (ACGIH). Guide to occupational
       exposure values - 2000. Cincinnati OH, USA: ACGIH®, Inc, 2000: 86.
ACG01  American Conference of Governmental Industrial Hygienists (ACGIH). 2001 TLVs ® and BEIs ®.
       Threshold Limit Values for chemical substances and physical agents. Biological Exposure Indices.
       Cincinnati OH, USA: ACGIH®, Inc, 2001: 43.
Ber88  Berdasco NM, Lomax LG, Zimmer MA, et al. Teratologic evaluation of orally administered nitrapyrin
       in rats and rabbits. Fundam Appl Toxicol 1988; 11: 464-71.
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.
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.
032-10 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>DFG01  Deutsche Forschungsgemeinschaft (DFG): Commission for the Investigation of Health Hazards of
       Chemical Compounds in the Work Area. List of MAK and BAT values 2001. Maximum
       concentrations and biological tolerance values at the workplace. Weinheim, FRG: Wiley-VCH, 2001;
       rep no 37.
Dow86  Dow Chemical Company. Initial submission: 6-Chloropicolinic acid: 2-year dietary chronic
       toxicity-oncogenicty study in B6C3F1 mice (final report) with cover letter dated 051492. Midland MI,
       USA: Dow Chemical Company, 1986 (available from NTIS, Springfield VA, USA; order no
       NTIS/OTS0539753).
How92  Howard PH, Neil M, ed. Dictionary of chemical names and synonyms. Chelsea MA, USA: Lewis
       Publishers, 1992.
HSE01  Health and Safety Executive (HSE). EH40/2001. Occupational exposure limits 2001. Sudbury (Suffolk),
       England: HSE Books, 2001: 14.
Jen71  Jensen DJ. Assays for residues in milk and cream from cows fed 6-chloropicolinic acid. J Agric Food
       Chem 1971; 19: 897-9.
Ken80  Kenaga EE. Correlation of bioconcentration factors of chemicals in aquatic and terrestrial organisms
       with their physical and chemical properties. Environ Sci Technol 1980; 14: 553-6.
Lew00  Lewis RJ Sr, ed. Sax's dangerous properties of industrial materials. 10th ed. New York, USA: Van
       Nostrand Reinhold, 2000; 909.
Mul76  Mullison WR, Norris MG. A review of the toxicological, residual and environmental effects of
       nitrapyrin and its metabolite 6-chloropicolinic acid. Down Earth 1976; 32: 22-7.
Ram74  Ramsey JC, Rose JQ, Braun WH, et al. Fate of 6-chloropicolinic acid following oral administration in
       rats. J Agric Food Chem 1974; 22: 870-3.
Red66  Redemann CT, Williams EA, Clark HW Jr, et al. The excretion of N-(6-chloropicolinoyl)glycine by the
       dog fed 2-chloro-6-(trichloromethyl)pyridine. J Agric Food Chem 1966; 14: 530-2.
Red67  Redemann CT, Clark HW Jr. Fate of 2-chloro-6-(-trichloromethyl)pyridine in the rat. J Agric Food
       Chem 1967; 15: 1127-8.
Ric96  Richardson ML, Gangolli S, ed. Nitrapyrin. In: The dictionary of substances and their effects.
       Cambridge, UK: Royal Society of Chemistry, 1996: 100-2 (Vol 6).
SZW01  Ministerie van Sociale Zaken en Werkgelegenheid (SZW). Nationale MAC-lijst 2001. The Hague, the
       Netherlands: Sdu, Servicecentrum Uitgevers, 2000: 21.
TRG00  TRGS900: Grenzwerte in der Luft am Arbeitsplatz; Technische Regeln für Gefahrstoffe. BArbBl 2000;
       2.
Zei88  Zeiger E, Anderson B, Haworth S, et al. Salmonella mutagenicity tests. 4. Results from the testing of
       300 chemicals. Environ Mol Mutagen 1988; 11 (suppl 12): 1-158.
032-11 2-Chloro-6-(trichloromethyl)pyridine (nitrapyrin)
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<pre>              Annex
Occupational exposure limits for 2-chloro-6-(trichloromethyl)pyridine in various countries.
country                                occupational                time-weighted      type of         note a       lit refb
- organisation                         exposure limit              average            exposure limit
                                       ppm          mg/m3
the Netherlands
- Ministry of Social Affairs and       -            10             8h                 administrative               SZW01
Employment
Germany
- AGS                                  -            -                                                              TRG00
- DFG MAK-Kommission                   -            -                                                              DFG01
Great Britain
- HSE                                  -            10             8h                 OES                          HSE01
                                       -            20             15 min
Sweden                                 -            -                                                              Arb00b
Denmark                                -            -                                                              Arb00a
USA
                                                                                                      C
- ACGIH                                -            10             8h                 TLV                          ACG01
                                       -            20             15 min             STEL
- OSHA                                 -            15d; 5e        8h                 PEL                          ACG00
- NIOSH                                -            10d; 5e        10 h                                            ACG00
                                       -            20d            15 min             REL
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
      Classified as A4 carcinogen, i.e., not classifiable as a human carcinogen: agents which cause concern that they could
      be carcinogenic for humens but which cannot be assessed conclusievely because of a lack of ata. In vitro or animal
      studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other
      categories
d
      Total dust
e
      Respirable dust
032-12        Health-based Reassessment of Administrative Occupational Exposure Limits
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