<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>Tungsten and tungsten compounds
(CAS No: 7440-33-7)
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/058, The Hague, 31 October 2002
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<pre>Preferred citation:
Health Council of the Netherlands: Committee on Updating of Occupational
Exposure Limits. Tungsten and tungsten compounds; Health-based
Reassessment of Administrative Occupational Exposure Limits. The Hague:
Health Council of the Netherlands, 2002; 2000/15OSH/058.
all rights reserved
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<pre>1     Introduction
      The present document contains the health hazard of tungsten and its compounds
      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 AD Wientjes, M.Sc. and Ir PMJ Bos (TNO Nutrition and Food
      Research, Zeist, the Netherlands).
          The evaluation of the toxicity of tungsten has been based on the review by
      the American Conference of Governmental Industrial Hygienists (ACG99).
      Where relevant, the original publications were reviewed and evaluated as will
      be indicated in the text. In addition, literature was retrieved from the on-line
      databases Medline, Toxline, and Chemical Abstracts covering the periods 1966
      to 20 April 1999 (1990420/UP), 1965 to 29 January 1999 (1990126/ED), and
      1967 to 10 April 1999, respectively, and using the following key words:
      tungsten and 7440-33-7. HSDB and RTECS, databases available from
      CD-ROM, were consulted as well (NIO99, NLM99). The final literature search
      was carried out in April 1999.
          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, physical and chemical properties
      Data on tungsten and some selected tungsten compounds are given in Table 1.
          Tungsten is a grey, hard, brittle, metallic element in group VIb of the
      periodic system, and has the highest melting point of all metals (ACG99).
          Tungsten exists in several states of oxidation 0, 2+, 3+, 4+, 5+, and 6+. The
      most stable is 6+, the lower valence states being relatively unstable.
          The tungsten of commercial importance includes the water-insoluble
      compounds (tungsten carbide, sulphide, carbonyl, silicide, and oxide, and
      tungsten acid) and the water-soluble compounds (tungsten chloride, fluoride,
      and tungstic acid). According to Beliles (Bel94), soluble compounds are
      distinctly more toxic than insoluble forms.
058-3 Tungsten and tungsten compounds
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<pre>Table 1 Identity and physical and chemical properties of tungsten and some of its compounds.
name                     tungsten         tungsten trioxide                         tungsten fluoride        tungsten carbide
synonyms                 wolfram          tungsten(VI) oxide; tungsten blue;        tungsten(VI) fluoride;
                                          tungsten oxide; tungstic anhydride;       tungsten hexafluoride
                                          tungsten acid anhydride; tungstic oxide;
                                          wolframic acid, anhydride
molecular formula        W                WO3                                       WF6                      WC
CAS number               7440-33-7        1314-35-8                                 7783-82-6                12070-12-1
molecular weight         183.85           231.85                                    297.84                   195.86
melting pointa           3410oC           1473oC                                    2.5oC420                 2870oC
boiling point            5660oC           -                                         17.5oC                   6000oC
flash point              -                -                                         -                        -
vapour pressure          -                -                                         -                        -
solubility in water      i                i                                         d                        i (cold)
Log P octanolwater       -                -                                         -                        -
d: decomposes; i: insoluble; s: soluble.
a
      Number in superscript represents the atmospheric pressure (mmHg) at which the presented value was determined.
Table 1 Continued.
name                 tungsten disulphide tungsten carbonyl tungsten silicide tungsten chloride sodium tungstate
synonyms             tungstenite                                                 tungsten           disodium tungstate;
                                                                                 hexachloride       sodium tungstate(VI);
                                                                                                    sodium tungsten oxide;
                                                                                                    tungstic acid, disodium
                                                                                                    salt
molecular formula    WS2                   W(CO)6              WSi2              WCl6               Na2WO4
CAS number           12138-09-9            14040-11-0          12039-88-2        13283-01-7         13472-45-2
molecular weight     247.97                351.91              240.02            396.57             293.83
melting point a      1250oCd               ~150oCd             >900°C            275oC              698oC
boiling point a      -                     175oC766            -                 346.7oC            -
flash point          -                     -                   -                 -                  -
vapour pressure      -                     -                   -                 -                  -
solubility in water  i (cold)              i                   i                 d (hot)            s
Log P octanolwater   -                     -                   -                 -                  -
d: decomposes; i: insoluble; s: soluble.
a
      Number in superscript represents the atmospheric pressure (mmHg) at which the presented value was determined.
Data from ACG99, Lid94, NIO99, NLM99, Ric94a, Ric94b.
058-4          Health-based Recommended Occupational Exposure Limits
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<pre>3     Uses
      Tungsten is a valuable metal, because it has the highest melting point of all
      metals, a great strength at high temperatures, and good conductivity for
      electricity and for heat. It is used to increase the hardness and tensile strength of
      steel. It plays a vital role in the production of a number of other alloys noted for
      their hardness, such as the chromium, cobalt, and tungsten alloy use for the
      tipping and facing lathe tools. It is also used for filaments in incandescent
      lamps, heating elements, and welding electrodes, in nozzles of rocket motors, in
      protecting shield for space crafts, and in solar energy devices (ACG99, Kaz79).
          Tungsten carbide finds its use in many drills and cutting edges of tools
      giving them a hardness comparable to that of diamond. The disulphide is used
      as a solid lubricant, the carbonyl, chloride, and fluoride in deposition of
      tungsten coatings, and tungstic acid and oxide in the textiles, ceramics, and
      plastics industries. Tungstates are used in X-rays tubes, fluorescent lamps and
      lasers, and as pigment in dyes and inks (ACG99, Kaz79).
4     Biotransformation and kinetics
      The kinetics of tungsten oxide were studied by exposing 6 anaesthetised Beagle
      dogs via nose-only inhalation to mists of radiolabelled 181WO3 of 98 µCi/mL
      specific activity, for 6 hours; the final air concentration was not reported.
      Tungstic oxide aerosols were found to have an Activity Median Aerodynamic
      Diameter of 0.70 µm with a geometric standard deviation of 1.5. The
      radioactivity deposited in the respiratory tract of each animal was estimated by 3
      independent methods: inhaled minus exhaled activity, in vivo γ-ray
      measurements of the body (lung area and posterior part of the dog’s body were
      measured separately), and analyses of activity excreted in urine and faeces
      during 100 days post-exposure. The fraction excreted during exposure is
      unknown, the reported excretion will, therefore, be underestimated to an
      unknown extent (it was, however, mentioned that no faecal excretion occurred
      before 20 hours post-exposure). The fact that the first method appeared to reveal
      a higher uptake than the third method confirms an underestimation. However,
      the results of the excretion analyses were used in the further analyses indicating
      that about 60% of the inhaled radioactivity was estimated to be deposited in the
      respiratory tract; half of this fraction was found in the lower portion of the
      respiratory tract. Under the assumption that oral absorption was approximately
058-5 Tungsten and tungsten compounds
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<pre>      25% (this assumption could not be verified), it was calculated from the
      excretion data that about 33% of the deposited activity entered the systemic
      circulation, most of it within 10 days after inhalation. The remaining ca. 66%
      was cleared from the lungs by way of the ciliary escalator system. Blood
      measurements indicated that the inhaled tungstic oxide entered the blood quite
      soon after inhalation. It was concluded that after inhalation, the rate of decrease
      in radioactivity in blood was clearly slower than after an intravenous injection
      of Na2181WO4. Based on the excretion analyses, excretion was estimated to
      occur in 3 phases with half-times of 14 h, 5.8 d, and 63 d, respectively; the
      average daily urine to faeces 181W ratio was 1.92. At sacrifice, 165 days
      post-exposure, only negligible amounts were found in tissues (Aam75).
          Retention and excretion were measured in two 18-month-old Beagle dogs
      (one male and one female) given intravenous injection of 0.5-2.3 µCi of 181W as
      sodium tungstate in normal saline. After 43 days, a second injection was given
      to each dog. Retention and excretion were followed for a further 131 days.
      Urine and faeces were collected separately and body burdens were determined
      by in vivo γ-ray counting. The results obtained from the first 42 days following
      the second injection (corrected for the expected remaining body burden from
      the first injection) were combined with those following the first injection.
      Clearance from the blood was relatively fast in the first 24 hours, and appeared
      to be 3-phasic with half-times of 36 min, 71 min, and 5 h, respectively. The
      average plasma to red blood cell 181W ratio was 3. Whole body retention was
      measured by whole-dog γ-ray counting. Removal from the body was estimated
      to be 4-phasic with biological half-times of 86 min, 8.8 h, 3.7 d, and 99 d,
      respectively. As to excretion, 91% of the injected radioactivity was excreted in
      urine within 24 hours. The urine to faeces 181W ratio stabilised by day 5, and
      finally averaged 38, indicating that 181W was excreted primarily in the urine
      (Aam73).
          Wide et al. studied the distribution of radiolabelled W (administered as
      Na2185WO4) by whole-body autoradiography and quantitative measurements in
      pregnant NMRI mice. As to the autoradiographic experiments, pregnant mice
      received an intravenous injection of either 0.12 or 20 mg radiolabelled W/kg
      bw, as Na2185WO4. Three mice received the low dose on gestation day 8, and
      were killed after 4, 24, or 48 hours. One mouse was administered the high dose
      and was killed after 48 hours. On gestation day 12, 4 mice received the low
      dose (sacrificed after 4, 24, or 48 hours, or 6 days), and one mouse the high
      dose (killed after 48 hours). Two mice were given the low dose at gestation day
      17, and killed after 4 and 24 hours. In addition, one non-pregnant female
058-6 Health-based Recommended Occupational Exposure Limits
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<pre>      C57BL mouse (killed after 24 hours) and 3 male NMRI mice (killed 1 hour, 24
      hours, or 10 days after injection) were administered the low dose. For
      quantitative tissue examinations, groups of 4 pregnant NMRI mice (per survival
      interval) were administered an intravenous dose of 0.12 mg radiolabelled W/kg
      bw (as Na2185W O4 on gestation day 12, and killed after 1, 4, or 48 hours, or on
      gestation day 17 and killed after 1 or 4 hours. In addition, groups of 4 mice
      received 20 mg/kg bw on gestation day 12 and were killed after 1 or 8 hours,
      respectively. Accumulation of radioactivity in adult male as well as in pregnant
      female mice was observed in the skeleton, liver, and kidney, with rapid
      excretion to the urine and intestinal contents. Relatively high activity was found
      in the thyroid, adrenal medulla and outer zone of the adrenal cortex, and
      pituitary. In the male mice, considerable accumulation was further observed in
      the seminal vesicles while in the non-pregnant female mouse, the interstitial
      tissues and ovary follicles showed relatively high concentrations. In pregnant
      animals, administration on day 8 resulted in accumulation in the zone of the
      ectoplacental cone, in the visceral yolk, and in the decidua basalis. Embryo
      uptake was considered to be low, but was difficult to evaluate due to the small
      size of the embryo. After administration on day 12, highest levels of
      radioactivity found one hour after administration were in the skeleton, kidney,
      liver, placenta, and fetus. These levels were decreased by approximately 50% 4
      hours after injection and to very low levels 48 hours after injection. At 1 hour
      after administration of the high dose, a relatively lower portion (as % of
      administered dose) as compared to the low dose, was observed in liver and
      kidney, but the relative portion distributed in fetus and placenta was comparable
      to that after the low dose. Four hours after injection, the relative concentrations
      in fetus and placenta were lower than after administration of the low dose, but
      still higher than in maternal tissues. Administration of the low dose at day 17
      resulted in higher tissue concentrations of W after 1 and 4 hours, as compared to
      day 12. At 1 hour after exposure, concentrations in fetus and placenta were
      approximately 70 and 40% higher, respectively, as on day 12, while 4 hours
      after injection on day 17, the concentration in the fetus was 50% higher when
      compared to day 12, but was similar in the placenta on both days. On day 12, an
      accumulation in the nervous tissue of the fetus was observed, as well as in the
      visceral yolk sac epithelium. The activity in the amniotic fluid was rather high
      compared to serum. Radioactivity in the fetus on day 17 was high in the
      skeleton, both at 4 and 24 hours after injection. Furthermore, in vitro
      cytotoxicity experiments showed inhibition by tungstate of cartilage production
058-7 Tungsten and tungsten compounds
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<pre>      in limb bud mesenchymal cultures at concentrations similar to those found in
      vivo (Wid86).
           Young et al. administered groups of 7 male rats diets containing 8, 16, or 32
      mg W/kg as ammonium tetrathiotungstate, for 4 weeks; in addition the copper
      content of the diet was varied. Although the time point of plasma sampling is
      not specified, it is assumed that plasma is sampled at the end of the 4-week
      exposure period. The plasma tungstate concentrations appeared to be
      independent of the dietary tungstate content, but were approximately 3- to
      4-fold higher at higher dietary copper levels. Liver tungstate concentrations
      increased with increasing tungstate dose, and were higher at higher copper
      levels. Copper levels appeared to have less influence on the tungstate levels in
      the kidneys. Plasma concentrations appeared to be 4- to 5-fold higher in rats
      administered 32 mg W/kg diet as WO2S22- (dithiotungstate, ammonium salt) for
      5 weeks than when administered as WS42- for 4 weeks. (Although in the
      description of the ‘Methods’it is stated that tungstate is administered as WS42-,
      under ‘Results’ tungstate is mentioned to be administered as WO2S22-, the latter
      is assumed to be the appropriate form). In contrast, 5-week administration of 32
      mg W/kg diet as WO2S22- resulted in a 50% lower liver tungstate content than
      4-week administration as WS42-, whereas the kidney concentration was even
      80% lower. Copper supplementation appeared to have less influence on the
      tissue tungstate concentration when tungstate was administered as WO2S22-
      (You82).
           Two complimentary studies were carried out with adult Rochester strain
      Wistar rats. Tungstate was administered as a single (unspecified) dose of WO42-.
      In the first experiments, 24 female rats were administered 187W by gastric
      intubation. At 0.5, 1, 3, 6, 12, 24, 48, and 72 hours, 3 animals were sacrificed.
      Carcass, gastrointestinal tract, blood, plasma, urine, and faeces were counted by
      γ−spectrometry. Tungsten was eliminated from the whole body with an initial
      biological half-time of 10 h. The gastrointestinal tract and contents accounted
      for the highest activity for the first 45 hours post-administration. A peak value
      of 17% of the administered dose was found in the carcass after 1 hour, plasma
      values also peaked after 1 hour. Excretion via the urine was fast, a steep curve
      for cumulative urine which crested by 12 hours post-exposure was found.
      Urinary excretion accounted for approximately 44% of the administered dose.
      Faecal excretion was slower, finally accounting for 53% of the administered
      dose after 72 hours. In the second experiment, 90 adult Wistar rats divided
      evenly between males and females were used. Seventy of the rats received a
      single dose of 185W by gastric intubation and groups of 10 rats (9 rats at the last
058-8 Health-based Recommended Occupational Exposure Limits
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<pre>      2 time points) were killed after 3, 7, 14, 32, 61, 104, and 195 days. At the latter
      2 sacrifices, only 4 females were killed, the 2 remaining females were killed
      after 254 days. Twenty rats were used as controls. In the first week, urinary and
      faecal collections were carried out daily for the first week on alternating groups
      of 6 rats (3 males and 3 females). Collections were made every 3-4 days during
      the following 4 weeks, and at approximately weekly intervals during the
      remainder of the study (collection of urine and faeces was not 100% efficient).
      Besides whole blood and plasma, 25 organs and tissues were removed from the
      animals soon after death and prepared by a special process for liquid
      scintillation counting of β-activity. Tungsten could not be detected in the faeces
      after 33 days. Urine sampling was stopped after 191 days, although some
      activity was still detectable. Highest concentrations in tissues collected after 3
      days were found in the spleen (0.013% of the administered dose per g tissue),
      hair (0.005%), and kidney (0.004%). The concentration in the kidney decreased
      more rapidly than in the spleen and hair. As to the absolute amount per organ,
      highest levels were found in the liver (0.03% of the administered dose)
      (Kay68).
5     Effects and mechanism of action
      Human data
      Letters sent to the TLV committee by the industry in 1966 reported no
      pneumoconiosis among workers exposed solely to approximately 5 mg/m3
      tungsten or its insoluble compounds and no difficulty in controlling atmospheric
      concentrations of tungsten and tungsten carbide to workplace air levels
      considerably below 5 mg/m3 (ACG99).
          A young soldier developed seizures and tubular necrosis after drinking 0.25
      L of a beverage prepared by rinsing still hot gun-barrels (that had been fired
      several times) with wine. Tungsten was present in gastric content
      (concentration: 8 mg/L), blood (serum concentration: 5 mg/L), and urine
      (concentration: 101 mg/L) of the soldier, as well as in the wine (concentration:
      1540 mg/L; estimated by preparing a similar drink several days later) (Mar96,
      Mar97).
          Most of the articles found in the literature search were based on exposure to
      hard metal. Hard metal is prepared by first heating finely divided tungsten and
      carbon to form tungsten carbide, and cobalt is added as a binder. Other metal
      components are also added depending on the specific hard metal to produce.
058-9 Tungsten and tungsten compounds
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<pre>       Therefore, the inhalable dust in hard metal plant may contain tungsten, cobalt,
       titanium, vanadium, niobium, hafnium, and tantalum both as oxides and as
       carbides. The major component of dust is, however, tungsten (Sah93). In most
       of the reports on hard-metal pneumoconiosis, the agent responsible for ‘hard
       metal disease’ is believed to be cobalt, but this has not yet been proven (Kaz79).
       Studies in a number of factories manufacturing tungsten carbide-based products
       have revealed the presence of respiratory symptoms associated with impaired
       respiratory functions and radiographic abnormalities in proportion of those
       exposed. Because of the mixed exposures and the uncertainty which of the
       above mentioned metals causes the disease, these articles are not included in the
       present evaluation.
       Animal data
       Irritation and sensitisation
       The committee did not find valid data on eye and skin irritation.
           In a briefly reported guinea pig maximisation test, 3 out of 20 guinea pigs
       showed positive reactions at a challenge concentration of 5% (w/w in saline).
       No positive reactions were found at lower concentrations (Bom82).
       Acute toxicity
       Female CD-1 mice (n=5; 6- to 8-week old), were submitted to a single
       intratracheal instillation of 250 µg calcium tungstate (CaWO4) particles
       suspended in 100 µL of saline. The animals were sacrificed by a lethal dose of
       diethyl ether 1, 3, 7, 14, and 21 days after the intratracheal instillation. Control
       animals received 100 µL sterile saline. One additional group of mice was used
       to collect bronchoalveolar lavage liquid and to evaluate the microanatomy of
       lung tissue from untreated animals. The effects were studied using 3
       microanatomical methods: cytological study of exudates obtained by
       bronchoalveolar lavage, histological examination of paraffin-embedded sections
       of lung samples, and scanning electron microscopic (SEM) examination of lung
       tissues. The metal induced a marked inflammatory response in the
       bronchoalveolar space characterised by a biphasic attraction of leukocytes with
       cellular peaks at day 1 and 14. In controls, only the first inflammatory peak was
       detected. Up to the 14th day after tungsten instillation, the presence of the metal
       particles attracted significantly higher number of inflammatory cells to the
058-10 Health-based Recommended Occupational Exposure Limits
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<pre>       animal airways than the instillation of saline alone; this difference disappeared
       after 21 days. Up to day 21, neutrophils were present in significantly higher
       numbers in the bronchoalveolar lavage preparations of tungsten treated-mice. In
       the bronchoalveolar lavage from untreated animals, virtually no granulocytes
       were available. More than 50% of the bronchoalveolar lavage macrophages
       showed ingested tungsten. Three days after the tungsten instillation, extensive
       inflammatory exudates were located at the periphery of the bronchus.
       Twenty-one days after instillation, the lung tissue showed several regions
       massively invaded by inflammatory cells, mononuclear granulocytes, and
       cellular debris. In the lung parenchyma, the inflammatory infiltrates were
       predominantly located at the periphery of the bronchiolar walls (Peã93).
           Oral LD50 values of sodium tungstate in the rat ranged between 223 to 255
       mg/kg. Guinea pigs treated orally or intravenously with tungsten or sodium
       tungstate developed anorexia, colic, incoordination of movement, trembling,
       and dyspnoea. When injected subcutaneously, the LD50 of sodium tungstate was
       reported to be between 140-160 mg/kg. Tungsten toxicity appeared to depend
       on the age and nutritional status of the rat: 30-day-old rats survived a dose that
       killed older rats; mortality was reduced when animals were fed before tungsten
       exposure. The LD50 by intramuscular injection of sodium tungstate was 105
       mg/kg. The intraperitoneal LD50 of tungsten metal powder in the rat was 5000
       mg/kg (ACG99). The average dose to kill male rabbits and cats (numbers not
       specified) receiving a continuous intravenous perfusion of sodium tungstate
       within approximately 1 hour were found to be 105 and 140 mg/kg, respectively
       (Pha65, Pha67).
       Subacute toxicity
       Young et al. studied the effects of tetrathiotungstate and dithiotungstate on
       copper metabolism in weanling rats (bw: 40-50 g). Groups of 7 male rats were
       administered diets containing 8, 16, or 32 mg W/kg as ammonium
       tetrathiotungstate for 4 weeks. All rats receiving the highest dose and one
       animal of the mid-dose group died within 1-3 weeks. A dose-related decrease in
       body weight gain, blood haemoglobin concentration, packed cell volume, and
       erythrocyte count was observed. No statistical analyses were presented; the
       decreases for these parameters were 27%, 33%, 31%, and 31%, respectively, in
       the low-dose group. The growth retardation was related to a decreased feed
       intake. Supplementation of the diet with copper diminished the tungstate-related
       toxicity. Ammonium dithiotungstate had no effect on these parameters at doses
058-11 Tungsten and tungsten compounds
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<pre>       up to 32 mg W/kg diet for 4 or 5 weeks. Furthermore, 16 mg W/kg diet as
       tetrathiotungstate decreased cytochrome oxidase activity by 50% and increased
       hepatic iron retention. These effects may be an indication of severe copper
       deficiency in rats. Dithiotungstate up to a dose of 32 mg W/kg diet induced no
       clinical or biochemical effects indicative of copper deficiency; it rather
       enhanced the copper content of liver, kidney, and plasma. Plasma ceruloplasmin
       activity was dose-relatedly decreased when tungstate was administered as
       tetrathiotungstate (70% reduction in the mid-dose group) while plasma copper
       concentration was almost doubled. In contrast, dithiotungstate administered at
       the same dose levels for 4 or 5 weeks rather increased the plasma ceruloplasmin
       activity and dose-relatedly increased the plasma copper concentration 4- to
       5-fold. Administration of 32 mg W/kg diet as tetrathiotungstate inhibited copper
       absorption from the diet, a smaller fraction of the absorbed copper was retained
       in liver and kidneys (60 to 75% reduction) while blood levels were relatively
       increased (expressed as percentage of absorbed dose) (You82).
            Following intratracheal instillation of tungsten metal and tungsten carbide
       dust in guinea pigs at 50 mg/week for 3 weeks, the dusts were reported to be
       relatively inert. Histological examinations showed moderate interstitial cellular
       proliferation (ACG99).
       Subchronic toxicity
       Kinard and Van de Erve administered diets containing different percentages of
       tungsten to groups of 5 to 6 male and 5 to 6 female rats as sodium tungstate
       (0.1, 0.5, or 2.0% W), tungstic oxide (0.1, 0.5, or 4.0% W), or ammonium
       paratungstate (0.5, 2.0, or 5.0% W; highest dose to male rats only) for 70 days.
       However, exact food consumption could not be determined due to occasional
       spills. (The molecular formula of ammonium paratungstate is unclear, both
       (NH4)10W12O41 as (NH4)6W7O24 are found). The only parameters studied were
       body weight gain and mortality. As to ammonium paratungstate, the lowest dose
       resulted in a slight growth retardation (3-6%) compared to controls after 70
       days of exposure. Only one male and one female of the mid-dose group
       survived the 70-day period. Males died after 10-19 days and females after 9-11
       days. After an initial weight loss, the male rat gained weight, but the final
       weight gain was little more than 50% of the weight gain of control males. The
       surviving female rat still showed a weight loss after 70 days. All male rats of the
       highest dose group died within 10 days. The lowest dose of tungstic oxide
       resulted in slight growth retardation (6-7%) after 70 days. One male and one
058-12 Health-based Recommended Occupational Exposure Limits
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<pre>       female (out of 6) rat of the mid-dose group survived the 70 days, but they never
       regained their initial body weight. Deaths occurred between day 10-23 for males
       and between day 12-18 for females. All animals of the highest dose group were
       dead within 4 days. As to sodium tungstate, all animals survived the low dose,
       but showed growth retardation (9-11%) compared to controls. Two female and
       3 male rats (both groups consisted of 6 rats) survived 70 days on the mid-dose
       administration; these rats never regained their initial body weight. Deaths in
       males occurred on day 22, females died between day 17 and day 29. At the
       highest dose, all animals died within 7 days. Although with respect to mortality
       and body weight gain, ammonium paratungstate appeared to be less toxic (based
       on consumption of W) than the other 2 compounds, no clear conclusions can be
       drawn due to the incomplete consumption assessment and the limited number of
       parameters examined (Kin41).
           In a second experiment, Kinard and Van de Erve fed diets containing
       metallic tungsten (2, 5, or 10%) to groups of 5 male and 5 female rats for 70
       days. All animals survived the experiment. Only females of the high-dose group
       showed growth retardation when compared to controls. No other parameters
       were investigated (Kin43).
       Chronic toxicity and carcinogenicity
       In a study on the effects of long-term exposure to different trace elements, 54
       male and 54 female Swiss Mice (Charles River strain) were exposed to 5 ppm
       W as sodium tungstate in drinking water for 540 days. The study was focused
       on the induction of tumours. Compared to controls, no significant effects were
       observed in body weight gain, longevity, or tumourigenicity (Sch75).
           Virgin female rats of the SD strain were fed ad libitum a nutritionally
       adequate semipurified diet and demineralised water; 22 animals were given an
       intravenous injection of 50 mg N-nitroso-N-methylurea (NMU)/kg bw after 2
       weeks, whereas 10 received only the vehiculum. A third group (n=24) received
       150 ppm tungsten (unspecified form) added to the drinking water, starting 2
       weeks prior to the NMU injection. Two experimental units were maintained for
       either 125 (unit I) or 198 (unit II) days following NMU administration; each
       unit consisted of the same exposure groups. In experimental unit I, the mean
       terminal body weights were slightly lower (6.5%, not statistically significant) in
       the tungsten/NMU- and NMU-only-treated groups compared to untreated
       controls (unit I groups). The tungsten/NMU treatment group exhibited a
       statistically significant increase in mammary carcinoma incidence compared to
058-13 Tungsten and tungsten compounds
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<pre>       the NMU-only-treated animals (79.2% vs. 50%; p<0.05; controls: 0%). There
       was no difference in the number of carcinomas per carcinoma-bearing rat (1.7
       vs. 2.0). The first mammary tumours were identified by palpation 56 and 71
       days after NMU treatment in the tungsten/NMU- and NMU-only-treated
       groups, respectively. In experimental unit II, there was a decrease in body
       weight of approximately 10% in both treated groups (not statistically
       significant). The increase in mammary carcinoma incidence amounted to 95.7%
       and 90.5% (no statistically significant difference) in the tungsten/NMU- and
       NMU-only-treated groups, respectively, while no such tumours were found in
       the untreated controls. The first palpable mammary tumours appeared 56 and 85
       days after NMU treatment in the tungsten/NMU- and NMU-only-treated group,
       respectively. The number of carcinoma per tumour-bearing rat was 2.6 and 2.0,
       respectively. At macroscopic examination, no other tumours were found in any
       of the treated groups (Wei85).
       Mutagenicity and genotoxicity
       Testing its DNA damaging potential using human peripheral lymphocytes,
       tungsten carbide did not induce alkaline labile sites and/or DNA single strand
       breaks detectable by an alkaline elution assay or alkaline single cell gel
       electrophoresis (‘Comet assay’) while cobalt and a cobalt-tungsten carbide
       mixture both caused a dose- and time-dependent increase in single strand
       breaks, the mixture being more potent than cobalt alone. However, closer
       examination of the results of the ‘Comet assay’ (analysis of tail lengths and
       moments) may suggest that tungsten carbide may either allow some uncoiling of
       the chromatin loops or induce formation of slowly migrating DNA fragments.
       By inducing uncoiling, the carbide might increase sensitivity to clastogenic
       effects (Ana97, Goe97). In human lymphocytes, tungsten carbide produced a
       statistically significant number of micronuclei at a concentration of 50 µg/mL
       which did not increase at the next higher doses of 75 and 100 µg/mL (dose
       range tested: 10-100 µg/mL) (Goe97).
       Reproduction toxicity
       The committee did not find data on the potential reproduction toxicity of
       tungsten and its compounds.
058-14 Health-based Recommended Occupational Exposure Limits
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<pre>6      Existing guidelines
       The current administrative occupational exposure limit (MAC) in the
       Netherlands is 5 mg/m3, 8-hour TWA, for tungsten and insoluble tungsten
       compounds and 1 mg/m3, 8-hour TWA, for soluble tungsten compounds.
           Existing occupational exposure limits for tungsten in some European
       countries and in the USA are summarised in the annex.
7      Assessment of health hazard
       There are no valid data from human studies.
           It was reported that in dogs, a large part of inhaled W (as tungsten oxide)
       was eliminated by secondary ingestion. Excretion of systemic W (as tungsten
       oxide) via the urine appeared to be relatively fast. Three days after intragastric
       intubation, only very low levels of radiolabelled W were detectable in tissues.
       One hour after an intravenous injection, levels of W administered as tungstate
       were highest in skeleton, intestinal contents, and kidneys. Administration of W
       through the diet for 4 to 5 weeks resulted in different plasma W concentrations
       for similar doses of W as tetrathiotungstate or as dithiotungstate. W
       administered as tungstate was able to reach the fetus, more in late than in early
       gestation.
           Oral LD50 values of sodium tungstate in the rat ranged between 223 to 255
       mg/kg. For guinea pigs injected subcutaneously with sodium tungstate, an LD50
       between 140-160 mg/kg is reported. The LD50 by intramuscular injection of
       sodium tungstate in rats is 105 mg/kg. The intraperitoneal LD50 of tungsten
       metal powder in the rat is 5000 mg/kg.
           No valid data on eye and skin irritation were reported. As to the skin
       sensitising potential, only a limited description of a negative sensitisation study
       was reported.
        Several studies have been performed with tungsten (compounds), some of
       which are rather old. The available studies were either performed to study
       specific aspects (e.g., on copper metabolism (You82)) or examined only a
       limited number of parameters (Kin41, Kin43). Furthermore, different tungsten
       compounds were used. It is noted that the effects on copper metabolism
       (You82; tungsten administration up to 32 mg W/kg diet) were observed at much
       lower doses than in the study by Kinard and Van de Erve (Kin41; lowest dose:
058-15 Tungsten and tungsten compounds
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<pre>       1000 mg W/kg diet). The data are insufficient to compare the toxicological
       potential of different tungsten compounds. Tungsten appears to interfere with
       copper metabolism, but also with molybdenum metabolism (e.g., increased
       excretion of molybdenum, decreasing xanthene oxidase activity (Hig56))
       inducing effects comparable with copper and molybdenum deficiency. These
       effects can (partly) be overcome by increasing the intake of the particular trace
       element. This indicates that the toxicity of tungsten is dependent on the intake
       of other trace elements, and greater toxicity will be observed (lower NOAELs
       found) in case subjects consume diets rather deficient in trace elements. In
       addition, the results of, e.g., Young et al. (You82) show that the interaction with
       trace elements like copper differed for different forms of tungsten.
            Tungsten carbide caused a statistically significant, but not dose-related
       increase in the frequency of micronuclei but no single strand breaks and/or
       alkaline labile sites in human lymphocytes. These tests might suggest that
       tungsten carbide may uncoil chromatin loops and, thus, might increase
       sensitivity to clastogenic effects by other compounds. The committee did not
       find other data on the mutagenicity/genotoxicity of tungsten or tungsten
       compounds.
            The committee did not find valid data on the reproduction toxicology of
       tungsten or its compounds.
       The committee considers the toxicological database on tungsten and its
       compounds 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
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       ACGIH®, 1999.
058-16 Health-based Recommended Occupational Exposure Limits
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<pre>ACG02a American Conference of Governmental Industrial Hygienists (ACGIH). Guide to occupational
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       392: 31-43.
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058-17 Tungsten and tungsten compounds
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<pre>Kin43  Kinard FW, van de Erve J. Effect of tungsten metal diets in the rat. J Lab Clin Med 1943; 28:
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058-18 Health-based Recommended Occupational Exposure Limits
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<pre>Wid86  Wide M, Danielsson BRG, Dencker L. Distribution of tungstate in pregnant mice and effects on
       embryonic cells in vitro. Environ Res 1986; 40: 487-98.
You82  Young BW, Bremmer I, Mills CF. Effects of tetrathiotungstate and dithiotungstate on copper
       metabolism in rats. J Inorg Biochem 1982; 16: 121-34.
058-19 Tungsten and tungsten compounds
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<pre>             Annex
Occupational exposure limits for tungsten and its compounds in various countries.
country                             occupational exposure          time-weighted        type of exposure notea  referenceb
-organisation                       limit                          average              limit
                                    ppm           mg/m3
the Netherlands
-Ministry of Social Affairs and     -             5c               8h                   administrative          SZW02
Employment                          -             1d               8h
Germany
-AGS                                -             5c, e            8h                                           TRG00
                                    -             1d, e            8h
-DFG MAK-Kommission                 -             -f                                                            DFG02
Great-Britain
-HSE                                              5c               8h                   OES                     HSE02
                                                  10c              15 min
                                                  1d               8h                   OES
                                                  3d               15 min
Sweden                              -             5c               8h                                           Arb00b
                                    -             1d               8h
Denmark                             -             5c               8h                                           Arb00a
                                    -             1d               8h
USA
- ACGIH                             -             5c               8h                   TLV                     ACG02b
                                    -             10c              15 min               STEL
                                    -             1d               8h                   TLV
                                    -             3d               15 min               STEL
- OSHA                              -             -                                                             ACG02a
- NIOSH                             -             5c               10 h                 REL                     ACG02a
                                    -             10c              15 min               STEL
                                    -             1d               10 h                 REL
                                    -             3d               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
     Metal (dust/powder) and insoluble compounds.
d
     Soluble compounds.
e
     Measured as the inhalable fraction of the aerosol.
f
     Listed among compounds for which studies of effects in man and in experimental animals have yielded insufficient
     information for the establishment of MAK values.
058-20       Health-based Recommended Occupational Exposure Limits
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