<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>Zirconium and zirconium compounds
(CAS No: 7440-67-7)
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/059, The Hague, 31 October 2002
</pre>

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<pre>Preferred citation:
Health Council of the Netherlands: Committee on Updating of Occupational
Exposure Limits. Zirconium and zirconium compounds; Health-based
Reassessment of Administrative Occupational Exposure Limits. The Hague:
Health Council of the Netherlands, 2002; 2000/15OSH/059.
all rights reserved
</pre>

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<pre>1     Introduction
      The present document contains the assessment of the health hazard of
      zirconium 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 zirconium and compounds has been based
      on the review by 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 period 1966 to 26 April 1999 (19990426/UP), 1965 to 29 January 1999
      (19990129/ED), and 1967 to 24 April 1999 (19940424/ED), respectively, and
      using the following key words: zirconium, zircon, 7440-67-7, 1291-32-3,
      7699-43-6, 13762-26-0, 12164-98-6, and 1314-23-4. HSDB and RTECS,
      databases available from CD-ROM, were consulted as well (NIO00a-e,
      NLM00a-d). 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. Comments were received from the following
      individuals and organisations: A Aalto (Ministry of Social Affairs and Health,
      Tampere, Finland). These comments were taken into account in deciding on the
      final version of the document.
2     Identity
      Data on zirconium and some selected zirconium compounds are presented
      below.
059-3 Zirconium and zirconium compounds
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<pre>name              : zirconium   zirconium     zirconium     zirconium         zirconium      zirconium sulphate zirconium
                                oxide         silicate      tetrachloride     dichloride                           oxychloride
synonyms          :             zirconia;     zircon        zirconium(IV)                    zirconium             basic zirconium
                                baddeleyite                 chloride (1;4);                  sulphate;             chloride;
                                                            terachloro-                      disulfatozirconic     chlorozirconyl;
                                                            zirconium;                       acid; sulphuric       dichlorooxo-
                                                            zirconium                        acid,                 zirconium;
                                                            chloride;                        zirconium (VI) salt   zirconium oxide
                                                            zirconium                        (2:1); zirconium      chloride;
                                                            chloride,                        disulphate;           zirconium,
                                                            tetra-                           zirconium             dichlorooxo-;
                                                                                             (IV)sulfate (1:2);    zirconium
                                                                                             zirconium             oxydichloride;
                                                                                             orthosulphate;        zirconyl chloride
                                                                                             zirconyl sulphate
molecular         : Zr          ZrO2          ZrSiO4        ZrCl4             ZrCl2          Zr(SO4)2.4H2O         ZrOCl2
formula
CAS               : 7440-67-7 1314-23-4       10101-52-7 10026-11-6           13762-26-0     14644-61-2            7699-43-6
number
Data from ACG99a, Lid94, NIO00a-e, NLM00a-d, Ric94.
3              Physical and chemical properties
               Physical and chemical properties of some selected zirconium compounds are
               listed below.
name                        : zirconium     zirconium     zirconium       zirconium      zirconium       zirconium      zirconium
                                            oxide         silicate        tetrachloride dichloride       sulphate       oxychloride
molecular weight            : 91.22         123.22        183.3           233.03         162.13          355.4          178.13
                                    o
boiling point               : 4377 C        -             -               -              -               -              210oC
                  a                 o             o              o            o              o  25               o
melting point               : 1853 C        2715 C        2550 C          350 C: d       437 C           135-150 C      150oC
                                                                                                         (-3H2O)
flash point                 : -             -             -               -              -               -              -
vapour pressure             : -             -             -               -              -               -             -
solubility in waterb        : i             i             i               cold: s        de              vs            vs
                                                                          hot: dc
Log P octanol/water         : -             -             -               -              -               -              -
a
      Number in superscript represents the atmospheric pressure in atm at which the presented value is determined; d:
      decomposes.
b
      d: decomposes; i: insoluble; s: soluble; vs: very soluble.
c
      Decomposes into hydrochlorid acid and zirconium oxychlorid.
d
      Decomposes evolving H2.
Data from ACG99, Lid94, NIO00a-e, NLM00a-d, Ric94.
059-4          Health-based Recommended Occupational Exposure Limits
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<pre>      Elemental zirconium is a bluish-black, amorphous metallic powder or a
      greyish-white lustrous metal. Zirconium is corrosion resistant and is not
      attacked by cold concentrated acid. However, it reacts slightly with hot
      concentrated acids. Zirconium powder is flammable and explosive in air when
      mixed with oxidising agents (ACG99).
4     Uses
      Zirconium metal is used in nuclear technology, in photoflash bulbs, as a
      scavenger in steel manufacture, and in vacuum tubes to remove traces of gases.
      Zirconium oxide is employed as a colourant for ceramics and for
      dispersion-hardening of platinum and ruthenium, and it has been used clinically
      as a radio-opaque compound for X-rays of the gut. The tetrachloride is used as a
      textile water repellent and as a tanning agent. Zircon, a natural zirconium
      silicate, is employed in making refractories, enamels, porcelain, and abrasives,
      and as a coating for casting moulds. Water-soluble salts (e.g., zirconium lactate)
      and zirconium oxide have been used in cosmetics, deodorants, and topical
      ointments (ACG99).
5     Biotransformation and kinetics
      The daily oral intake (food and water) of total zirconium by man has been
      estimated to be ca. 4 mg (Sch66). Most of it is excreted in the faeces (4 mg) and
      hardly any in the urine (0.15 mg) (Gre99). Levels in tissues are generally below
      10 µg/g (wet weight). Highest amounts were found in fat (19 µg/g) and gall
      bladder (14 µg/g). Levels in erythrocytes amounted to ca. 6 µg/g (data from 4
      deceased; Sch66). Binding to albumin and globulins has been demonstrated
      (Gre99).
      In coal miners, the presence of zirconium has been demonstrated in the lungs,
      pulmonary lymph nodes, blood, and urine (Bel94). Biological half-lives of
      zirconium in human lung of ca. 70 and 225 days have been reported (Gre99). In
      several animal species, zirconium was demonstrated to be deposited and
      retained primarily in the lungs and pulmonary lymph nodes following exposure
      by inhalation to its oxide and oxychloride. Concentrations in these tissues were
      of similar order of magnitude but varied largely among species. Concentrations
      in kidney, liver, and femur were only a few tenths of a per cent of those in the
      lung. Twenty-four weeks post-exposure, there were still significant amounts in
059-5 Zirconium and zirconium compounds
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<pre>      the lungs and lymph nodes of rats (other species not examined). Generally, in
      this experiment, no difference was found regarding amounts deposited and
      pattern of distribution between the insoluble oxide and the soluble oxychloride
      (Spi56).
          In one rat study, the maximal uptake of various zirconium compounds from
      the gastrointestinal tract into the bloodstream was reported to be 0.2 % of the
      elemental zirconium dose while in another study, only 0.001% of the zirconium
      dose (ZrCl4) was taken up from the gastrointestinal tract into the blood (no more
      data presented) (Gre99). In a chronic study, tissue levels of exposed rats
      receiving ca. 500 µg/kg bw/day were similar to those of controls receiving ca.
      160 µg/kg bw/day. Highest levels were found in the spleen (Sch68a).
6     Effects and mechanism of action
      Human data
      Cases of lung fibrosis and granulomatous interstitial pneumonia in workers
      exposed to zirconium compounds have been described. Significant amounts of
      zirconium-containing particles were present in the lungs (Bar91, Lii93, Kot92,
      Rom94; see also Gre99).
          In 178 men working at a plant in Manchester (UK) with zirconium
      compounds, principally zirconium silicate, effects on the lungs were evaluated
      by chest radiographs (in 1975, 1978, and 1982) and lung function (FEV1, FVC)
      measurements (from 1975-1988). Of these 178 men, 144 entered the study at
      the start in 1975, having a mean age at that time of 37.6 years (range: 17-61
      years) and a mean employment time of 10.0 years (range: 0-38; 58% less than
      10 years); of the total group of 178 men, 37 had been exposed for more than 20
      years. Static air sampling performed in 1974 and in 1991-1992 showed total
      dust levels ranging from 0.5-8.8 and 0.4-9.8 mg/m3, respectively. Total dust
      levels (8-hour time-weighted average) obtained from personal air sampling for 7
      different operators in 1974 ranged from 2.5 to 30.0 mg/m3, while the highest
      respirable dust level measured amounted to 3.4 mg/m3. Particle size,
      distribution, and composition were not reported. Each man was interviewed to
      obtain a general medical and work history and a summary of current symptoms
      and smoking habits. In addition, specific attention was paid with respect to dust
      exposure (such as in coal mining, foundry work, cotton milling) in previous
      jobs. Based on job titles, work locations, and the number of years spend in a
      job, a cumulative dust exposure score was calculated for each man. No
059-6 Health-based Recommended Occupational Exposure Limits
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<pre>      granulomas were seen. In 12/175 men, there were calcified nodules read in their
      films but there was no correlation found between the presence of these nodules
      and exposure duration, cumulative dust exposure, or age. Overall, the study did
      not reveal any evidence of a relation between (cumulative) zirconium exposure
      and abnormal chest radiographs or impaired pulmonary function (Mar96).
          A group of 32 hand finishers of nuclear fuel components were exposed to
      zirconium metal and silicon carbide, binding agent, and general dusts for 1 to 17
      years. Breathing zone sampling resulted in dust levels of 5.75 to 14.7 mg/m3
      consisting of 25% zirconium. Analysis of the high volume sample showed that
      85% of the particles had a diameter less than 10 µm. Of samples between 0.67
      and 3.2 mg/m3 of zirconium, 95% had a diameter less than 10 µm. When
      compared to a control group selected from the same plant (considered not to be
      exposed to dusts or respiratory irritating substances, and matched for age and
      for current and total smoking history), no significant differences were found
      concerning respiratory questionnaire and chest x-ray findings. The values of the
      various expiratory lung function tests were consistently, but not statistically
      significantly lower for the exposed group when compared to those for the
      controls (Had81).
          Twenty-two workers involved in the production of zirconium for 1 to 5
      years were examined clinically (history, physical examination, vital capacity
      determination) and chest radiographically. The workers were stated to be
      exposed to fumes but concentrations and composition were not reported.
      Further, they were exposed to dusts of zirconium tetrachloride (which
      hydrolyses to zirconium oxychloride), zirconium oxide, and to metallic
      zirconium as well as to ‘low and non-toxic’ concentrations of hydrochloric acid,
      chlorine, phosgene, and magnesium, aluminium, titanium, and hafnium oxides
      and chlorides. However, exposure characteristics (levels, particle size and
      distribution, etc.) were not mentioned. Fifteen out of the 22 workers did not
      have symptoms of lung disease. Of the remaining 7, 2 had mild bronchial
      asthma and 5 had chronic bronchitis which required medical treatment. The
      vital capacity was affected in 2 men, both among those having chronic
      bronchitis. Chest radiography did not reveal striking abnormalities such as
      pulmonary granulomatosis. Slightly increased peripheral lung markings were
      seen in 4 workers; 3 of them were among the cases with chronic bronchitis. The
      authors concluded that this study did not show effects attributable to exposure
      to zirconium. The effects found were thought to be chlorine related (Ree56).
          Pneumoconiosis (small — Categories 1 to 3 — densities on chest X-rays)
      was reported in 8 workers of a zirconium process plant adjacent to an antimony
059-7 Zirconium and zirconium compounds
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<pre>      smelting plant in the UK (McC67). This aforementioned group of zircon
      workers was included in a study carried out to examine the mortality among a
      group of workers exposed to antimony in this UK smelter (study period:
      1960-1992). Other study groups included maintenance workers and a group
      consisting of office workers and management staff. The total cohort consisted of
      1420 men; figures for the subgroups were not given. Data on exposure levels
      were not presented. As to the zircon workers, there were no statistically
      significant findings. Mortality from all causes, from all neoplasms, from lung
      cancer, and from respiratory disease were all lower than expected based on local
      rates (56 vs. 68.6, 14 vs. 20.1, 5 vs. 8.8, and 6 vs. 8.2, respectively) while
      mortality from ischaemic heart disease and from other circulatory diseases was
      similar to that expected (Jon94).
          Both clinical and experimental reports of allergic reactions appearing as
      epithelioid granulomas at the site of applying deodorants containing both water
      soluble as insoluble zirconium compounds have been published (Mon97,
      Ske93; see also Gre99). ACGIH referred to a study in which no granulomas
      were found in 54 volunteers topically treated with zirconium oxychloride
      (ACG99).
      Animal data
      Irritation and sensitisation
      The committee did not find experimental animal data on possible skin- and
      eye-irritating properties of zirconium or its compounds.
          Sodium zirconium lactate was positive in 3 methods of immunisation (Split
      adjuvant, Maximisation, and Polak). In these tests, 6 guinea pigs (outbred
      Hartley strain) per test were used. Reactions at 24 and 48 hours were typically
      erythematous. These delayed hypersensitivity-like reactions developed into
      nodular lesions which reached peak intensity at 8 days and histologically
      contained histiocytes with an epithelioid cell appearance and giant cells
      (Tur77).
          In a study designed to address the potential sensitising and granulomagenic
      capacities of selected metallic salts, white New Zealand rabbits of both sexes
      (bw: 2 to 3 kg) were inoculated intradermally with zirconium aluminium
      glycinate (ZAG) or sodium zirconium lactate (NZL) by single and multiple
      injections. One group of animals was exposed to 10.0 mg ZAG or NZL in
      complete Freund’s adjuvant (0.4 mL/animal) via the toe pad route while animals
059-8 Health-based Recommended Occupational Exposure Limits
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<pre>      of another group were injected intradermally with 100 µg of each compound in
      saline solution, twice weekly for 6 weeks (0.1 mL/rabbit). The initial injections
      for weeks 1 and 4 consisted of 200 µg of each compound in saline solution
      administered via the toe pad route (0.4 mL/rabbit). The total cumulative dose in
      each subgroup was 1.4 mg of either ZAG or NZL. A third untreated group
      served as controls for skin testing, lymphocyte stimulation, assays, and
      histological observations. Neither single nor multiple injections of ZAG resulted
      in clear-cut positive skin reaction, macrophage migration inhibitory factor
      (MIF) production, or lymphocyte stimulation. Rabbits inoculated with multiple
      injections of NZL showed some marginally positive macrophage migration
      inhibition and skin reactivity. Histologically, ZAG induced well-organised
      foreign-body granulomas after intradermal injection in both normal and
      inoculated rabbits. NZL also induced skin granulomas, but these were less
      organised (Kan77).
          Inbred 4-month old female CBA/J strain agouti mice were injected
      (0.02-0.05 mL) intradermally in the foot pads and the pinnae, or
      intraperitoneally with zirconium lactate (an insoluble salt in 10% suspension in
      physiological saline solution) and sodium zirconium lactate (as water soluble
      complex). Control injections were made using a mixture of sodium stearate (0.2
      M) and lactic acid. Biopsy specimens of the foot pads and ears as well as
      autopsy material from the liver, kidney, spleen were taken. The intradermal and
      intraperitoneal injections produced local foreign body granulomas which
      regularly persisted for over 8 months. None of the animals exhibited evidence
      of the late delayed immune type of epitheliod cell granulomatous
      hypersensitivity. Benign chondromas developed locally in the ear cartilage in
      87/182 of the mice receiving zirconium oxychloride and 12/24 mice receiving
      sodium zirconium lactate (She71).
          Contact sensitisation capacity of zirconium tetrachloride was evaluated in
      the guinea pig maximisation test (GPMT) as well as in the adjuvant and patch
      test (APT) using 5 adult female Hartley strain guinea-pigs per test, and in a
      sensitive mouse lymph node assay (SLNA) using 5 female BALB/c strain mice
      (6-8-week old). In none of these tests, zirconium tetrachloride caused any
      sensitisation responses (Ika96).
      Acute toxicity
      The acute oral toxicity of inorganic zirconium salts was concluded to be very
      low due to their poor gastrointestinal absorption: LD50 values ranged between
059-9 Zirconium and zirconium compounds
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<pre>       700 and 3500 mg/kg bw. Oral LD50values in rats were 1690 mg/kg bw for
       zirconium tetrachloride and >10,000 mg/kg bw for basic zirconium carbonate
       (ACG99).
       Subacute and subchronic toxicity
       Dogs (n=2), rabbits (n=6), and rats (n=20) were exposed to zirconium oxide
       dust (average particle size: 1.5 µm) at concentrations of 75 mg Zr/m3, for 60
       days, and cats (n=4/group), dogs (n=8/group), guinea pigs (n=20/group), rabbits
       (n=19 or 20), and rats (n=72/group) to zirconium oxide dust at 11 mg Zr/m3, for
       30 days, or to a mist of zirconium tetrachloride dissolved in water (average
       particle size: 0.6 µm) at an average concentration of 6 mg Zr/m3, for 60 days.
       All groups were exposed 6 hours/day, 5 days/week. Zirconium oxide produced
       no significant changes in the end points examined, viz., mortality, growth rate,
       blood non-protein nitrogen or fibrinogen, urinary protein, haematological
       values, or histological parameters. Exposure to zirconium tetrachloride —
       which was converted into zirconium oxychloride upon being dissolved —
       increased mortality rates in rats (8/72) and guinea pigs (3/20), but not in rabbits,
       cats, or dogs. The cause of death, although not well established, was stated to be
       an intercurrent respiratory infection. Post-mortem examination showed varying
       congestion, oedema, and haemorrhage in the lungs of one-half of the exposed
       animals, but similar changes were seen in the control animals. Apart from
       borderline reductions in haemoglobin content and erythrocyte count in dogs, no
       other changes were found. Overall, only effects were noted following inhalation
       of zirconium tetrachloride at 6 mg/m3, which presumably were due to the
       liberation of hydrogen chloride. The study did not include cat, dog, or guinea
       pig control groups (Spi56).
       Chronic toxicity and carcinogenicity
       Rats, hamsters, and guinea pigs (n=10/group; strain and sex not reported) were
       exposed to 15 or 150 mg/m3 of zirconium lactate (according to Gre99 ca. 5 and
       36 mg Zr/m3) (particle size: 82% <0.3 µm) or to 15 mg/m3 barium zirconate (ca.
       5 mg Zr/m3; see Gre99) (particle size: 91% <1.2 µm, 79% <0.6 µm, 50% <0.3
       µm), 7 hours/day, 5 days/week, for 225 days. Apart from the death of 3 guinea
       pigs exposed to 15 mg/m3 of the lactate, no mortality occurred. Body weights of
       the rats and hamsters were lower when compared to controls; those of guinea
       pigs exposed to 150 mg/m3 were higher while the body weights of the animals
059-10 Health-based Recommended Occupational Exposure Limits
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<pre>       of the other groups were similar when compared to controls. No statistical
       evaluation was presented. At necropsy, a chronic interstitial pneumonitis with
       associated hypertrophy of the media of the arterioles was found in all exposed
       groups. These changes were stated to be more pronounced in the animals
       exposed to the zirconate. Only very little histological changes were seen in the
       lungs of the control animals. They consisted of minimal thickening of the
       alveolar walls and a minimal amount of round cell infiltration. There was no
       evidence of changes in the bronchial or vascular tissues. Data presented on
       lung, liver, and kidney weights were not very informative since only absolute
       weights were given and no statistical evaluation was made. No abnormalities
       were seen in liver, spleen, and kidneys (Bro63).
       Schroeder et al. administered 5 ppm zirconium sulphate to the drinking water of
       Long-Evans rats (56 males and 58 females) from the time of weaning until
       natural death. Treatment did not affect survival and longevity. The body
       weights of the exposed females were generally higher than those of controls
       throughout the study, reaching statistical significance at 30, 150, and 540 days
       (the last measurement point listed). Exposed males were heavier in the first 180
       days of the study while statistically lower body weights were observed in the
       following part at 360 and 540 days. Upon post-mortem examinations, there
       were no differences between exposed and control animals concerning the
       incidences of grossly visible tumours. Mean absolute and relative heart weights
       were higher and lower in females and males, respectively, when compared to
       controls. No other data on organ weights or macroscopic or microscopic lesions
       were presented. An increased incidence of glycosuria was found in the male
       animals (52% vs. 23% in controls). The authors estimated the mean daily
       zirconium intake to be 510 µg/kg bw for the exposed animals. Since the food
       contained some zirconium, the control animals received 160 µg/kg bw/day
       (Sch70). In a separate paper, Schroeder et al. reported on the possible effects of
       the aforementioned exposure level of zirconium on serum cholesterol levels of
       these rats. In mature rats (age: 893 days; n=12/sex), the serum cholesterol levels
       were decreased in males (89.7±5.6 vs. 122.9±8.17 mg/100 mL in controls;
       p<0.01) and increased in females (100.7±9.0 vs. 94.5±11.19 mg/100 mL)
       (Sch68a).
           The group of Schroeder reported the results for mice (Charles River CD-1;
       54 males, 53 females) receiving a similar treatment — 5 ppm zirconium
       sulphate in the drinking water from weaning until death — as described above
       for rats in 2 separate papers. Treatment caused shortening of life span (mean,
059-11 Zirconium and zirconium compounds
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<pre>       median, and 75% life span) when compared to controls. Body weights were
       generally comparable to those of controls; at 540 days of age, the last
       observation presented, body weights were significantly lower for both treated
       males and females. There was no difference in tumour incidence between
       treated and control groups. Apart from a somewhat higher incidence of hepatic
       fatty degeneration in the zirconium-treated animals (36.7% vs. 22.2% in
       controls), no other data on organ weights and non-neoplastic macroscopic and
       microscopic lesions were presented. The authors estimated the mean daily
       zirconium intake to be 510 µg/kg bw for the exposed animals. Since the food
       contained some zirconium, the control animals received 160 µg/kg bw/day
       (Kan69, Sch68b).
           When a single dose of ca. 20 µg of zirconium oxychloride (octahydrate)
       (vehiculum: aqueous 0.9% sodium chloride solution) was injected into the dorsa
       of the ear lobes of female ICR and CBA/J mice (n=10/strain), all treated mice
       showed ecchondromas (outgrowths from the cartaliginous plate) at post-mortem
       examinations after 2 and 5 months, respectively. These chondromas were not
       seen in a separate group of 10 female CBA/J mice sacrificed 2 weeks after the
       treatment (She73).
       Mutagenicity and genotoxicity
       Zirconium tetrachloride was reported to be negative when tested in
       S. typhimurium strains TA98, TA100, TA102, TA1537, and TA2637.
       Experimental details such as concentrations, metabolic activation, etc., were not
       given. Zirconium tetrachloride was co-mutagenic — in strains TA1537 and
       TA2637 only — when tested at concentrations of 1-10,000 µmol/plate in the
       presence of the mutagen 9-aminoacridine (100 µmol/plate). At the optimal
       concentration of 10 µmol/plate, zirconium tetrachloride produced 1.6 times
       more revertants than aminoacridine alone (Oga87). Zirconium oxychloride was
       negative in S. typhimurium strains TA98, TA100, TA1535, and TA1537 both in
       the presence and absence of a metabolic activating system derived from rat and
       hamster liver (Mor86). Zirconocene dichloride ((C5H5)2 ZrCl2) (dose range:
       100-10,000 µg/plate) was found positive when tested without metabolic
       activation in S. typhimurium strains TA98 and TA100 and weakly positive in
       strain TA97 with a hamster liver S9 mix added (with rat liver S9: negative).
       Negative results were obtained at testing in strains TA98 and TA100 with rat or
       hamster liver S9 mix added, in strain TA97 without metabolic activation, and in
059-12 Health-based Recommended Occupational Exposure Limits
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<pre>       strain TA1535 with and without metabolic activation (both rat and hamster)
       (Zei88).
             Zirconium oxychloride (10-20 µg/mL culture medium) induced an increase
       in frequency of cell division (mitotic index), chromosomal aberrations, and
       SCE’s in vitro in cultured human peripheral blood leukocytes (Gho91a).
            In vivo, zirconium oxychloride caused an increase in the percentage of
       mitotic cells in the bone marrow of mice (albino Swiss; n=5/group) of the mid-
       and high-dose groups sacrificed 24 hours after giving single oral doses of 220,
       734, and 2200 (females) or 225, 750, and 2250 mg/kg bw (males). Treatment
       induced a dose-related increase in the percentage of total aberrant metaphases
       including both chromosomal aberrations (mainly chromatid and chromosome
       breaks) and spindle disturbances (polyploidy) (Gho90). In a follow-up
       experiment using similar doses, statistically significant increases in the
       frequency of chromosomal aberrations and breaks per cell, excluding gaps, were
       found in male mice sacrificed 12 and 24 hours and in female mice sacrificed 6,
       12, and 24 hours after exposure. The increases were dose and, to a lesser extent,
       duration related (Gho91b).
       Reproduction toxicity
       The committee did not find data on the potential reproduction toxicity of
       zirconium or its compounds.
       Immunotoxicity
       The effects of zirconium on the humoral immune response were studied by
       measuring the level of IgM-plague forming cells (IgM-PFC) against sheep red
       blood cells (SRBC) in the spleen of C57 BL mice intraperitoneally injected with
       zirconium oxychloride. One group (n=25/dose) was treated with a single
       injection (total n=125) of zirconium oxychloride of 1.7, 3.4, 17, or 34 mg/kg bw
       (i.e., 1/100, 1/50, 1/10, and 1/5 of the LD50), while another group
       (n=10/treatment) received doses of 2.125, 4.25, or 8.5 mg/kg bw (i.e., 1/80,
       1/40, 1/20 of the LD50), every other day for 2 or 4 weeks. In case of a single
       injection, zirconium oxychloride was administered either on days -1, 0, +1, +2,
       or +3 in relation to SRBC immunisation. The control group was injected with
       saline. Both single and repeated treatment enhanced the IgM response to sheep
       red blood cells (Shi87).
059-13 Zirconium and zirconium compounds
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<pre>       Similar immunostimulating effects were reported in an abstract for zirconium
       oxychloride, zirconium oxide, and zirconium silicate after single or repeated
       (every other day for 2, 4, or 6 months) injections into the thorax cavity or the
       peritoneum of mice, respectively (Ric94). In addition, in an in vitro study,
       zirconium sulphate was found to exhibit a mitogenic effect in mouse
       splenocytes (an increased 3H-thymidine incorporation into lymphocyte DNA)
       (Pri86).
7      Existing guidelines
       The current administrative exposure limit (MAC) for zirconium and zirconium
       compounds in the Netherlands is 5 mg/m3, 8-hour TWA.
            Existing occupational exposure limits for zirconium in some European
       countries and in the USA are summarised in the annex.
8      Assessment of health hazard
       Zirconium was found in lungs, pulmonary lymph nodes, and blood and urine of
       miners, indicating that it can be absorbed from the lungs. Biological half-lives
       in human lung of ca. 70 as well as 225 days were reported. Daily human intake
       via food, water, etc., is about 4 mg. The predominant excretion route is via the
       faeces; hardly any is excreted in the urine. Tissue levels are generally below 10
       µg/g wet tissue. Highest amounts were found in fat (19 µg/g) and gall bladder
       (14 µg/g). Animal experiments showed a similar picture. Following oral
       absorption, absorption percentages of 0.2 and 0.001% were reported.
            Clinical and experimental reports indicated that zirconium compounds can
       induce allergic reactions appearing as epithelioid granulomas at the site of
       exposure. A study on a group of workers exclusively exposed to zircon
       (zirconium silicate) — as part of a more extensive investigation among workers
       of an antimony smelter — did not show evidence of an increased mortality from
       all causes, all cancer, or respiratory or circulatory diseases. No evidence of a
       relation between (cumulative) zirconium dust exposure and abnormal chest
       radiographs or impaired pulmonary function was found in a group of 178 men
       with mean employment time of 10.0 years. Results from static air sampling
       performed in 1974 and in 1991-1992 suggest that exposure was similar
       throughout these years with total dust levels ranging from ca. 0.5-10 mg/m3.
       Personal air sampling performed for 7 workers in 1974 showed total dust levels
       (8-hour TWA) ranging from 2.5 to 30.0 mg/m3 with highest respirable dust
059-14 Health-based Recommended Occupational Exposure Limits
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<pre>       levels amounting to 3.4 mg/m3. However, particle size, distribution, and
       composition of the dust were not given. In another study on 32 workers exposed
       to zirconium metal for 1 to 17 years, no significant differences were found in
       respiratory questionnaires and chest X-ray findings when compared to controls
       matched for age and smoking habits. The values of the various expiratory lung
       function tests were consistently, but not statistically significantly lower for the
       exposed group when compared to the controls. Breathing zone air sampling
       resulted in dust levels of ca. 6 to 15 mg/m3 consisting of 25% zirconium.
       Although the results suggest that some marginal effects may have been induced
       at these dust levels, workers were exposed to silicon carbide as well. Therefore,
       the committee feels that no firm conclusions can be drawn from this study with
       respect to a dose-response relationship for zirconium.
           The committee did not find experimental animal data on possible skin- and
       eye-irritating properties of zirconium or its compounds. Sodium zirconium
       lactate and zirconium aluminium glycinate demonstrated skin sensitising
       properties while zirconium tetrachloride did not cause any sensitisation
       response.
           The committee did not find data on the effects of zirconium or its compound
       following single inhalation exposures. Following single oral administration,
       LD50 values ranging from 700 to 3500 mg/kg bw were found for inorganic
       zirconium salts.
           Repeated inhalation studies using several animal species reported not to
       induce changes in mortality or growth rates, haematology or histological
       parameters following exposure to zirconium oxide dust at concentrations of 75
       mg Zr/m3 for 60 days or to 11 mg Zr/m3 for 30 days. Exposure to zirconium
       tetrachloride (which was converted into zirconium oxychloride upon being
       dissolved) at an average concentration of 6 mg Zr/m3 caused some histological
       changes in the lungs — comparable to those found in controls — in 50% of the
       exposed animals. However, since this study could not be retrieved by the
       committee, the significance of this study as a (possible) basis for standard
       setting could not be assessed. In another study in which rats, hamsters, and
       guinea pigs were exposed to 15 or 150 mg/m3 of zirconium lactate (i.e., ca. 5
       and 36 mg Zr/m3) or 15 mg/m3 barium zirconate (i.e., ca. 5 mg Zr/m3) body
       weight decreases were found in rats and hamsters and chronic interstitial
       pneumonitis in all exposed groups. However, because of limited design and
       reporting, the committee considers this study not suitable to serve as a basis in
       standard setting.
059-15 Zirconium and zirconium compounds
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<pre>            Zirconium tetrachloride appeared to be positive in mutagenicity assays
       (co-mutagenic in the presence of 9-aminoacridine) using S. typhimurium strains
       TA1537 and TA2637 and zirconocene dichloride is positive in TA98 en TA100
       strains of S. typhimurium without metabolic activation. Zirconium oxychloride
       induced chromosomal aberrations in human leukocytes in vitro and
       chromosomal aberrations and polyploidy in bone marrow of orally exposed
       male mice in vivo. The committee considers these positive findings of concern
       requiring confirmation and further investigation.
            The committee did not find data on the reproduction toxicology of
       zirconium.
       The committee considers the toxicological database on zirconium and its
       compounds too poor to justify recommendation of a health-based occupational
       limit.
       The committee concludes that there is insufficient information to comment on
       the level of the present MAC-value.
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<pre>Mon97  Montemarano AD, Sau P, Johnson FB, et al. Cutaneous granulomas caused by an aluminium-
       zirconium complex: An ingredient of antiperspirants. J Am Acad Dermatol 1997; 37: 496-8.
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059-19 Zirconium and zirconium compounds
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<pre>             Annex
Occupational exposure limits for zirconium and its compounds in various countries.
country                            occupational exposure            time-weighted      type of          notea       referenceb
-organisation                      limit                            average            exposure limit
                                   ppm           mg/m3
the Netherlands
-Ministry of Social Affairs        -             5                  8h                 administrative               SZW02
and Employment
Germany
-AGS                               -             5c                 8h                                              TRG00
                                   -             20c,d              15 min
-DFG MAK-Kommission                -             1e                 8h                                  sensg,h     DFG02
                                   -             1e                 15 minf
Great-Britain
-HSE                               -             5                  8h                 OES                          HSE02
                                   -             10                 5 min
Sweden                             -             -                                                                  Arb00b
Denmark                            -             5                  8h                                              Arb00a
USA
-ACGIH                             -             5                  8h                 TLV              A4i         ACG02b
                                   -             10                 15 min             STEL
-OSHA                              -             5                  8h                 PEL                          ACG02a
-NIOSH                             -             5j                 10 h               REL                          ACG02a
                                                 10j                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
     Inhalable dust fraction.
d
     Holds for zirconium compounds.
e
     Inhalable dust fraction; holds for zirconium and its insoluble compounds. The soluble compounds were listed among
     compounds for which studies of the effects in man and in experimental animals have yielded insufficient information
     for the establishment of MAK-values.
f
     Maximum number per shift: 4, with a minimum interval between peaks of 1 hour.
g
     For both skin and respiratory tract; holds for the metal, the soluble, and the insoluble compounds
h
     Listed among compounds for which the possible rsik of damage to the embryo/fetus was investigated but for which
     classification was not possible.
i
     Classified in carcinogenicity category A4, i.e., not classifiable as a human carcinogen: agents which cause concern that
     they could be carcinogenic for humans but which cannot be assessed conclusively because of a lack of data. In vitro or
     animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the
     other categories.
j
     Not for zirconium tetrachloride.
059-20       Health-based Recommended Occupational Exposure Limits
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