This report contains the collective views of an international group of experts and does not necessarily represent the decisions or the stated policy of the United Nations Environment Programme, the International Labour Organization, or the World Health Organization.

Concise International Chemical Assessment Document 29

VANADIUM PENTOXIDE AND OTHER INORGANIC VANADIUM COMPOUNDS

Note that the layout and pagination of this pdf file are not identical to the printed CICAD

First draft prepared by Dr M. Costigan and Mr R. Cary, Health and Safety Executive, Liverpool, United Kingdom, and Dr S. Dobson, Centre for Ecology and Hydrology, Huntingdon, United Kingdom

Published under the joint sponsorship of the United Nations Environment Programme, the International Labour Organization, and the World Health Organization, and produced within the framework of the Inter-Organization Programme for the Sound Management of Chemicals.

World Health Organization Geneva, 2001 The International Programme on Chemical Safety (IPCS), established in 1980, is a joint venture of the United Nations Environment Programme (UNEP), the International Labour Organization (ILO), and the World Health Organization (WHO). The overall objectives of the IPCS are to establish the scientific basis for assessment of the risk to human health and the environment from exposure to chemicals, through international peer review processes, as a prerequisite for the promotion of chemical safety, and to provide technical assistance in strengthening national capacities for the sound management of chemicals. The Inter-Organization Programme for the Sound Management of Chemicals (IOMC) was established in 1995 by UNEP, ILO, the Food and Agriculture Organization of the United Nations, WHO, the United Nations Industrial Development Organization, the United Nations Institute for Training and Research, and the Organisation for Economic Co-operation and Development (Participating Organizations), following recommendations made by the 1992 UN Conference on Environment and Development to strengthen cooperation and increase coordination in the field of chemical safety. The purpose of the IOMC is to promote coordination of the policies and activities pursued by the Participating Organizations, jointly or separately, to achieve the sound management of chemicals in relation to human health and the environment.

WHO Library Cataloguing-in-Publication Data

Vanadium pentoxide and other inorganic vanadium compounds.

(Concise international chemical assessment document ; 29)

1.Vanadium compounds - adverse effects 2.Risk assessment 3.Environmental exposure I.International Programme on Chemical Safety II.Series

ISBN 92 4 153029 4 (NLM Classification: QV 290) ISSN 1020-6167

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Publications of the World Health Organization enjoy copyright protection in accordance with the provisions of Protocol 2 of the Universal Copyright Convention. All rights reserved. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the World Health Organization concerning the legal status of any country, territory, city, or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. The Federal Ministry for the Environment, Nature Conservation and Nuclear Safety, Germany, provided financial support for the printing of this publication.

Printed by Wissenschaftliche Verlagsgesellschaft mbH, D-70009 Stuttgart 10 TABLE OF CONTENTS

FOREWORD ...... 1

1. EXECUTIVE SUMMARY ...... 4

2. IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES ...... 6

3. ANALYTICAL METHODS ...... 6

3.1 Workplace air monitoring ...... 6 3.2 Biological monitoring ...... 6 3.3 Environmental monitoring ...... 7

4. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE ...... 8

5. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION ...... 9

5.1 Chemical speciation of vanadium ...... 9 5.2 Essentiality of vanadium ...... 9 5.3 Bioaccumulation ...... 9 5.4 Leaching and bioavailability in soils ...... 10

6. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE ...... 10

6.1 Environmental levels ...... 10 6.1.1 Air ...... 10 6.1.2 Surface waters and sediments ...... 11 6.1.3 Biota ...... 11 6.1.4 Soil ...... 12 6.2 Human exposure ...... 12

7. COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS ...... 14

8. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS ...... 14

8.1 Single exposure ...... 15 8.1.1 Vanadium pentoxide ...... 15 8.1.2 Other pentavalent vanadium compounds ...... 15 8.1.3 Tetravalent vanadium compounds ...... 15 8.1.4 Trivalent vanadium compounds ...... 15 8.2 Irritation and sensitization ...... 15 8.3 Effects of inhaled vanadium compounds on the respiratory tract ...... 16 8.4 Other short-term exposure studies ...... 17 8.4.1 Vanadium pentoxide ...... 17 8.4.2 Other pentavalent vanadium compounds ...... 17 8.4.3 Tetravalent vanadium compounds ...... 18 8.5 Medium-term exposure ...... 18 8.5.1 Vanadium pentoxide and other pentavalent vanadium compounds ...... 18 8.5.2 Tetravalent vanadium compounds ...... 19 8.6 Long-term exposure and carcinogenicity ...... 19 8.6.1 Vanadium pentoxide and other pentavalent vanadium compounds ...... 19

iii Concise International Chemical Assessment Document 29

8.6.2 Tetravalent vanadium compounds ...... 19 8.7 Genotoxicity and related end-points ...... 19 8.7.1 Studies in prokaryotes ...... 19 8.7.1.1 Vanadium pentoxide ...... 19 8.7.1.2 Other pentavalent vanadium compounds ...... 19 8.7.1.3 Tetravalent vanadium compounds ...... 19 8.7.1.4 Trivalent vanadium compounds ...... 19 8.7.2 In vitro studies in eukaryotes ...... 19 8.7.2.1 Vanadium pentoxide ...... 19 8.7.2.2 Other pentavalent vanadium compounds ...... 20 8.7.2.3 Tetravalent vanadium compounds ...... 21 8.7.2.4 Trivalent vanadium compounds ...... 21 8.7.3 Sister chromatid exchange ...... 21 8.7.4 Other in vitro studies ...... 21 8.7.4.1 Vanadium pentoxide ...... 21 8.7.4.2 Other pentavalent vanadium compounds ...... 21 8.7.4.3 Tetravalent vanadium compounds ...... 22 8.7.5 In vivo studies in eukaryotes (somatic cells) ...... 22 8.7.5.1 Vanadium pentoxide ...... 22 8.7.5.2 Other pentavalent vanadium compounds ...... 22 8.7.5.3 Tetravalent vanadium compounds ...... 22 8.7.6 In vivo studies in eukaryotes (germ cells) ...... 22 8.7.6.1 Vanadium pentoxide ...... 22 8.7.6.2 Other pentavalent and tetravalent vanadium compounds ...... 23 8.7.7 Supporting data ...... 23 8.8 Reproductive toxicity ...... 23 8.8.1 Effects on fertility ...... 23 8.8.1.1 Vanadium pentoxide and other pentavalent vanadium compounds ...... 23 8.8.1.2 Tetravalent vanadium compounds ...... 24 8.8.2 Developmental toxicity ...... 24 8.8.2.1 Vanadium pentoxide ...... 24 8.8.2.2 Other pentavalent vanadium compounds ...... 24 8.8.2.3 Tetravalent vanadium compounds ...... 25 8.9 Immunological and neurological effects ...... 25 8.9.1 Vanadium pentoxide ...... 25 8.9.2 Other pentavalent vanadium compounds ...... 26 8.9.3 Tetravalent vanadium compounds ...... 26

9. EFFECTS ON HUMANS ...... 26

9.1 Studies on volunteers ...... 26 9.1.1 Vanadium pentoxide ...... 26 9.1.2 Other pentavalent vanadium compounds ...... 27 9.1.3 Tetravalent vanadium compounds ...... 27 9.2 Clinical and epidemiological studies for occupational exposure ...... 27 9.2.1 Vanadium pentoxide ...... 27 9.2.2 Tetravalent vanadium compounds ...... 29 9.3 Epidemiological studies for general population exposure ...... 29

iv Vanadium pentoxide and other inorganic vanadium compounds

10. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD ...... 30

10.1 Aquatic environment ...... 30 10.2 Terrestrial environment ...... 30

11. EFFECTS EVALUATION ...... 32

11.1 Evaluation of health effects ...... 32 11.1.1 Hazard identification and dose–response assessment ...... 32 11.1.2 Criteria for setting tolerable intakes or guidance values for vanadium pentoxide ...... 33 11.1.3 Sample risk characterization ...... 33 11.1.4 Uncertainties ...... 34 11.2 Evaluation of environmental effects ...... 34

12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES ...... 35

REFERENCES ...... 36

APPENDIX 1 — SOURCE DOCUMENTS ...... 42

APPENDIX 2 — CICAD PEER REVIEW ...... 42

APPENDIX 3 — CICAD FINAL REVIEW BOARD ...... 43

INTERNATIONAL CHEMICAL SAFETY CARDS ...... 44

RÉSUMÉ D’ORIENTATION ...... 48

RESUMEN DE ORIENTACIÓN ...... 51

v Vanadium pentoxide and other inorganic vanadium compounds

FOREWORD provided as guidance only. The reader is referred to EHC 1701 for advice on the derivation of health-based Concise International Chemical Assessment tolerable intakes and guidance values. Documents (CICADs) are the latest in a family of publications from the International Programme on While every effort is made to ensure that CICADs Chemical Safety (IPCS) — a cooperative programme of represent the current status of knowledge, new informa- the World Health Organization (WHO), the International tion is being developed constantly. Unless otherwise Labour Organization (ILO), and the United Nations stated, CICADs are based on a search of the scientific Environment Programme (UNEP). CICADs join the literature to the date shown in the executive summary. In Environmental Health Criteria documents (EHCs) as the event that a reader becomes aware of new informa- authoritative documents on the risk assessment of tion that would change the conclusions drawn in a chemicals. CICAD, the reader is requested to contact IPCS to inform it of the new information. International Chemical Safety Cards on the relevant chemical(s) are attached at the end of the Procedures CICAD, to provide the reader with concise information on the protection of human health and on emergency The flow chart shows the procedures followed to action. They are produced in a separate peer-reviewed produce a CICAD. These procedures are designed to procedure at IPCS. They may be complemented by take advantage of the expertise that exists around the information from IPCS Poison Information Monographs world — expertise that is required to produce the high- (PIM), similarly produced separately from the CICAD quality evaluations of toxicological, exposure, and other process. data that are necessary for assessing risks to human health and/or the environment. The IPCS Risk Assess- CICADs are concise documents that provide sum- ment Steering Group advises the Co-ordinator, IPCS, on maries of the relevant scientific information concerning the selection of chemicals for an IPCS risk assessment, the potential effects of chemicals upon human health whether a CICAD or an EHC is produced, and which and/or the environment. They are based on selected institution bears the responsibility of the document national or regional evaluation documents or on existing production, as well as on the type and extent of the EHCs. Before acceptance for publication as CICADs by international peer review. IPCS, these documents undergo extensive peer review by internationally selected experts to ensure their The first draft is based on an existing national, completeness, accuracy in the way in which the original regional, or international review. Authors of the first data are represented, and the validity of the conclusions draft are usually, but not necessarily, from the institution drawn. that developed the original review. A standard outline has been developed to encourage consistency in form. The primary objective of CICADs is characteri- The first draft undergoes primary review by IPCS and zation of hazard and dose–response from exposure to a one or more experienced authors of criteria documents in chemical. CICADs are not a summary of all available data order to ensure that it meets the specified criteria for on a particular chemical; rather, they include only that CICADs. information considered critical for characterization of the risk posed by the chemical. The critical studies are, The draft is then sent to an international peer however, presented in sufficient detail to support the review by scientists known for their particular expertise conclusions drawn. For additional information, the and by scientists selected from an international roster reader should consult the identified source documents compiled by IPCS through recommendations from IPCS upon which the CICAD has been based. national Contact Points and from IPCS Participating Institutions. Adequate time is allowed for the selected Risks to human health and the environment will experts to undertake a thorough review. Authors are vary considerably depending upon the type and extent required to take reviewers’ comments into account and of exposure. Responsible authorities are strongly revise their draft, if necessary. The resulting second draft encouraged to characterize risk on the basis of locally measured or predicted exposure scenarios. To assist the reader, examples of exposure estimation and risk 1 International Programme on Chemical Safety (1994) characterization are provided in CICADs, whenever Assessing human health risks of chemicals: derivation possible. These examples cannot be considered as of guidance values for health-based exposure limits. representing all possible exposure situations, but are Geneva, World Health Organization (Environmental Health Criteria 170).

1 Concise International Chemical Assessment Document 29

CICAD PREPARATION FLOW CHART

SELECTION OF PRIORITY CHEMICAL

SELECTION OF HIGH QUALITY NATIONAL/REGIONAL ASSESSMENT DOCUMENT(S)

FIRST DRAFT PREPARED

PRIMARY REVIEW BY IPCS ( REVISIONS AS NECESSARY)

REVIEW BY IPCS CONTACT POINTS/ SPECIALIZED EXPERTS

REVIEW OF COMMENTS (PRODUCER/RESPONSIBLE OFFICER), PREPARATION OF SECOND DRAFT 1

FINAL REVIEW BOARD 2

FINAL DRAFT 3

EDITING

APPROVAL BY DIRECTOR, IPCS

PUBLICATION

1 Taking into account the comments from reviewers. 2 The second draft of documents is submitted to the Final Review Board together with the reviewers’ comments. 3 Includes any revisions requested by the Final Review Board.

2 Vanadium pentoxide and other inorganic vanadium compounds

is submitted to a Final Review Board together with the reviewers’ comments.

A consultative group may be necessary to advise on specific issues in the risk assessment document.

The CICAD Final Review Board has several important functions:

– to ensure that each CICAD has been subjected to an appropriate and thorough peer review; – to verify that the peer reviewers’ comments have been addressed appropriately; – to provide guidance to those responsible for the preparation of CICADs on how to resolve any remaining issues if, in the opinion of the Board, the author has not adequately addressed all comments of the reviewers; and – to approve CICADs as international assessments.

Board members serve in their personal capacity, not as representatives of any organization, government, or industry. They are selected because of their expertise in human and environmental toxicology or because of their experience in the regulation of chemicals. Boards are chosen according to the range of expertise required for a meeting and the need for balanced geographic representation.

Board members, authors, reviewers, consultants, and advisers who participate in the preparation of a CICAD are required to declare any real or potential conflict of interest in relation to the subjects under discussion at any stage of the process. Representatives of nongovernmental organizations may be invited to observe the proceedings of the Final Review Board. Observers may participate in Board discussions only at the invitation of the Chairperson, and they may not participate in the final decision-making process.

3 Concise International Chemical Assessment Document 29

1. EXECUTIVE SUMMARY 64 000 tonnes of vanadium that are emitted to the atmos- phere each year from both natural and anthropogenic sources comes from oil combustion. This CICAD on vanadium pentoxide and other inorganic vanadium compounds was based on a review The environmental chemistry of vanadium is com- of human health concerns (primarily occupational) plex. In minerals, the oxidation state of vanadium may be prepared by the United Kingdom’s Health and Safety +3, +4, or +5. Dissolution in water rapidly oxidizes V3+ Executive (HSE, in press). This review focuses on and V4+ to the pentavalent state, the most usual form of exposures via routes relevant to occupational settings, the metal in the environment. Vanadate, the pentavalent but it also contains environmental information. Data species in solution, may polymerize (mainly to dimeric identified as of November 1998 were covered. A further and trimeric forms), particularly at higher concentrations literature search was performed up to May 1999 to of the salts. Within tissues of organisms, V3+ and V4+ identify any additional information published since this predominate because of largely reducing conditions; in review was completed. An Environmental Health Criteria plasma, V5+ predominates. monograph (IPCS, 1988) was used as a source document for environmental information. As no more recent source Vanadium is probably essential to enzyme systems document was available for environmental fate and that fix nitrogen from the atmosphere (bacteria) and is effects, the literature was searched for additional concentrated by some organisms (tunicates, some poly- information. Information on the nature of the peer review chaete annelids, some microalgae), but its function in and availability of the source documents is presented in these organisms is uncertain. Whether vanadium is Appendix 1. Information on the peer review of this essential to other organisms remains an open question. CICAD is presented in Appendix 2. This CICAD was There is no evidence of accumulation or biomagnifica- approved as an international assessment at a meeting of tion in food chains in marine organisms, the best studied the Final Review Board, held in Helsinki, Finland, on group. 26–29 June 2000. Participants at the Final Review Board meeting are listed in Appendix 3. The International There is very limited leaching of vanadium through Chemical Safety Cards on vanadium trioxide (ICSC 0455) soil profiles. and vanadium pentoxide (ICSC 0596), produced by the International Programme on Chemical Safety (IPCS, Higher levels of vanadium have been reported in 1999a,b), have also been reproduced in this document. air close to industrial sources and oil fires. Representa- tive deposition rates are 0.1–10 kg/ha per annum for Vanadium (CAS No. 7440-62-2) is a soft silvery- urban sites affected by strong local sources, 0.01– grey metal that can exist in a number of different oxida- 0.1 kg/ha per annum for rural sites and urban ones with tion states: !1, 0, +2, +3, +4, and +5. The most common no strong local source, and <0.001–0.01 kg/ha per annum commercial form is vanadium pentoxide (V2O5; CAS No. for remote sites. 1314-62-1), and this exists in the pentavalent state as a yellow-red or green crystalline powder. Most surface fresh waters contain less than 3 µg vanadium/litre; higher levels of up to about 70 µg/litre Vanadium is an abundant element with a very wide have been reported in areas with high geochemical distribution and is mined in South Africa, Russia, and sources. Data on levels of vanadium in surface water China. During the smelting of iron ore, a vanadium slag close to industrial activity are few; most reports suggest is formed that containvanadium pentoxide, which is used levels approximately the same as the highest natural for the production of vanadium metal. Vanadium pentox- ones. Seawater concentrations in the open ocean range ide is also produced by solvent extraction from uranium from 1 to 3 µg/litre, and sediment concentrations range ores and by a salt roast process from boiler residues or from 20 to 200 µg/g; the highest levels are in coastal residues from elemental phosphate plants. During the sediments. burning of fuel oils in boilers and furnaces, vanadium pentoxide is present in the solid residues, soot, boiler A few organisms concentrate vanadium, with up to scale, and fly ash. 10 000 µg/g in ascidians and 786 µg/g in polychaete annelids. Most other organisms contain generally less Atmospheric emissions from natural sources have than 50 µg/g and usually much lower concentrations. been estimated at 8.4 tonnes per annum globally (range 1.5–49.2 tonnes). By far the most important source of Estimates of total dietary intake of humans range environmental contamination with vanadium is combus- from 11 to 30 µg/day. Levels in drinking-water range up tion of oil and coal; about 90% of the approximately to 100 µg/litre. Some groundwater sources supplying

4 Vanadium pentoxide and other inorganic vanadium compounds

potable water show concentrations above 50 µg/litre. pentoxide dust and fume. Overall, there are insufficient Levels in bottled spring water may be higher. data to reliably describe the exposure–response relation- ship for the respiratory effects of vanadium pentoxide In humans, there is limited toxicokinetic informa- dust and fume in humans. tion suggesting that vanadium is absorbed following inhalation and is subsequently excreted via the urine Pentavalent and tetravalent forms of vanadium with an initial rapid phase of elimination, followed by a have produced aneugenic effects in vitro in the presence slower phase, which presumably reflects the gradual and absence of metabolic activation. There is evidence release of vanadium from body tissues. Following oral that these forms of vanadium as well as trivalent vana- administration, tetravalent vanadium is poorly absorbed dium can also produce DNA/chromosome damage in from the gastrointestinal tract. There were no dermal vitro, both positive and negative results having emerged studies available. from the available studies. The weight of evidence from the available data suggests that vanadium compounds In inhalation and oral studies in laboratory animals, do not produce gene mutations in standard in vitro tests absorbed vanadium in either pentavalent or tetravalent in bacterial or mammalian cells. states is distributed mainly to the bone, liver, kidney, and spleen, and it is also detected in the testes. The main In vivo, both pentavalent and tetravalent vanadium route of vanadium excretion is via the urine. The pattern compounds have produced clear evidence of aneuploidy of vanadium distribution and excretion indicates that in somatic cells following exposure by several different there is potential for accumulation and retention of routes. The evidence for vanadium compounds also absorbed vanadium, particularly in the bone. There is being able to express clastogenic effects is, as with in evidence that tetravalent vanadium has the ability to vitro studies, mixed, and the overall position on clasto- cross the placental barrier to the fetus. genicity in somatic cells is uncertain. A positive result was obtained in germ cells of mice receiving vanadium The one acute inhalation study available reported pentoxide by intraperitoneal injection. However, the 3 3 an LC67 of 1440 mg/m (800 mg vanadium/m ) following a underlying mechanism for this effect (aneugenicity; 1-h exposure of rats to vanadium pentoxide dust. Oral clastogenicity) is uncertain. It is also unclear how these studies in rats and mice resulted in LD50 values in the findings can be generalized to more realistic routes of range 10–160 mg/kg body weight for vanadium pentox- exposure or to other vanadium compounds. ide and other pentavalent vanadium compounds, while tetravalent vanadium compounds have LD50 values in The nature of the genotoxicity database on vana- the range 448–467 mg/kg body weight. No information is dium pentoxide and other vanadium compounds is such available concerning dermal toxicity. that it is not possible to clearly identify the threshold level, for any route of exposure relevant to humans, Eye irritation has been reported in studies in below which there would be no concern for potential vanadium workers. No skin irritation was reported in genotoxic activity. 100 human volunteers following skin patch testing with 10% vanadium pentoxide, although patch testing in No useful information is available on the carcino- workforces has produced two isolated reactions. No genic potential of any form of vanadium via any route of clear information is available from animal studies with exposure in animals1 or in humans. regard to the potential of vanadium compounds to produce skin or eye irritation or skin sensitization. A fertility study in male mice, involving exposure to sodium metavanadate in drinking-water, suggests the In a group of human volunteers, a single 8-h possibility that oral exposure of male mice to sodium exposure to 0.1 mg vanadium pentoxide dust/m3 caused metavanadate at 60 and 80 mg/kg body weight directly delayed but prolonged bronchial effects involving exces- caused a decrease in spermatid/spermatozoal count and sive production of mucus. At 0.25 mg/m3, a similar in the number of pregnancies produced in subsequent pattern of response was seen, with the addition of cough matings. However, significant general toxicity (decreased for some days post-exposure. Exposure to 1.0 mg/m3 body weight gain) was also evident at 80 mg/kg body produced persistent and prolonged coughing after 5 h. weight. A no-effect level for bronchial effects was not identified in this study.

Repeated inhalation exposure to the dust and fume 1 The authors of this document are aware that a 2-year of vanadium pentoxide is associated with irritation of the inhalation bioassay in rodents has recently been eyes, nose, and throat. Wheeze and dyspnoea are completed at the US National Toxicology Program. commonly reported in workers exposed to vanadium However, results are not available at this time.

5 Concise International Chemical Assessment Document 29

There are a number of developmental studies on provides some physicochemical properties of vanadium pentavalent and tetravalent vanadium compounds, and a compounds that are referred to in this review. consistent observation is that of skeletal anomalies. Interpretation of these studies is difficult because of Vanadium (CAS No. 7440-62-2) is a soft silvery- unconventional routes of exposure and evidence of grey metal with a relative molecular mass of 50.9. maternal toxicity that may itself contribute to the effects seen in pups. Vanadium pentoxide (CAS No. 1314-62-1) is the most commonly used vanadium compound and exists in The toxicological end-points of concern for the pentavalent state as a yellow-red or green crystalline humans are genotoxicity and respiratory tract irritation. powder of relative molecular mass 181.9. Other common Since it is not possible to identify a level of exposure synonyms include vanadic anhydride and divanadium that is without adverse effect, it is recommended that pentoxide. levels be reduced to the extent possible. Vapour pressures (and hence Henry’s law con-

Acute LC50 values for aquatic organisms range stants) and octanol/water partition coefficients are not from 0.2 to about 120 mg/litre, with the majority lying available for vanadium compounds. between 1 and 12 mg/litre. More ecotoxicologically relevant end-points were development of oyster larvae (significantly reduced at 0.05 mg vanadium/litre) and reproduction of Daphnia (21-day no-observed-effect 3. ANALYTICAL METHODS concentration at 1.13 mg/litre). There are few terrestrial studies. Most plant studies have been on hydroponic cultures where effects occurred at 5 mg/litre and higher; 3.1 Workplace air monitoring these studies are difficult to interpret in relation to plants growing in soil. Airborne monitoring is largely based on measure- ment of vanadium, rather than vanadium pentoxide. The Concentrations in environmental media are sub- Health and Safety Executive has published MDHS 91 stantially lower than reported toxic concentrations. Few Metals and metalloids in workplace air by X-ray data are available on concentrations at specific industrial fluorescence spectrometry (HSE, 1998). This method can sites, and it is not possible to conduct a risk assessment be used for measuring vanadium and vanadium on this basis. However, reported concentrations appear compounds in workplace air, but no method performance to be similar to the highest natural concentrations, data are available for vanadium. suggesting that risk would be low. Local measurements must be carried out to assess risk in any particular The US National Institute of Occupational Safety circumstance. and Health (NIOSH, 1994) and the US Occupational Safety and Health Administration (OSHA, 1991) have published methods that are suitable for measuring vanadium and vanadium compounds in workplace air. 2. IDENTITY AND PHYSICAL/CHEMICAL Both are generic methods for metals and metalloids in PROPERTIES which samples are collected by drawing air through a membrane filter mounted in a cassette-type filter holder, dissolved in acid on a hotplate, and analysed by induc- Vanadium can exist in a number of different tively coupled plasma – atomic emission spectrometry oxidation states: !1, 0, +2, +3, +4, and +5. The most (ICP-AES). For both methods, the lower limit of the common commercial form of vanadium is vanadium working range is approximately 0.005 mg/m3 for a 500-litre pentoxide (V2O5), in which vanadium is in the +5 air sample, although these methods are not widely oxidation state. Other forms of vanadium in the +5 available. oxidation state mentioned in this review derive from the – 3.2 Biological monitoring vanadate ion (VO3 ) and include ammonium meta- vanadate (NH4VO3), sodium metavanadate (NaVO3), and sodium orthovanadate (Na3VO4). Compounds in the +4 The measurement of vanadium in end-of-shift urine oxidation state are derived from the vanadyl ion (VO2+) samples is appropriate for biological monitoring of

— for example, vanadyl dichloride (VOCl2) and vanadyl vanadium exposure and has been widely used to monitor sulfate (VOSO4). Compounds containing vanadium in the occupational exposure to vanadium compounds in a +3 oxidation state include vanadium oxide (V2O3). Table 1 number of industrial activities (Angerer & Schaller, 1994).

6 Vanadium pentoxide and other inorganic vanadium compounds

Table 1: Physical/chemical properties of vanadium and selected inorganic vanadium compounds.

Solubility (g/litre) CAS Molecular/ Melting Boiling Cold water Compound number atomic mass point (°C) point (°C) (20–25 °C) Hot water Other solvents

Vanadium, V 7440-62-2 50.942 1890 ± 10; 3380 Insoluble Insoluble Not attacked by hot or 1917 cold hydrochloric acid or cold sulfuric acid, but soluble in hydrofluoric acid, nitric acid, and aquaregia

Vanadium 1314-62-1 181.9 690 1750 8 No data Soluble in acid/alkali; pentoxide, insoluble in absolute

V2O5 alcohol

Sodium meta- 13718-26- 121.93 No data No data 211 388 (at 75 No data vanadate, 8 °C)

NaVO3 Sodium ortho- 13721-39- 183.91 850–856 No data Soluble No data Soluble in alcohol vanadate, 6

Na 3VO4

Ammonium 7803-55-6 116.98 200 No data 58 Decomposes Soluble in ammonium meta- (decom- carbonate vanadate, poses)

NH4VO3

Vanadium 7727-18-6 Soluble, No data Soluble in alcohol, oxytrichloride, decomposes ether, acetic acid

VOCl 3

Vanadyl 27774-13- Very soluble No data No data sulfate, 6

VOSO4

Vanadyl 10213-09- Decomposes No data Soluble in dilute nitric oxydichloride, 9 acid

VOCl 2 Vanadium 1314-34-7 Slightly Soluble Soluble in nitric acid,

trioxide, V2O3 soluble hydrofluoric acid, alkali

Vanadium is eliminated in the urine with a half-life spectrophotometry (AAS), with pre-concentration by of 15–40 h (Sabbioni & Moroni, 1983). Pre-shift and chelation and solvent extraction, is the most widely used post-shift urine vanadium levels measured at the analytical method for the determination of vanadium in beginning and the end of a working week will, therefore, urine, and validated methods have been described in the give a measure of daily absorption and accumulated literature. This analytical method gives typical detection dose from exposures over the preceding days. A further limits of 0.1 µg/litre for vanadium in urine, with analytical study of workers exposed to vanadium pentoxide (Kawai precisions of 11% relative standard deviation at 1 µg/litre et al., 1989) demonstrated the utility of measuring mid- and 4% at 10 µg/litre. shift urinary vanadium as an indicator of exposure. Blood vanadium levels were also determined but offered 3.3 Environmental monitoring no advantage over urine measurements. As non- invasive sampling is normally preferred for routine Various methods have been described for analysis biological monitoring, the measurement of vanadium in of vanadium in air, surface waters, and biota (e.g., urine is generally recommended. Ahmed & Banerjee, 1995). Flameless AAS (NIOSH, 1977) gives a detection limit of 1 ng/ml in air, corresponding to In biological monitoring studies of occupational an absolute sensitivity of 0.1 ng vanadium. ICP-AES has vanadium exposure, urinary levels of vanadium asso- a working range of 5–2000 µg/m3 for a 500-litre air sample ciated with airborne exposures have been measured (see (NIOSH, 1994). Direct aspiration and graphite furnace Table 4 in section 6.2). AAS methods for determining vanadium compounds in water were reported in US EPA (1983). The detection Urinary vanadium may be determined accurately limits for these two methods are 200 and 4 µg/litre, by several analytical techniques (Hauser et al., 1998; respectively (US EPA, 1986). Instrumental neutron HSE, in press). Electrothermal atomic absorption activation analysis gave detection limits of 0.01 µg/g in

7 Concise International Chemical Assessment Document 29

the context of sea mammal tissues (Mackey et al., 1996). outside the United Kingdom, is used in very small quan- The instrumental detection limit was 0.1 ng/ml using tities for research purposes. inductively coupled plasma – mass spectrometry (Saeki et al., 1999). Vanadium pentoxide is used as the catalyst for a variety of gas-phase oxidation processes, particularly the conversion of sulfur dioxide to sulfur trioxide during the manufacture of sulfuric acid. The most frequently 4. SOURCES OF HUMAN AND used vanadium pentoxide catalyst contains 4–6% ENVIRONMENTAL EXPOSURE vanadium as vanadium pentoxide on a silica base.

Vanadium pentoxide is also used in some pigments Vanadium is a relatively abundant element with a and inks used in the ceramics industry to impart a colour very wide distribution; however, workable deposits are ranging from brown to green. Pigments and inks are very rare. Vanadium occurs in the minerals vanadinite, made containing up to about 15% vanadium pentoxide, chileite, patronite, and carnotite. It constitutes about the higher-concentration ones being supplied in an oil 0.01% of the crust of the Earth (Budavari et al., 1996). It base rather than as a dry powder. is derived mainly from titaniferous magnetites containing 1.5–2.5% vanadium pentoxide, which are mined in South Vanadium pentoxide can be used as a colouring Africa, Russia, and China (HSE, in press). During the agent and to provide ultraviolet filtering properties in smelting of iron ore, a vanadium slag is formed that some glasses. Normally, the vanadium content in the contains 12–24% vanadium pentoxide, which is used for batch materials is less than 0.5%. the production of vanadium metal. Worldwide produc- tion of vanadium was stable at just over 27 000 tonnes Atmospheric emissions of vanadium from natural per annum between 1976 and 1990. Estimated production sources have been estimated at 8.4 tonnes per annum in 1990 was 30 700 tonnes, comprising approximately globally (range 1.5–49.2 tonnes). Natural sources, in 15 400 tonnes from South Africa, 4100 tonnes from order of importance, are continental dusts, volcanoes, China, 8200 tonnes from the former USSR, 2100 tonnes seasalt spray, forest fires, and biogenic processes from the USA, and under 900 tonnes from Japan (Hilliard, (Nriagu, 1990). 1992). Vanadium pentoxide is also produced by solvent extraction from uranium ores and by a salt roast process By far the most important source of environmental from boiler residues or residues from elemental contamination with vanadium is combustion of oil, with phosphate plants. Ferrovanadium can be obtained from coal combustion as the second most important. Of the vanadium pentoxides or vanadium slags by the alumino- estimated total global emissions from both natural and thermic process. anthropogenic sources of 64 000 tonnes per annum to the atmosphere, 58 500 tonnes come from oil All crude oils contain metallic impurities, including combustion, with more than 33 500 tonnes of this vanadium, which is present as an organometallic accounted for by the developing economies in Asia and complex. The vanadium concentration in the oils varies just under 14 500 tonnes by Eastern Europe and the greatly, depending on their origin. The concentration of former USSR. There are considerable regional variations vanadium in crude oil ranges from 3 to 260 µg/g and in in vanadium emissions. For example, emissions to the residual fuel oil from 0.2 to 160 µg/g (NAS, 1974). During Great Lakes area fell between 1980 and 1995, whereas the burning of fuel oils in boilers and furnaces, the those to the Mediterranean basin have continued to rise, vanadium is left behind as vanadium pentoxide in the dominated by emissions from a few countries (Turkey solid residues, soot, boiler scale, and fly ash. The vana- 20%, Egypt 19%, and Lebanon 15% of the total) (Nriagu dium content of these residues varies from less than 1% & Pirrone, 1998). up to almost 60%. Vanadium is also present in coal, typically at a concentration between 14 and 56 ppm (mg/kg).

Vanadium is used in the United Kingdom in cer- tain ferrovanadium alloys, being added in relatively small proportions at the refining stage of steelmaking. Titanium-boron-aluminium (TiBAl) rod, containing less than 1% vanadium, is used by the secondary aluminium industry as a grain refiner. The hard metals industry uses small amounts of vanadium carbide in the production of tungsten carbide tool bits. Pure vanadium, imported from

8 Vanadium pentoxide and other inorganic vanadium compounds

5. ENVIRONMENTAL TRANSPORT, atmospheric nitrogen to ammonia. The best characterized DISTRIBUTION, AND TRANSFORMATION nitrogenase is molybdenum-dependent, and its detailed structure has been published (Chan et al., 1993). Although it has been known for a long time (Bortels, 5.1 Chemical speciation of vanadium 1936) that vanadium could substitute for molybdenum as a trace element in nitrogen-fixing bacteria, only recently The chemistry of vanadium is extremely complex, has it been studied in detail. The structure of the and the reader is referred elsewhere for detailed dis- vanadium-dependent enzyme is not fully known but is cussion of the origin, speciation, bioaccumulation, and assumed to be similar to the molybdenum–iron protein complex-forming chemistry of the metal related to the (Chan et al., 1993). The vanadium enzyme has been environment and biological systems (Crans et al., 1998). shown to function under conditions of low molybdenum, A simple summary of vanadium chemistry is presented but it may also operate under all conditions; genetic here. variants lacking the molybdenum–iron enzyme and relying exclusively on the vanadium–iron enzyme are Under environmental conditions, vanadium may known. exist in oxidation states +3, +4, and +5. V3+ and V4+ act as cations, but V5+, the most common form in the aquatic Vanadium-dependent haloperoxidases have been environment, reacts both as a cation and anionically as found in marine macroalgae and also in a lichen and an analogue of phosphate. fungus. Amavadin, a complex molecule centred on vanadium, is found in fungi of the genus Amanita; its In minerals, the oxidation state of vanadium may be function is not known, but it may act as a mediator in +3, +4, or +5, but all mineral dissolution rapidly oxidizes electron transfer. In ascidians (Tunicata; Protochordata), V3+ and V4+ to the pentavalent state. Dry weathering commonly called sea squirts, it has been suggested that produces dusts that may be distributed over great vanadium interacts with tunichromes, oligopeptides that distances; deposition of dust into water will also lead to are the building blocks of the tunic. In fan worms exclusively pentavalent vanadium. Vanadium is a non- (Polychaeta; Annelida), a function for vanadium in volatile metal, and atmospheric transport is via oxygen absorption and storage has been suggested. particulates. In fuel oils and coal, vanadium is present as very stable porphyrin and non-porphyrin complexes Recent reviews on the role of vanadium in biologi- (Yen, 1975; Fish & Komlenic, 1984) but is emitted as cal systems include those by Rehder & Jantzen (1998), oxides when these fossil fuels are burned. The native Wever & Hemrika (1998), Chasteen (1990), and Sigel & oxides are sparingly soluble in water but undergo Sigel (1995), where details of the chemistry of vanadium hydrolysis to generate “vanadate” in solution. Vanadate in biological systems can be found. is often used as a generalized term for vanadium species in solution. Speciation of vanadium in solution is com- Whether vanadium is an essential trace element for plex and highly dependent on vanadium concentration. mammals remains an open question. Deficiency states Under most common environmental conditions of pH have been described for goats and chicks, consisting of and redox potential, and at the low concentrations reproductive anomalies and deleterious effects on bone reported for vanadium in natural waters, the vanadate is growth (Nielsen & Uthus, 1990). However, there is largely monomeric. At higher concentrations, such as disagreement on results, and, if vanadium is essential, those used in toxicity testing, dimeric and trimeric forms requirement levels of the order of a few nanograms per may predominate, and this can have an effect on how the day are likely (Mackey et al., 1996). vanadium compounds interact with biological systems (Crans et al., 1998). 5.3 Bioaccumulation

Within tissues in organisms, V3+ and V4+ predom- Ascidians have been known to accumulate large inate because of largely reducing conditions; in plasma, residues of vanadium since a first report in 1911 (Henze, however, which is high in oxygen, V5+ is formed (Crans 1911). The metal accumulates in blood cells (vanado- et al., 1998). cytes). The highest reported concentration is 350 mmol/ litre in the blood cells of Ascidia gemmata (Michibata et 5.2 Essentiality of vanadium al., 1991), a concentration factor above that in seawater of 107. Recent reviews of accumulation and the signifi- Vanadium has been characterized as a constituent cance of vanadium in these organisms include those by of several enzyme systems and complexes within living Kustin & Robinson (1995), Michibata (1996), and organisms. Nitrogen-fixing bacteria and cyanobacteria Michibata & Kanamori (1998). Recently (Ishii et al., 1993), contain nitrogenases, which catalyse the reduction of high vanadium accumulation was demonstrated for

9 Concise International Chemical Assessment Document 29

polychaetes of the genus Pseudopotamilla; polychaetes the Alaskan marine environment as possible of other genera did not accumulate the metal. explanations (Mackey et al., 1996). Pseudopotamilla occelata showed concentrations in whole soft body ranging from 320 to 1350 mg/kg dry Marine biota are thought to contribute to the weight. Distribution, speciation, and possible physio- sedimentation of vanadium from seawater via shells, logical roles of the metal are discussed in Ishii (1998). faecal pellets, and moult. Coastal sediments appear to be a sink for vanadium (Miramand & Fowler, 1998). Apart from the specific accumulators mentioned above, organisms generally do not concentrate or accu- 5.4 Leaching and bioavailability in soils mulate vanadium from environmental media to a high degree, and there is no indication of biomagnification in A field study conducted over 30 months examined food chains. Miramand & Fowler (1998) reviewed movement of vanadium added to the top 7.5 cm of reported levels of vanadium in marine organisms and coastal plain soil and its availability to bean plants. Less calculated concentration factors for components of a than 3% of applied metal moved down the soil profile. typical marine food chain based on average seawater Extractable concentrations decreased over the first concentrations of 2 ng/g. Concentration factors for 18 months of the study and remained constant thereafter. primary producers ranged from 40 to 560, for primary Uptake of vanadium into the roots and upper parts of the consumers from 40 to 150, for secondary consumers from bean plants did not change significantly between approximately 20 to 150, and for tertiary consumers from 18 months and the end of the experiment but was approximately 2 to 400. Although vanadium reduced during the initial period, suggesting reduced concentrations are higher in sediment than in open bioavailability over time as a result of binding to soil seawater, only one study has attempted to quantify materials (Martin & Kaplan, 1998). uptake from sediment using 48V; the ragworm Nereis diversicolor accumulated vanadium from the sediment with a low transfer factor of about 0.02 (Miramand, 1979). Using labelled food, assimilation coefficients have been 6. ENVIRONMENTAL LEVELS AND calculated for several marine organisms. For the HUMAN EXPOSURE carnivorous invertebrates Marthasterias glacialis, Sepia officianalis, Carcinus maenus, and Lysmata seticaudata, assimilation coefficients of 88% (Miramand 6.1 Environmental levels et al., 1982), 40% (Miramand & Fowler, 1998), 38%, and 25% (Miramand et al., 1981) were reported, respectively. A very substantial literature exists on environmen- Biological half-lives in the same organisms were 57, 7, 10, tal levels of vanadium. The metal has been monitored in and 12 days, respectively. A high proportion of the geographical areas with naturally high occurrence of the vanadium was present in the digestive gland (63–98.8%). metal (mainly volcanic regions) where local water con- For a single fish species (Gobius minutus), assimilation tributes to drinking supplies, and vanadium has been was much lower, at 2–3%, with a half-life of 3 days used to monitor general industrial contamination, since it (Miramand et al., 1992), and accumulation was also low is a common component of oil and coal. In addition, in a bivalve feeding on suspended matter (Mytilus accumulation of the metal has been studied intensively galloprovincialis), at 7%, with a half-life of 7 days for marine organisms, since vanadium is known to (Miramand et al., 1980). Comparison of uptakes via food accumulate in a few species (section 5). In this section, and directly from water showed that invertebrates representative levels are presented. The reader is referred accumulated much of the vanadium from food to several recent reviews for more detailed coverage of (Miramand & Fowler, 1998). Recent studies on bioaccu- the literature in each of the subsections following. mulation of vanadium in pinnipeds and cetaceans in Swedish (Frank et al., 1992), northern Pacific (Saeki et al., 6.1.1 Air 1999), and Alaskan/Atlantic (Mackey et al., 1996) waters have shown a correlation of residues with age, Earlier measurements of vanadium in air were comparable to other metal residues. Liver showed the reviewed by Schroeder et al. (1987); most measurements highest accumulation of the metal of all tissues analysed. were performed in the 1970s, with a few in the early However, bone, which might be expected to accumulate 1980s. A review of later measurements and comparison the element, was not analysed. Alaskan sea mammals with the earlier review were conducted by Mamane & showed the highest levels, ranging up to 1.2 µg/g wet Pirrone (1998). The ranges they reported are presented in weight. The authors suggest a unique dietary source, a Table 2, together with reported concentrations down- unique geochemical source, or anthropogenic input to wind of the Kuwait oil fires in 1991–1992. The ranges are very large, and there is no simple explanation for the

10 Vanadium pentoxide and other inorganic vanadium compounds

Table 2: Ranges of concentrations of vanadium in air. 1969). A wider survey of Wyoming, Idaho, Utah, and Colorado in the USA showed vanadium concentrations Atmospheric concentration of 2.0–9.0 µg/litre (Parker et al., 1978). Unfiltered water Area (ng/m3) Reference from the source area of the Yangtze River in China con- Urban air 0.4–1460 Schroeder et al., 1987 tained between 0.24 and 64.5 µg/litre, whereas concentra- Rural air 2.7–97 tions in filtered water ranged from 0.02 to 0.46 µg/litre Remote areasa 0.001–14 (Zhang & Zhou, 1992). The highest levels reported are in Urban air 0.5–1230 Mamane & Pirrone, surface waters in the area of Mount Fuji in Japan. Two Rural air 0.4–500 1998 springs had 14.8 and 16.4 µg/litre, and five river samples Remote areas 0.01–2 showed between 17.7 and 48.8 µg/litre (Hamada, 1998). Dhahran, Saudi 2.4–1170 (in Sadiq & Mian, 1994 Arabia, during the PM10 Data on concentrations of vanadium in wastewater Kuwait oil fires fraction) and local surface water are few, and studies are old; a Includes the Arctic and oceanic islands in the Atlantic and reliability for present-day operations is questionable. A Pacific. single concentration of 2 mg/litre for surface water from 1961, reported in IPCS (1988), seems much higher than other more recent reports, where levels of up to 60 µg/li- variation; possible causes are reviewed by Mamane & tre in industrial areas seem more likely. Pirrone (1998), although they can draw no firm conclu- sions. Seawater concentrations have been reviewed by Miramand & Fowler (1998). Most reported concentra- Vanadium in air from oil combustion tends to be in tions in the open ocean have been in the range 1–3 µg/li- smaller particulate fractions. In arid areas with dust tre, with the highest reported value at 7.1 µg/litre. Sedi- storms, high levels of vanadium have been reported; ment concentrations range from 20 to 200 µg/g dry here, particle size tends to be much larger (Mamane & weight, with higher levels in coastal sediments. Pirrone, 1998). 6.1.3 Biota Bulk precipitation concentration ranges have been reported at 4.1–13 µg/litre for the rural United Kingdom Ranges of concentrations of vanadium in marine (Galloway et al., 1982) and 0.12–0.65 µg/litre (mean 0.45 organisms are given in Table 3, based on a review of the µg/litre) in Switzerland (Atteia, 1994). Wet deposition in literature in Miramand & Fowler (1998), where the an area of New England remote from anthropogenic original references can be found. The ranges include input showed concentrations of vanadium ranging from values from areas of likely local contamination from 0.2 to 1.16 µg/litre (average 0.67 µg/litre) and in Bermuda industrial sources. With the exception of ascidians ranging from 0.049 to 0.111 µg/litre (average 0.096 (tunicates), some annelids, and molluscs, concentrations µg/litre) (Church et al., 1984). Ice and snow levels in of vanadium in marine organisms are low. The range for northern Norway and Alaska were 0.31 and 0.13 µg/litre, planktonic species is heavily influenced by a single respectively (Galloway et al., 1982), and two ice core study showing accumulation up to 290 mg/kg dry levels in Greenland were reported at 0.022 and 0.016 weight; this was mainly into shells of planktonic forms of µg/litre. Levels in rain ranged from 1.1 to 46 µg/litre for molluscs. Generally, planktonic organisms show rural and urban sites in North America and Europe concentrations of vanadium around 1 mg/kg. (Galloway et al., 1982). There are fewer data for freshwater organisms. The Based on these reported concentrations, Mamone most comprehensive study of organisms was conducted & Pirrone (1998) calculated representative total depo- in the Mount Fuji area of Japan, where concentrations in sition rates of vanadium at 0.1–10 kg/ha per annum for organisms from water with high (43.4 µg/litre) and lower urban sites affected by strong local sources, 0.01– (0.72 or 0.4 µg/litre) concentrations of vanadium were 0.1 kg/ha per annum for rural sites and urban ones with compared. Water plants from the high-vanadium area no strong local source, and <0.001–0.01 kg/ha per annum contained 21.8 ± 11.3 µg/g dry weight of the metal (range for remote sites. 5.6–43.7 µg/g), compared with 0.79 ± 0.52 µg/g (range 0.22–1.91 µg/g) in the low-vanadium area. A green 6.1.2 Surface waters and sediments microalga in the high-concentration area contained the highest reported concentration of the metal, at 118–168 Most surface fresh waters contain less than 3 µg µg/g dry weight. The vanadium concentration in rainbow vanadium/litre (Hamada, 1998). The vanadium content of trout (Oncorhynchus mykiss) farmed in water from these water from the Colorado River basin (USA) ranged from areas was measured: bone concentrations 0.2 to 49.2 µg/litre, with the highest levels associated with uranium–vanadium mining (Linstedt & Kruger,

11 Concise International Chemical Assessment Document 29

Table 3: Concentrations of vanadium in marine organisms.a 6.2 Human exposure

Concentration of vanadium Organism (mg/kg dry weight) The quantitative data available to the authors of this document are restricted mainly to the occupational Phytoplankton 1.5–4.7 environment (HSE, in press). Information on control Zooplankton 0.07–290 measures has been derived from industry sources in the Macroalgae 0.4–8.9 United Kingdom. Ascidians 25–10 000 The main activity where workers can be exposed to Annelids 0.7–786 vanadium in the United Kingdom is the cleaning of oil- Other invertebrates 0.004–45.7 fired boilers and furnaces where vanadium pentoxide is a Fish 0.08–3 major component of the boiler residues. It is estimated that 1000 workers in the United Kingdom are employed Mammals <0.01–1.04 (fresh weight) by specialist boiler maintenance contractors, although a From Miramand & Fowler (1998). they probably spend less than 20% of their time cleaning oil-fired boilers. Measured vanadium exposures (total inhalable fraction) can approach 20 mg/m3 (during task), were 0.87, 4.77, and 17.2 µg/g and kidney concentrations but can be lower than 0.1 mg/m3. The lowest results are were 0.43, 2.38, and 4.63 µg/g for water concentrations of obtained where wet cleaning methods are used. Respira- 0.72, 43.4, and 82.7 µg/litre, respectively. In all cases, tory protective equipment is usually worn during boiler muscle concentrations were low and did not differ cleaning operations. between areas (0.016–0.024 µg/g) (Hamada, 1998). A pooled sample of 279 larval razorback sucker (Xyrauchen Handling of catalysts in chemical manufacturing texanus) from the Green River in Utah, USA, showed a plants is carried out by specialist contractors. Fewer vanadium concentration of 1.7 mg/kg dry weight. The than 50 workers in the United Kingdom are exposed to Green River receives irrigation drainage and typically vanadium pentoxide during such activities. Exposure shows higher concentrations of a range of elements depends on the type of operations being carried out. compared with the input streams (Hamilton et al., 2000). During the removal and replacement of the catalyst, exposures can be between 0.01 and 0.67 mg/m3. Sieving A single study detected vanadium in 19 out of of the catalyst can lead to higher exposures, and results 120 canvasback ducks (Aythya valisineria) wintering in of between 0.01 and 1.9 mg/m3 (total inhalable vanadium) Louisiana, USA; the maximum concentration in duck have been obtained. Air-fed respiratory protective liver was 0.94 µg/g dry weight (Custer & Hohman, 1994). equipment is normally worn during catalyst removal and The mean vanadium concentration in four species of replacement and sieving. Japanese waterfowl ranged from 3.69 to 8.11 µg/g dry weight in kidney and from 0.39 to 3.69 µg/g in liver tissue Fewer than 200 workers in the United Kingdom are (Mochizuki et al., 1999). exposed to vanadium during the manufacture of ferrovanadium alloys and TiBAl rod. The limited 6.1.4 Soil exposure data available indicate exposures below the limit of detection of 0.01 mg/m3. No data have been At distances of 600–2400 m from a metallurgical found to quantify exposures during the manufacture of plant producing vanadium pentoxide, to a depth of TiBAl rod. 10 cm, the surface layer of the soil contained 18–136 mg vanadium/kg dry weight (Lener et al., 1998). The back- There are fewer than 50 workers who are exposed ground concentration for the area is not stated, although to vanadium compounds in the United Kingdom during levels at 600 m from the plant are clearly elevated com- the manufacture of vanadium-containing pigments for pared with those at greater distances. Concentrations in the ceramics industry. Exposure is controlled by the use soil globally are very variable. Schacklette et al. (1971) of local exhaust ventilation, and measured data indicate found concentrations in soils in the USA ranging from that levels are normally below 0.2 mg/m3 (total inhalable <7 to 500 mg/kg, with the median at around 60 mg/kg and fraction). the 90th percentile at 130 mg/kg. The average worldwide soil concentration is around 100 mg/kg (Hopkins et al., Occupational exposure data are also available from 1977). Finland, including personal monitoring data from a range of work processes in a vanadium refining plant (Kivilu- oto, 1981). Generally, two samples were taken per person over a 2-month period. The mean respirable fraction

12 Vanadium pentoxide and other inorganic vanadium compounds

Table 4: Biological monitoring studies of occupational vanadium exposure.

Sample Measured air V Urine V (µg/litre) Industry matrix No. of subjects (mg/m3) (TWA) (range) Reference

V2O5 production Urine 58 Up to 5 28.3 (3–762) Kucera et al., 1992

Boiler cleaning Urine 4 2.3–18.6 2–10.5 White et al., 1987 (0.1–6.3)

Incinerator workers Urine 43 Not known <0.1–2 Wrbitsky et al., 1995 Boiler cleaners Urine 10 (!RPE)a Not known 92 (20–270) Todaro et al., 1991 10 (+RPE) 38

Boiler cleaners Urine 30 0.04–88.7 (0.1–322) Smith et al., 1992

V alloy production Urine 5 Not known 3.6 (0.5–8.9) Arbouine, 1990

Pigment Urine 8 Not known 2.3 (0.8–6.3) Arbouine, 1990 manufacture

V2O5 staining Urine 2 (<0.04–0.13) <4–124 Kawai et al., 1989

Unexposed (general Urine 213 012 0.22 (0.07–0.5) Kucera et al., 1992 population) <0.4 White et al., 1987 <0.1 Smith, 1992 a RPE = respiratory protective equipment.

(particle size 5 µm or less) of the dust was 20%. The to a vanadium slag processing plant in the Czech highest values (expressed as total inhalable vanadium) Republic showed concentrations ranging from 0.01 to were obtained in the laboratory (range 0.25–4.7 mg/m3, 0.44 µg/litre; the local municipal supply contained mean shift length exposure 1.7 mg/m3) and the smelting 0.01 µg/litre (Lener et al., 1998). Groundwater in the room (0.055–0.47 mg/m3, mean 0.21 mg/m3), but were vicinity of Mount Fuji in Japan contains high vanadium usually much lower for other processes (around 0.002– levels from leaching of larval flows rich in the metal; 0.18 mg/m3, mean 0.005–0.037 mg/m3). measured concentrations in deep wells were between 89 and 147 µg/litre, levels higher than those measured in Biological monitoring studies of occupational spring water (Hamada, 1998). A sample of drinking-water vanadium exposure also indicate the magnitude of from Kanagawa Prefecture in Japan contained a airborne exposures (Table 4). A further recent example is vanadium concentration of 22.6 µg/litre, the highest detailed (Kucera et al., 1992, 1994, 1998; see also sections value in a survey of Japanese cities and 21 cities in the 7 and 9): a group of workers from the Czech Republic USA (Tsukamoto et al., 1990). The water here was involved in the manufacture of vanadium pentoxide from influenced by Mount Fuji groundwater. Groundwater in slag rich in vanadium for periods of 0.5–33 years (mean the region of Mount Etna in Sicily has been used as a duration of exposure 9.2 years) was exposed to airborne source of drinking-water. The western basin showed the vanadium concentrations of 0.016–4.8 mg/m3. Urinary highest levels of vanadium; 33% of samples had concen- vanadium content was 3.02–769 ng/ml, compared with trations between non-detectable and 20 µg/litre, 54% 0.066–53.4 ng/ml in controls. In blood, vanadium levels between 20 and 50 µg/litre, and 13% higher than 50 µg/li- were 3.1–217 ng/ml, compared with 0.032–0.095 ng/ml in tre (Giammanco et al., 1996). Older studies summarized in controls. The vanadium content in the hair of exposed IPCS (1988) report drinking-water concentrations up to and non-exposed persons was in the range of 0.103–203 70 µg/litre, although the majority of samples contained mg/kg and 0.009–3.03 mg/kg, respectively, and the less than 10 µg/litre, and in many the metal was vanadium content in the fingernails was in the range of undetectable. Levels in bottled waters from mineral 0.260–614 mg/kg and 0.017–16.5 mg/kg, respectively. springs may contain much higher levels of vanadium; Determinations of the vanadium content were carried out one study of bottled waters from Switzerland reported a by both radiochemical and instrumental neutron range of 4–290 µg/litre (Schlettwein-Gzell & Mommsen- activation analyses in all instances. Straub, 1973).

Estimates given in IPCS (1988) for total dietary The mean concentration of vanadium in cigarettes intake of the general population in food range from 11 to was 1.11 ± 0.35 µg/g, and the mean concentration in 30 µg/day (adults). The mean vanadium concentration in cigarette smoke was 0.33 ± 0.06 µg/g (Adachi et al., 1998). drinking-water in Cleveland, USA, was 5 µg/litre, with a maximum of 100 µg/litre (Strain et al., 1982). Wells close

13 Concise International Chemical Assessment Document 29

Following the major contamination of the marine Oral studies (Parker & Sharma, 1978; Conklin et al., environment with oil in the Gulf War, levels of vanadium 1982; Ramanadham et al., 1991; summarized by HSE, in in seafood (six species of fish and two species of shrimp) press) indicate that vanadium compounds are poorly were measured. Mean daily consumption of seafood by absorbed from the gastrointestinal tract (approximately people in five districts of Kuwait ranged from 0.15 to 1.16 3% of the administered dose). g seafood/kg body weight; the mean vanadium content of seafood edible tissues ranged from 0.48 to 1.48 µg/g No dermal studies are available. dry weight (Bu-Olayan & Al-Yakoob, 1998). Absorbed vanadium in either pentavalent or tetra- valent states is distributed mainly to the bone (around 10–25% of the administered dose 3 days after admin- 7. COMPARATIVE KINETICS AND istration) and to a lesser extent to the liver (about 5%), METABOLISM IN LABORATORY ANIMALS kidney (about 4%), and spleen (about 0.1%), while small AND HUMANS amounts are also detected in the testes (about 0.2%) (Sabbioni et al., 1978; Ramanadham et al., 1991; Sanchez et al., 1998; HSE, in press). Distribution studies in which rats received a total of approximately 224 and 415 mg Human exposure data suggest that vanadium (chemical form unknown) is absorbed following inhala- vanadium pentoxide/kgin drinking-water over a period of tion exposure to 0.03–0.77 mg vanadium/m3 and is sub- 1 and 2 months indicated that the vanadium content sequently excreted via the urine with an initial rapid (assessed in 13 specific tissues) was greatest in the phase of elimination, followed by a slower phase, which kidneys, spleen, tibia, and testes (Kucera et al., 1990). presumably reflects the gradual release of vanadium from Similar distribution was seen in a study conducted using body tissues (Kiviluoto et al., 1981a). vanadyl sulfate (tetravalent vanadium) (Kucera et al., 1990). Further evidence for the distribution of vanadium Following oral administration of 50–125 mg/day, to testes comes from genotoxicity studies in germ cells ammonium vanadyl tartrate (tetravalent vanadium) is (section 8.7) and reproductive studies (section 8.8). poorly absorbed from the gastrointestinal tract in The main route of vanadium excretion is via the humans (Dimond et al., 1963). Less than 1% of the administered dose was eliminated in the urine within the urine (HSE, in press). Following oral (drinking-water) first 24 h post-administration. No other information is administration of vanadyl sulfate (tetravalent vanadium), available in humans. the half-time for elimination via urine in rats was calcu- lated to be around 12 days (this is in contrast to the Groups of two rats were exposed to ammonium initial short half-time seen in humans, presumably metavanadate (pentavalent vanadium, median mass reflecting post-exposure clearance from the bloodstream, aerodynamic diameter [MMAD] 0.32 µm) at a concen- followed by a more gradual release from other body tration of 2 mg/m3 for 8 h/day for 4 days (Cohen et al., compartments). The pattern of vanadium distribution 1996b). There was a tendency for vanadium to accumu- and excretion indicates that there is potential for late in the lung; lung levels increased by around 44% accumulation and retention of absorbed vanadium, over the first 2 days, followed by an additional 10% on particularly in the bone. One oral study in which groups each of days 3 and 4. Twenty-four hours after the final of 22 pregnant mice received vanadyl sulfate exposure, lung vanadium levels decreased by about 39% pentahydrate at doses of 0, 38, 75, or 150 mg/kg body (from 27 to 17 µg/g lung). weight per day by oral gavage (Paternain et al., 1990) indicates that tetravalent vanadium has the ability to Intratracheal studies in animals (Oberg et al., 1978; cross the placental barrier to the fetus. Conklin et al., 1982; Rhoads & Sanders, 1985; Sharma et al., 1987) indicate that vanadium, from either vanadium pentoxide or other pentavalent and tetravalent vanadium compounds, is absorbed to a significant extent from the 8. EFFECTS ON LABORATORY lungs. Following intratracheal instillation of 40 µg MAMMALS AND IN VITRO TEST SYSTEMS vanadium pentoxide, 72% of the administered dose was absorbed from the lungs within 11 min (Rhoads & Sanders, 1985). The remaining 28% was absorbed over 2 Where data on vanadium pentoxide are lacking, days. Forty per cent of the administered dose was information on properties of other pentavalent or tetra- retained within the carcass after 14 days (12% in bones), valent vanadium compounds is utilized. There is no and 40% was eliminated via urine and faeces. Similar toxicological information on elemental vanadium and results were obtained by the other authors. negligible information on the trivalent forms.

14 Vanadium pentoxide and other inorganic vanadium compounds

In this section, reference is made to a review of the and decreased sensitivity to pain. At the highest doses toxicity of vanadium compounds (including vanadium (not clearly defined), intense diarrhoea, irregular res- pentoxide) by Sun (1987). However, it has not been piration, and increased cardiac rhythm and ataxia were possible to trace the majority of the primary references reported. The effects had mostly disappeared in sur- from which the review is constructed, and so it has not vivors at 48 h after treatment. No histopathology was been possible to perform a critical evaluation of the performed. quality of the information presented.

The MAK (1992) review cites rat oral LD50 values 8.1 Single exposure in the range 18–160 mg/kg body weight for ammonium metavanadate. No further details are available. 8.1.1 Vanadium pentoxide

An oral LD50 value of 75 mg/kg body weight in The one acute inhalation study available reported male mice was reported for sodium metavanadate (Llobet 3 an LC67 of 1.44 mg/litre (1440 mg/m ) following a 1-h & Domingo, 1984). No deaths were reported at 41 mg/kg exposure of rats to vanadium pentoxide dust (US EPA, body weight. Clinical signs of toxicity reported were the 1992). Additional inhalation data are cited in the MAK same as those seen in rats. (1992) review. Two out of four rabbits exposed to 205 mg/m3 for 2 h (30% of particles had a diameter less 8.1.3 Tetravalent vanadium compounds than 5 µm) died within 12–24 h. Clinical signs of toxicity included respiratory distress, “mucosal irritation” An oral LD50 value of 448 mg/kg body weight in (tissues unstated), and diarrhoea. male rats exposed to vanadyl sulfate pentahydrate was reported (Llobet & Domingo, 1984). No deaths were Further information relating to single inhalation reported at 296 mg/kg body weight. Signs of toxicity exposures is presented in section 8.3. No information on were similar to those reported following treatment with single exposures via the dermal route is available. sodium metavanadate, although to a lesser degree.

Oral studies in rats and mice demonstrate greater For mice, the oral LD50 value reported for vanadyl toxicity of vanadium as oxidation state increases. The sulfate pentahydrate was 467 mg/kg body weight (Llobet review by Sun (1987) cites a study by Yao et al. (1986b) & Domingo, 1984). No deaths were reported at 186 mg/kg in which rat oral LD50 values for vanadium pentoxide in body weight. Clinical signs of toxicity reported were the the range 86–137 mg/kg body weight are reported. same as those seen in rats. Clinical signs of toxicity included lethargic behaviour, lacrimation, and diarrhoea, and histological examination A study by Paternain et al. (1990) investigating revealed necrosis of liver cells and cloudy swelling of developmental toxicity in mice reported an LD50 for renal tubules. The dose–response characteristics of vanadyl sulfate pentahydrate of 450 mg/kg body weight. these effects were not described. 8.1.4 Trivalent vanadium compounds A further review of vanadium pentoxide cites oral

LD50 values of around 10 mg/kg body weight for rats and The MAK (1992) review cites a rat oral LD50 value 23 mg/kg body weight for mice (MAK, 1992). No further of 350 mg/kg body weight and a mouse LD50 value of details are available. around 23 mg/kg body weight for vanadium trichloride

and a mouse oral LD50 of 130 mg/kg body weight for For mice, oral LD50 values for vanadium pentoxide vanadium trioxide. No further details are available. were in the range 64–117 mg/kg body weight (Yao et al.,

1986b). Similarly, an oral LD50 of 64 mg/kg body weight 8.2 Irritation and sensitization for vanadium pentoxide administered to male rabbits was reported. For both rabbits and mice, the signs of toxicity No information is available from animal studies reported were the same as those observed in rats. with regard to the potential of vanadium compounds to induce skin or eye irritation. 8.1.2 Other pentavalent vanadium compounds The primate inhalation studies by Knecht et al. Groups of 10 male rats received aqueous sodium 1992 (see section 8.3) also included an unconventional metavanadate by gavage (Llobet & Domingo, 1984). The evaluation of skin sensitization; this investigation gave a

LD50 value reported was 98 mg/kg body weight. No negative response for immediate and delayed skin deaths were reported at 39 mg sodium metavanadate/kg reactions to vanadium only or in combination with a body weight. Clinical signs of toxicity reported were carrier protein. decreased locomotor activity, paralysis of the hind legs,

15 Concise International Chemical Assessment Document 29

8.3 Effects of inhaled vanadium the percentage rise in nitrogen at 25% vital capacity (VC; compounds on the respiratory tract 167% of baseline values), an indication of narrowing of the dependent, peripheral small airways. No significant Presumably owing to the serious nature and rapid changes were reported in forced vital capacity (FVC), onset of the respiratory effects that have been observed total lung capacity (TLC), or diffusion capacity for in humans in occupational settings (see also section 9), carbon monoxide (DL50), indicating the absence of the following series of single and repeated inhalation parenchymal dysfunction. However, although studies was conducted in an attempt to further elucidate statistically significant, the magnitude of the observed the possible mechanisms and dose–response relation- changes was small. ships. BAL analysis revealed statistically significant A study by Knecht et al. (1985) investigated increases in numbers of polymorphonuclear leukocytes pulmonary responses to inhaled vanadium pentoxide and decreases in mast cells following exposure to 5.0 mg dust and sodium vanadate aerosols (thought to contain vanadium pentoxide/m3. Numbers of macrophages and the polymeric vanadium species most likely to be present lymphocytes were unaltered by exposure. in the respiratory mucosa after inhalation of vanadium pentoxide) in a group of 16 cynomolgus monkeys. The Another study in monkeys by Knecht et al. (1992) study design attempted to simulate exposure patterns compared bronchial reactivity following challenge with and their consequences in humans. Animals were given vanadium pentoxide dust, both before and after sub- sequential exposures to 0, 19, and 39 mg vanadium/m3 in chronic exposure to vanadium pentoxide dust. Both the form of sodium vanadate aerosol (characteristics not before and after subchronic exposure, the animals reported) for 1 min, at 30-min intervals (duration unclear). underwent 6-h whole-body challenges with vanadium Two weeks later, the animals were exposed, whole body, pentoxide aerosol (stated to be “generally 1–5 micro- to 0.5 and then to 5.0 mg vanadium pentoxide dust/m3 metres”) at concentrations of 0.5 and 3.0 mg/m3 (0.28 and (0.28 and 2.8 mg vanadium/m3; particle size 0.59–0.61 µm) 1.68 mg vanadium/m3), separated by a 2-week interval. for 6 h, with a 1-week interval between the two Two weeks later, the animals were challenged with exposures. Pulmonary function was evaluated before methacholine to assess non-specific bronchial reactivity. any exposures began and then immediately after The subchronic exposure regime involved exposure to exposure to sodium vanadate and 18–21 h after exposure vanadium pentoxide 6 h/day, 5 days/week, for 26 weeks. to vanadium pentoxide. The reason for this pattern of Two vanadium pentoxide-exposed groups (n = 9 each) investigating was that experience in humans suggested received equal weekly exposures (concentration × time) that respiratory effects had appeared approximately 1 with different exposure profiles. One vanadium day after exposure to vanadium pentoxide; the pentoxide-exposed group received a constant pulmonary investigations made immediately after sodium concentration of 0.1 mg/m3 (0.06 mg vanadium/m3) for vanadate exposure were explained on the basis that it 3 days/week and an exposure at a constant was known that inhalation of soluble zinc salt can concentration of 1.1 mg/m3 (0.62 mg vanadium/m3) for 2 produce an immediate irritant response. Bronchoalveolar days/week. The other vanadium pentoxide-exposed lavage (BAL) was performed pre-exposure and following group received a constant daily concentration of 0.5 exposure to 5.0 mg vanadium pentoxide/m3. mg/m3. A control group (n = 8) received filtered, conditioned air. The animals were allowed a 2-week Evidence of slight impairment of pulmonary func- recovery period before being retested as before. tion was reported following the single 6-h inhalation of 5.0 mg vanadium pentoxide dust/m3, but not 0.5 mg/m3. Blood cytological and immunological analysis was This was based on statistically significant decreases in carried out before both sets of acute challenges with peak expiratory flow rate (PEFR; median 89% of baseline vanadium pentoxide. Pulmonary function testing was values), forced expiratory volume (FEV0.5; 95% of carried out pre-exposure, the day after each acute baseline values), and forced expiratory flow (FEF50; 92% challenge with vanadium pentoxide, and immediately of baseline values), these changes giving an indication after challenge with methacholine. BAL fluid was of airflow limitation in the large central airways; a statis- collected for cytological and immunological analysis tically significant decrease in FEF25 (77% of baseline before each series of challenges and after challenge with values), which gives an indication of airflow limitation in 3.0 mg/m3. the peripheral airways; and statistically significant increases in functional residual volume (FRV; 124% of Respiratory distress developed in three monkeys baseline values), residual volume (133% of baseline from the subchronic exposure group, which received the values), closing volume (127% of baseline values), and intermittent peaks of 1.1 mg vanadium pentoxide/m3, characterized by audible wheezing and coughing, which

16 Vanadium pentoxide and other inorganic vanadium compounds

occurred only on peak exposure days during the first few 8.4.1 Vanadium pentoxide weeks of exposure. Pre-subchronic exposure provocation challenges with vanadium pentoxide Short-term immunotoxicity studies are described produced statistically significant changes in average briefly in section 8.9.1. flow resistance (RL; mean, 103% and 114% of baseline values at 0.5 and 3.0 mg/m3, respectively) and FVC (96% 8.4.2 Other pentavalent vanadium compounds and 97% of baseline values, respectively) at both dose levels used, while statistically significant differences Groups of 10 male rats received 0, 5, 10, and 3 were observed only at 3.0 mg/m for FEF50/FVC (99% and 50 ppm (mg/litre) sodium metavanadate in drinking-water 87% of baseline values, respectively) and residual for 3 months, which corresponded to 0, 2.1, 4.2, and 21 volume (RV; 105% and 114% of baseline values, ppm vanadium. This intake was equivalent to about 0, respectively), which indicates an obstructive pattern of 0.3, 0.6, and 3 mg sodium metavanadate/kg body weight impaired pulmonary function. No statistically significant per day, assuming 350 g body weight and 20 ml/day change in dynamic compliance (CLdyn) was observed. water consumption (Domingo et al., 1985). Limited numbers of animals were selected for liver and renal At the second challenge, after subchronic expo- function tests and organ weight analysis (liver, kidneys, sure, the pattern of findings was similar to that from the heart, spleen, and lungs only). Histological examination first challenge, but none of the changes was statistically was performed on only three animals of each group. significantly different from baseline values, nor was there any statistically significant difference between the There was no effect on weight gain, consumption controls, the “peak” exposure group, or the “constant” of water, urine volume, or urinary protein levels during group. Large, statistically significant increases in RL and the treatment period. No significant difference was

FEF50/FVC were observed following challenge with reported in the relative organ weights of the groups. methacholine, but this reactivity was not significantly Plasma concentrations of urea, uric acid, and creatinine increased following subchronic exposure to vanadium were reported to be within the normal range for all pentoxide. groups of animals, except in 50 ppm animals, in which urea and uric acid values were significantly greater than A significant increase in the total number of in concurrent controls. No effect on liver function was respiratory cells in BAL fluid was observed following apparent from the results. Dose-dependent histological pre-subchronic exposure challenge with 3.0 mg vana- changes, including hypertrophy and hyperplasia in the dium pentoxide/m3. The increase in the total number of white pulp of spleen, corticomedullary microhaemor- cells occurred through a highly significant increase in rhagic foci in kidneys, and mononuclear cell infiltration, the number of neutrophils (393% of baseline values). mostly perivascular, in lungs, were apparent in all treated The number of eosinophils recovered from the lung was animals. Hence, no no-observed-adverse-effect level also increased (170% of baseline values), while the (NOAEL) could be derived from this study, although numbers of lymphocytes, macrophages, and mast cells changes at the lowest exposure level were considered by were not. Significant challenge responses were not the authors to be minimal. observed for total protein, albumin, leukotriene C4, or the immunoglobulins IgG and IgE, despite the significant Groups of eight male rats were administered 0 or cellular response to vanadium pentoxide challenge. A about 9.7 mg vanadium/kg body weight per day as similar pattern of cellular and immunological response ammonium metavanadate via the drinking-water for was observed after subchronic exposure. Post-exposure 12 weeks (Dai et al., 1995). Before the start of the study challenge responses for neutrophils were greater than and at weeks 1, 2, 4, 8, and 12 following vanadium treat- 400% of baseline values. A post-exposure trend ment, haematological indices (haematocrit, haemoglobin (statistically significant for eosinophils) towards concentration, erythrocyte count, leukocyte count, decreased responses was observed in the vanadium platelet count, reticulocyte count, and erythrocyte pentoxide-exposed groups as compared with the control osmotic fragility) of the peripheral blood were investi- group. The number of circulating neutrophils and gated in all animals. There were no other investigations. eosinophils in venous blood was not affected by sub- No difference in food intake or body weight was appar- chronic vanadium pentoxide exposure. Similarly, serum ent between the groups. There were no differences in immunoglobulins were unchanged throughout the haematological parameters between the groups. study. Groups of 15–16 male and female rats were admin- 8.4 Other short-term exposure studies istered 0, 1.5, or 5–6 mg vanadium/kg body weight per day as ammonium metavanadate in drinking-water for Oral studies are described below; no dermal 4 weeks (Zaporowska et al., 1993). No differences in studies are available.

17 Concise International Chemical Assessment Document 29

external appearance or locomotor behaviour were the reduction in total distance travelled could have been reported between the groups. Body weight increase in related to other factors such as palatability that may the treated groups was lower than in control animals, but have affected behaviour and movement. Also, given the this was not dose-related. Slight, but statistically signif- extremely limited range of observations, substantial icant, decreases in erythrocyte number and haemoglobin interindividual variation, and absence of histopathology, concentration (top dose only, all about 10% less than it is impossible to draw any firm conclusions from this control) were observed. Similarly, a slight but statis- study. tically significant decrease in haematocrit was reported in treated males (mean value was 98% of controls). No Short-term immunotoxicity studies are described significant differences in leukocyte numbers were briefly in section 8.9.2. reported between the groups. No clinically significant changes in biochemical parameters were reported. 8.4.3 Tetravalent vanadium compounds Overall, the changes were slight. As previously described for sodium metavanadate Groups of 12–13 male and female Wistar rats were (section 8.4.2), Dai et al. (1995) also investigated the administered 0 or about 13 mg ammonium metavanadate/ potential effect of 7.7 mg vanadium/kg body weight per kg body weight per day in drinking-water for 4 weeks day as vanadyl sulfate (+4) and 9.2 mg vanadium/kg (Zaporowska & Wasilewski, 1992). Investigations body weight per day in the form of bis(maltolato)oxo- included water and food consumption, body weight, and vanadium (+4) on haematological parameters. No a range of haematological parameters; there were no difference in food intake or body weight was apparent further investigations conducted. between the groups (control and vanadium in valency states +4 and +5). There were no differences in haema- There was a marked decrease in water consumption tological parameters between the groups. with concomitant decreases in food consumption and body weight gain. Although there were statistically Short-term immunotoxicity studies are described significant reductions in some of the haematological briefly in section 8.9.3. parameters measured (as above), it is impossible to draw any conclusions regarding the toxicological significance 8.5 Medium-term exposure due to the limited study design and confounding due to impaired water consumption (which may have been 8.5.1 Vanadium pentoxide and other related to unpalatability). pentavalent vanadium compounds

Groups of 12 male Sprague-Dawley rats received 0, Medium-term oral and dermal exposures to 4, 8, or 16 mg aqueous sodium metavanadate/kg body vanadium pentoxide have not been studied. weight per day by oral gavage for 8 weeks (Sanchez et al., 1998). Investigations were limited to body weight, Groups of six male rats received 0, 10, or 40 µg/ml open field activity, avoidance of electrical stimulus as sodium metavanadate (about 0, 0.6, or 2.4 mg/kg body (recorded over a 3-week period, starting after the 8-week weight per day, assuming 20 ml water consumed per day treatment period), and a limited range of tissues removed and 350 g body weight) in drinking-water for 210 days for analysis of vanadium content (see section 7). (Boscolo et al., 1994). In the second experiment, groups of six male rats received 0 or 1 µg sodium Reduced body weight gain was noted only at metavanadate/ml (approximately 0.06 mg/kg body weight 16 mg/kg body weight per day (20% lower than per day using the same assumptions) in drinking-water controls). There was no observable effect on rearing for 180 days. Investigations included urinalysis, counts. However, a statistically significant reduction in haemodynamic measurements, and histopathology. total distance travelled in the open field activity investigation (recorded 3 weeks after cessation of No treatment-related effect on cardiovascular treatment only) was recorded in the first 5 min at 8 and 16 function was reported. Histopathological investigation mg/kg body weight per day, but not at 5–10 or 10– showed no change in the brain, liver, lungs, heart, or 15 min. Decreased avoidance compared with controls blood vessels of treated animals. An increase (5 times was noted among all vanadium-exposed animals over greater than controls) in urinary kininase I (measured to 3 consecutive days, although there was no clear dose– assess arterial hypertension) and II (twice control response relationship and no indication of other results values) activities was reported in treated rats at 40 µg/ml, for the 3-week testing period. Hence, this would seem to although the significance of this is unclear. No effect be a rather selective presentation of results. There was was reported on urinary excretion of creatinine, total no discussion of whether or not the transient nature of nitrogen, protein, or sodium. Urinary potassium decreased with dose, whereas urinary calcium was

18 Vanadium pentoxide and other inorganic vanadium compounds

reduced at 10 µg/ml only. Again, this study did not 8.7.1.2 Other pentavalent vanadium compounds reveal any clearly toxicologically significant changes attributable to vanadium exposure. There are no data available.

8.5.2 Tetravalent vanadium compounds 8.7.1.3 Tetravalent vanadium compounds

There are no data available. There are no data available.

8.6 Long-term exposure and 8.7.1.4 Trivalent vanadium compounds carcinogenicity One Ames test has been performed with vanadium 8.6.1 Vanadium pentoxide and other (+3) trichloride. Negative results were obtained, in the pentavalent vanadium compounds presence and absence of metabolic activation, at concen- trations between 1 and 200 µg/plate with Salmonella Long-term oral and dermal exposures to vanadium typhimurium strains TA98, TA100, TA1535, TA1537, pentoxide and other pentavalent vanadium compounds and TA1538 and Escherichia coli WP2uvrA (JETOC, have not been studied. 1996).

In a study conducted by Yao et al. (1986a) and 8.7.2 In vitro studies in eukaryotes cited by Sun (1987), groups of 62–84 male and female mice were exposed to 0, 0.5, 2, or 8 mg vanadium 8.7.2.1 Vanadium pentoxide pentoxide dust/m3 (particle size not reported) for 4 h/day for 1 year. “Papillomatous and adenomatous tumours” in Vanadium pentoxide was added, at concentrations the lungs were reported in 2 of 79 and 3 of 62 mice at 2 of 0, 2, 4, and 6 µg/ml (0, 1, 2, and 3 µg vanadium/ml), in and 8 mg/m3, respectively. No tumours were reported in replicate experiments, to cultures of human lymphocytes controls or at 0.5 mg/m3. No further information is (Roldan & Altamirano, 1990). Cells were incubated in the available. absence of metabolic activation with vanadium pentoxide for 48 h. A minimum of 100 well-spread first- 8.6.2 Tetravalent vanadium compounds division metaphases were analysed for structural and numerical aberrations (polyploid only). Long-term inhalation and dermal exposures to tetravalent vanadium compounds have not been studied. Mitotic index was statistically significantly decreased (74, 41, and 42% of control value at 2, 4, and 6 As part of a study related to the investigation of µg/ml, respectively). The frequency of structural chro- diabetes, groups of 8–23 male Wistar rats received mosome aberrations did not increase in the presence of approximately 0, 34, 54, or 90 mg vanadyl sulfate/kg body vanadium pentoxide. However, a statistically significant weight per day in drinking-water for up to 52 weeks (Dai increase in the frequency of polyploid cells was reported & McNeill, 1994; Dai et al., 1994a,b). Investigations were at all dose levels, which did not show a clear dose– extensive and included blood biochemistry, response relationship (4/226, 10/224, 8/200, and 10/218, haematology, blood pressure and pulse rate, respectively). This study also reported a dose-related ophthalmoscopy, organ weights, and microscopic increase in the number of cells with “satellite associa- pathology. The only adverse effect observed was tions” (a tendency for satellite-bearing chromosomes to reduced body weight gain (around 33% reduction at lie side by side, with their satellite regions facing each 90 mg/kg body weight per day and 10% at 34 and other). This finding, along with the induction of poly- 54 mg/kg body weight per day). ploidy, is indicative of vanadium pentoxide exerting its effects at the level of spindle formation. 8.7 Genotoxicity and related end-points The potential of vanadium pentoxide exposure to 8.7.1 Studies in prokaryotes induce micronuclei and centromere-positive micronuclei in vitro was investigated in Chinese hamster V79 cells, in 8.7.1.1 Vanadium pentoxide the absence of metabolic activation (Zhong et al., 1994). Studies of cytotoxicity were performed in cells exposed Only very limited data are available (see section to concentrations of vanadium pentoxide up to 12 µg/ml 8.7.7). (6.7 µg vanadium/ml) for 24 h. In each group, the numbers of mononucleated and binucleated cells per 1000 cells were determined for cell cycle kinetics. The investigation of centromere-positive micronuclei was

19 Concise International Chemical Assessment Document 29

performed in cells cultured with vanadium pentoxide Significant increases were reported in the numbers concentrations of 0, 1, 2, or 3 µg/ml (0, 0.6, 1.1, or 2.2 µg of chromosome aberrations (excluding gaps) induced vanadium/ml) for 24 h. Binucleated cells were scored and compared with solvent control values in both the numbers of micronuclei determined. presence and absence (up to 8 times controls in each case) of metabolic activation. The positive controls gave Cytotoxic effects of vanadium pentoxide, as appropriate responses. defined by a reduced number of binucleated cells, were apparent at all doses. A dose-related, statistically Migliore et al. (1993) investigated the potential of significant increase in micronucleus induction was three pentavalent vanadium compounds — sodium reported at all vanadium dose levels tested (2.4, 4.2, 6.2, metavanadate, ammonium metavanadate, and sodium and 7.6% of cells, for solvent control, 1, 2, and 3 µg/ml, orthovanadate — to induce micronuclei in human respectively). This dose–response relationship was also lymphocytes in vitro. The aneugenic potential was observed in the numbers of centromere-positive micro- investigated using fluorescence in situ hybridization nuclei (49, 70, 82, and 89% of micronuclei, respectively). (FISH), the number of micronuclei with fluorescent spots (centromere-positive micronuclei) being reported. The Induction of gene mutation at the HPRT locus was final concentrations tested were 0 and 2.5–160 µmol/litre investigated following exposure of Chinese hamster V79 (approximately 0 and 0.13–8.0 µg vanadium/ml) in all cells, in the absence of metabolic activation, to 0, 1, 2, 3, experiments, apart from the study involving in situ or 4 µg vanadium pentoxide/ml (0, 0.6, 1.1, 1.7, or 2.2 µg hybridization, where only 0, 10, 40, and 80 µmol/litre vanadium/ml) for 24 h (Zhong et al., 1994). No significant (approximately 0, 0.5, 2.1, and 4.2 µg vanadium/ml) were increase in the frequency of gene mutation was reported used. Cells were incubated with the test substances for following treatment with vanadium pentoxide. 48 h. Two thousand binucleated cells (when possible), 100 clear first metaphases, and 25 clear second 8.7.2.2 Other pentavalent vanadium compounds metaphases were analysed for micronuclei.

Human lymphocyte cells were incubated in the The highest dose of vanadium used, 160 µmol/litre, absence of metabolic activation for 24 h with sodium was found to be toxic to the cells in all studies. metavanadate, ammonium metavanadate, and sodium Ammonium metavanadate (up to 6% at the highest orthovanadate at concentrations of 0, 2.5, 5, 10, 20, 40, dose), sodium metavanadate (up to 4.6% at the highest 80, or 160 µmol/litre (approximately 0, 0.13–8.0 µg dose), and sodium orthovanadate (up to 2.4% at the vanadium/ml), and the induction of structural and highest dose) all induced a dose-related, statistically numerical chromosome aberrations was investigated significant number of micronuclei at 10 µmol/litre and (Migliore et al., 1993). above, although the increases were in general relatively small. Dose-related decreases in the number of The highest dose of vanadium compounds used, binucleated cells were also reported for all compounds, 160 µmol/litre, was found to be toxic to the cells in all which could be due to general toxicity or specific studies. There was no significant difference in the inhibition of cell cytokinesis. A dose-related increase in incidences of chromosome aberrations (excluding gaps, the number of micronuclei was reported in the cells used although the nature of the aberrations was not defined) for the FISH technique, although the increases were, as induced by any of the three compounds, for any of the before, relatively small. Statistically significant increases dose levels used. A statistically significant number of in the numbers of centromere-positive micronuclei were hypoploid cells (missing chromosomes) was reported at reported at all dose levels for all the compounds, which all doses following treatment with sodium metavanadate were comparable with the positive control values. and sodium orthovanadate and at the top two doses with ammonium metavanadate. No significant increases The ability of ammonium metavanadate to induce in the numbers of hyperploid or polyploid cells were mutations, with exogenous metabolic activation, at the reported. HPRT locus in V79 cells in Chinese hamster ovary was investigated using concentrations of 0, 5, 10, 20, 25, 40, Chinese hamster ovary cells were exposed to 0, 4, and 50 µmol/litre (Cohen et al., 1992). No treatment- 8, or 16 µg ammonium metavanadate/ml (0, 1.7, 3.3, or 6.7 related increase in mutation frequency was reported, µg vanadium/ml) for 2 h in the presence and absence of with testing up to cytotoxic concentrations of ammonium metabolic activation, and then for a further 22 h in fresh metavanadate. medium (Owusu-Yaw et al., 1990). At least 100 metaphases per flask were scored for chromosome Ammonium metavanadate induced both mitotic aberrations (experiment carried out in duplicate). gene conversion and reverse point mutation in the D7 strain of Saccharomyces cerevisiae at dose levels of

20 Vanadium pentoxide and other inorganic vanadium compounds

between 80 and 210 mmol/litre in both the presence and sulfate/litre in both the presence and absence of meta- absence of metabolic activation (Bronzetti et al., 1990). bolic activation (Galli et al., 1991).

Cell transformation and gap junctional intercellular Vanadyl chloride did not produce an increased communication were assessed in Syrian hamster embryo incidence of transformations in the C3H10T1/2 mouse cells exposed to 0, 0.2, 0.4, 1.9, 2.3, or 6.9 µmol sodium fibroblast cell line at dose levels up to 5 µg/ml (Doran et orthovanadate/litre (Rivedal et al., 1990; Kerckaert et al., al., 1998). 1996). A marked increase in cell transformation was noted only at the highest concentration, although there 8.7.2.4 Trivalent vanadium compounds were no effects on cloning efficiency, indicating a positive result for genotoxicity in this system. There was Using protocols similar to that previously ascribed no observed effect on gap junctional intercellular to these authors, Chinese hamster ovary cells were communication. exposed to 12 or 18 µg vanadium oxide/ml (8.2 or 12.2 µg vanadium/ml) (Owusu-Yaw et al., 1990). Significant 8.7.2.3 Tetravalent vanadium compounds increases in induction of chromosome aberrations were reported in both the presence (up to 4 times controls) Migliore et al. (1993) also investigated the ability of and absence (up to 6 times controls) of metabolic vanadyl sulfate to induce structural and numerical activation. chromosome aberrations in human lymphocytes in the absence of exogenous metabolic activation. No signifi- 8.7.3 Sister chromatid exchange cant difference in the incidence of chromosome aberra- tions (excluding gaps) was induced. A statistically Vanadium pentoxide did not increase incidences of significant number of hypoploid cells was reported at the sister chromatid exchange, while studies with other top three doses (20–80 µmol/litre). pentavalent, tetravalent, and trivalent compounds did, in a number of different cell systems, over a range of con- Owusu-Yaw et al. (1990) also exposed Chinese centrations (0.3–19.2 µg/ml) (Owusu-Yaw et al., 1990; hamster ovary cells to 6, 12, or 24 µg vanadyl sulfate/ml Roldan & Altamirano, 1990; Migliore et al., 1993; Zhong (1.9, 3.7, or 7.4 µg vanadium/ml) for investigation of et al., 1994). chromosome aberrations. Significant increases in induction of chromosome aberrations were reported in 8.7.4 Other in vitro studies both the presence (up to 6 times controls) and absence (up to 13 times controls) of metabolic activation. 8.7.4.1 Vanadium pentoxide

Migliore et al. (1993) also investigated the potential A study by Rojas et al. (1996) investigated the of vanadyl sulfate to induce micronuclei in human induction of DNA strand breaks in human lymphocytes lymphocytes. Dose-related decreases in the number of by vanadium pentoxide using the Comet assay. At dose binucleated cells were also reported, although these levels of 0.5, 5.5, and 546 µg vanadium pentoxide/ml, a were less pronounced than those observed with statistically significant increase in DNA migration was pentavalent vanadium compounds. A dose-related, reported, indicating the DNA-damaging potential of statistically significant increase in the number of vanadium pentoxide. There was no cytotoxicity detected. micronuclei was reported at 10 µmol/litre and above, although the increases were in general relatively small. 8.7.4.2 Other pentavalent vanadium compounds Statistically significant increases in the numbers of centromere-positive micronuclei were reported at all dose Chinese hamster V79 cells and human leukaemic T- levels. lymphocyte (MOLT4) cells were exposed to ammonium metavanadate to investigate the formation of Vanadyl sulfate induced no convertants or rever- DNA–protein cross-links (Cohen et al., 1992). Dose- tants in the D7 strain of S. cerevisiae at dose levels of related increases in cross-links were reported following between 420 and 1000 mmol/litre in both the presence 24-h exposure to ammonium metavanadate in both cell and absence of metabolic activation (Galli et al., 1991). types. Also, no mutagenic activity was detected in hamster V79 cells at dose levels between 0 and 7.5 mmol/litre in both Ammonium vanadate gave positive results in a the presence and absence of metabolic activation. transformation assay in BALB/3T3 mouse embryo cells at doses of 5 and 10 µmol/litre (Sabbioni et al., 1993). No mutagenic activity was detected in hamster V79 cells at dose levels between 0 and 7.5 mmol vanadyl

21 Concise International Chemical Assessment Document 29

8.6.4.3 Tetravalent vanadium compounds Polychromatic erythrocyte/normochromatic erythrocyte (PCE/NCE) ratios were lower in the test Vanadyl sulfate gave negative results in a trans- animals (down to 50% of control values at some time formation assay in BALB/3T3 mouse embryo cells at points), indicating that the vanadium compounds had doses of 5 and 10 µmol/litre (Sabbioni et al., 1993). For reached the bone marrow and expressed cytotoxicity. this study and the above-mentioned work on ammonium Compared with negative controls, there was a small but metavanadate by these authors (section 8.7.4.2), cyto- statistically significant increase (at least twice control toxicity, as evidenced by about a 50% reduction in values) in the percentage of PCEs with micronuclei for colony-forming efficiency compared with controls, was sodium orthovanadate at 24, 30, and 48 h and with seen at a concentration of 5 µmol/litre. ammonium metavanadate at 18, 24, and 30 h.

8.7.5 In vivo studies in eukaryotes (somatic 8.7.5.3 Tetravalent vanadium compounds cells) Ciranni et al. (1995) also investigated the ability of 8.7.5.1 Vanadium pentoxide vanadyl sulfate to induce chromosome aberration and aneuploidy in the bone marrow of male mice. Male mice Only very limited data are available (see section were administered a single dose, intragastrically, of 0 or 8.7.7). 100 mg vanadyl sulfate/kg body weight (0 or 31 mg vana- dium/kg body weight). A statistically significant increase Other pentavalent vanadium compounds 8.7.5.2 in the number of aberrant cells (excluding gaps) was found at 24 and 36 h (4.3 and 2.7%, respectively, com- Ciranni et al. (1995) investigated the ability of pared with 0.6% in negative controls). Statistically sig- sodium orthovanadate and ammonium metavanadate to nificant increases in cells with hypoploidy were reported induce chromosome aberration and aneuploidy in the following treatment at both sampling times and in cells bone marrow of male mice. Male mice (three per with hyperploidy 24 h post-treatment. No significant experimental group or four per control group) were induction of polyploidy was reported. administered a single dose, intragastrically, of either 0 or 75 mg sodium orthovanadate/kg body weight (21 mg Groups of male mice were administered a single vanadium/kg body weight) or 50 mg ammonium meta- dose of 0 or 100 mg vanadyl sulfate/kg body weight (0 or vanadate/kg body weight (42 mg vanadium/kg body 31 mg vanadium/kg body weight) intragastrically weight) dissolved in sterile water. Groups of animals (Ciranni et al., 1995). There was a small but statistically were sacrificed at 24 and 36 h post-dose. significant increase (at least twice control values) in the percentage of PCEs with micronuclei at 6, 12, 18, 24, 30, Although increases in chromosome aberrations 36, and 48 h. were reported after 36 h with sodium orthovanadate and ammonium metavanadate, these were not statistically 8.7.6 In vivo studies in eukaryotes (germ cells) significant. No increases were seen at 24 h. Clear and statistically significant increases in cells with 8.7.6.1 Vanadium pentoxide hypoploidy and with hyperploidy were apparent at one or both sampling times with both vanadium compounds. As part of a larger study (not performed to current Statistically significant, dose-related increases in cells standard Organisation for Economic Co-operation and with hypoploidy were reported following treatment with Development [OECD] guidelines) to investigate other sodium orthovanadate and ammonium metavanadate. reproductive and genotoxic end-points, a dominant Statistically significant increases in cells with hyper- lethal-type assay was reported by Altamirano-Lozano et ploidy were reported 24 h post-treatment with sodium al. (1996). On the basis of deaths reported following orthovanadate and at both 24 and 36 h post-treatment repeated administration of 17 mg vanadium pentoxide/kg with ammonium metavanadate. No significant induction body weight by intraperitoneal injection in a previous of polyploidy was reported. study by the same authors, male mice (15–20 per group) received 0 or 8.5 mg vanadium pentoxide/kg body weight Groups of 3–4 male mice were administered a single in saline by intraperitoneal injection every third day for dose, intragastrically, of either 0 or 75 mg sodium 60 days. From day 61, each male had five overnight orthovanadate/kg body weight (21 mg vanadium/kg matings with two untreated females, and successful body weight) or 50 mg ammonium metavanadate/kg copulation was determined by the presence of a copula- body weight (42 mg vanadium/kg body weight) tion plug or sperm in the vagina. dissolved in sterile water (Ciranni et al., 1995). Bone marrow cells were sampled at 6, 12, 18, 24, 30, 36, 42, 48, A statistically significantly reduced body weight in and 72 h post-treatment and assessed for induction of treated animals at the end of the treatment period was micronuclei.

22 Vanadium pentoxide and other inorganic vanadium compounds

reported (79% of control value). The study did not refer pentoxide was tested at concentrations of 0, 10, 50, 100, to any other signs of toxicity in male mice. Whereas 34 of 500, 1000, and 2000 µg/plate in both the presence and 40 (85%) of the females mated with controls became absence of S9. A highly significant, dose-related pregnant, the rate for the treated group was 33% (10/30). increase in the number of revertants was reported at 10, There was a statistically significant reduction in implan- 50, and 100 µg/plate in strains WP2, WP2uvrA, and tation sites per dam for the treatment groups compared CM891 in both the presence and absence of S9. Above with controls (10.9 and 5.8 in the control and treated these dose levels, vanadium pentoxide produced groups, respectively). A statistically significant increase toxicity. No significant increase was reported in strains in the number of resorptions per litter (0.2 and 2.0 in the ND-160 and MR 102. control and treated groups, respectively) and a statis- tically significant reduction in the number of live fetuses Vanadium pentoxide did not increase incidences of per litter (10.5 and 3.4 in the control and treated groups, sister chromatid exchange in vitro over a range of con- respectively) were apparent in the vanadium pentoxide centrations (0.3–30 µg/ml) (Sun, undated). group. There was no statistically significant difference in the numbers of dead fetuses per litter. Post-implantation Bone marrow micronucleus tests on vanadium loss (number of dead fetuses per number of liveborn pentoxide via the intraperitoneal, subcutaneous, inhala- pups) was approximately 10 times greater in the treatment tion, and oral routes in mice are briefly reported (Si et al., group than in controls (0.41 and 0.04, respectively). 1982; Yang et al., 1986b,c; Sun et al., undated). A statistically significant increase (approximately doubled) Given that vanadium pentoxide is poorly absorbed in the frequency of micronucleus formation was reported following oral exposure and well absorbed and widely at all dose levels in mice administered 0, 0.2 (or 0.7), 2, or distributed when inhaled, the use of the intraperitoneal 6 mg vanadium pentoxide/kg body weight intra- route in this assay is considered a valid surrogate for peritoneally daily for 5 days. A positive result was also relevant exposure routes in this instance. Overall, while reported in mice following subcutaneous administration this study is of limited quality in view of the non- of 0.25, 1.0, or 4.0 mg vanadium pentoxide/kg body standard protocol, poor reporting, and clearly reduced weight, 6 days/week, for 5 weeks, although no further pregnancy rate in females mated with treated males, the details were provided. An increase in the frequency of clear increases in resorptions per litter and post- micronuclei was reported following exposure of mice to implantation losses in the vanadium pentoxide group are 0, 0.5, 2.0, or 8.0 mg vanadium pentoxide dust/m3 (no indicative of a dominant lethal effect. details of dust characteristics given). No increase in induction of micronuclei was reported in mice orally 8.7.6.2 Other pentavalent and tetravalent vanadium administered 1, 3, 6, or 11 mg vanadium pentoxide/kg compounds body weight in a 3% starch suspension for 6 weeks.

There are no data available. 8.8 Reproductive toxicity

8.7.7 Supporting data 8.8.1 Effects on fertility

The following studies cited in a review prepared by 8.8.1.1 Vanadium pentoxide and other pentavalent Sun (1987) have been included here as they provide vanadium compounds further supporting evidence of genotoxic activity of vanadium pentoxide. However, no firm conclusions can No fertility studies are available on vanadium be drawn from the results due to the limited reporting. pentoxide.

An Ames test using S. typhimurium strains TA98, Groups of 24 male mice received sodium meta- TA100, TA1535, TA1537, and TA1538 is briefly reported vanadate in drinking-water for 64 days at concentrations (Si et al., 1982). Vanadium pentoxide at 0, 50, 100, and 200 of 0, 20, 40, 60, or 80 mg/kg body weight per day (Llobet µg/plate was tested in both the absence and presence of et al., 1993). At the end of the exposure period, each S9 mix. The numbers of induced revertants at all test group was divided into two subgroups: a group of levels were less than 2-fold greater than control 8 animals for a mating trial and a group of 16 animals for numbers; hence, vanadium pentoxide gave a negative pathology and sperm examinations (utilizing postmortem result under the conditions of the test. samples). In the fertility study, each male was mated with two untreated females for 4 days. The females were In an E. coli reversion assay using strains WP2, sacrificed 10 days after the end of the mating period and WP2uvrA, CM891 (base pair substitutions), ND-160, and their uterine contents examined. MR 102 (frameshift mutations) (Si et al., 1982), vanadium

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A 13% reduction in male body weight was appar- Statistically significant decreases in maternal body ent in the 80 mg/kg body weight group, compared with weight gain were reported in animals of the 9 and the controls, immediately after the exposure period. 18 mg/kg body weight groups (75% and 40% of control Decreases relative to the controls in the number of values, respectively). No treatment-related increases in pregnant females were reported in some of the vana- the numbers of resorptions or dead fetuses were dium-treated group, but no dose–response relationship observed, although the results were not reported on a was observed. No information was given on mating per litter basis. Fetal body weight, body length, and tail behaviour. There were no significant differences length were all statistically significantly decreased in the between the groups regarding the numbers of implan- top dose group (87%, 92%, and 94% of control values, tations, early or late resorptions, or dead or live fetuses. respectively). In males, no significant differences were observed in testes weights. Absolute epididymis weight was reduced Delayed occipital ossification (top-dose animals) at 80 mg/kg body weight (88% of control value), and non-ossification or delayed ossification of the although no difference was observed in relative weight, sternum (all dose groups) were reported; however, these reflecting the reduced body weight in animals of this results were not given on a per litter basis, and so their dose group. A significant 30% reduction in spermatid significance is unclear. It was also observed that skeletal count was reported at 80 mg/kg body weight, and a abnormalities were statistically significantly increased in significant decrease in spermatozoal count was reported the top two dose groups, but again these findings were at 60 and 80 mg/kg body weight, although this was not not reported on a per litter basis. No visceral abnormal- clearly dose-related (99%, 104%, 56%, and 69% of ities were reported. control values in the 20, 40, 60, and 80 mg/kg body weight groups, respectively). There were no significant Although the reported increase in skeletal abnor- differences in sperm motility or sperm abnormalities malities at 18 mg/kg body weight is a concern, inter- between the groups. No histopathological changes were pretation is hindered by the evidence of significant reported between the groups. maternal toxicity. Furthermore, bearing in mind the nature of the abnormalities seen and data not having been This study suggests the possibility that oral expo- related to the litter as a unit, no decision can be made sure of male mice to sodium metavanadate at 60 and regarding the reliability of the reported findings. 80 mg/kg body weight directly caused a decrease in spermatid/spermatozoal count and in the number of 8.8.2.2 Other pentavalent vanadium compounds pregnancies produced in subsequent matings. However, the results are not convincing, and significant general Groups of 20 mated, presumed pregnant, rats were toxicity, reflected in decreased body weight gain, was administered 0, 5, 10, or 20 mg sodium metavanadate/kg also evident at 80 mg/kg body weight. Overall, the body weight (0, 2.1, 4.2, and 8.4 mg vanadium/kg body results do not provide convincing evidence that oral weight) in distilled water, intragastrically, on days 6–14 exposure to sodium metavanadate produced specific of gestation (Paternain et al., 1987). The fetuses were fertility effects in this study. removed on day 20 by caesarean section.

8.8.1.2 Tetravalent vanadium compounds No information regarding maternal toxicity was reported. The numbers of litters produced were 14, 14, No data are available. 12, and 8 at 0, 5, 10, and 20 mg/kg body weight, respec- tively. There was no statistical difference in the numbers 8.8.2 Developmental toxicity per litter of corpora lutea, implantations, resorptions, or live fetuses between the groups. A non-dose-related 8.8.2.1 Vanadium pentoxide increase in the number of abnormal fetuses was reported. No visceral or skeletal abnormalities were reported. Groups of 18–21 pregnant Wistar rats received 0, 1, Although fetal dermal haemorrhage (haematoma) in the 3, 9, or 18 mg vanadium pentoxide/kg body weight per facial area, dorsal area, thorax, and extremities was day in vegetable oil by oral gavage on days 6–15 of reported, this is a common background finding in gestation (Yang et al., 1986a). Animals were sacrificed on developmental toxicology studies and is not considered day 20 of gestation and the uterine contents examined. to be an indicator of specific developmental toxicity. The numbers of implantations, resorptions, and live and Hydrocephaly was reported in 2 of 98 fetuses at dead fetuses were recorded. Fetuses were examined for 20 mg/kg body weight compared with none in other gross anomalies, and fetal body weight and length were groups. No significant difference was reported for fetal measured. One-third were subsequently examined for body weight or body length. Overall, there is no clear visceral abnormalities, and two-thirds for skeletal evidence of direct developmental toxicity following abnormalities. exposure to sodium metavanadate.

24 Vanadium pentoxide and other inorganic vanadium compounds

Groups of 18–20 pregnant mice were administered 150 mg/kg body weight (4 fetuses in 3 litters and 0, 7.5, 15, 30, or 60 mg sodium orthovanadate/kg body 58 fetuses in 12 litters, respectively) and micrognathia weight (0, 2.1, 4.2, 8.3, or 16.6 mg vanadium/kg body at 37.5, 75, and 150 mg/kg body weight (2 fetuses in weight) in deionized water by oral gavage on days 6–15 1 litter, 3 fetuses in 1 litter, and 12 fetuses in 3 litters, of pregnancy (Sanchez et al., 1991). The animals were respectively). The only visceral abnormality reported sacrificed on day 18 of pregnancy. was hydrocephaly at 75 and 150 mg/kg body weight (2 fetuses in 2 litters and 4 fetuses in 3 litters, respec- Severe maternal toxicity resulted from the dosing tively). Delayed ossification was reported in all groups, with 30 and 60 mg/kg body weight (4/18 and 17/19 dams, including controls. respectively, died as a result of treatment). The two remaining dams at 60 mg/kg body weight were not The effects on fetal development (cleft palate, included in the final evaluation. Body weight gain was micrognathia, hydrocephaly) reported in this study significantly reduced (approximately 20%) at 15 mg/kg occurred in the presence of significant maternal toxicity body weight. However, no significant difference was as defined by decreased body weight gain. It is possible reported at the end of the study. No differences were that the fetal effects were secondary to maternal toxicity. reported in final body weight, gravid uterine weight, or Unfortunately, the study did not include a dose level at corrected body weight. There were no differences in the which there was no maternal toxicity. number of total implants per dam, number of live fetuses per dam, sex ratio, average fetal body weight, or the A number of other studies have been reported in number of stunted fetuses. There were also no differ- which vanadium compounds have been administered via ences between the groups in the incidences of skeletal intraperitoneal, subcutaneous, and intravenous routes or visceral abnormalities. There was some evidence of (Carlton et al., 1982; Wide, 1984; Sun, 1987; Zhang et al., delayed ossification at 30 mg/kg body weight; this is 1991, 1993a,b; Gomez et al., 1992; Bosque et al., 1993). considered to be a secondary consequence of the Effects were observed on the developing fetus, pronounced maternal toxicity produced at this dose including (but not in every report) increased skeletal level. Overall, sodium orthovanadate did not produce abnormalities, increased numbers of resorbed/dead developmental toxicity in this thorough investigation. fetuses, increased incidences of delayed ossification, and decreased fetal body weight and length. However, 8.8.2.3 Tetravalent vanadium compounds given the routes of exposure used, no conclusion can be drawn from these studies in relation to the potential Groups of 22 pregnant mice were administered developmental toxicity of vanadium compounds in vanadyl sulfate pentahydrate at 0, 37.5, 75, or 150 mg/kg humans exposed occupationally. body weight per day by gavage on days 6–15 of gesta- tion (Paternain et al., 1990). The animals were sacrificed 8.9 Immunological and neurological on day 18 of gestation. Three fetuses from each dam effects were used for whole-body analyses of vanadium. After external examination, one-third of the remaining fetuses 8.9.1 Vanadium pentoxide were examined for visceral abnormalities and the rest for skeletal abnormalities. Groups of 6–8 female rats received a solution of 0, 0.042, or 0.42 mg vanadium pentoxide in phosphate- Over the study period, there was a dose-related buffered saline by single intratracheal administration decrease in body weight gain down to 62% of control (Pierce et al., 1996). Cells were collected by BAL and values at 150 mg/kg body weight, with no corresponding subsequently lysed for RNA isolation. Hybridization difference in food consumption. Final body weights were studies were conducted to determine the expression of significantly reduced (81%, 83%, and 80% of controls, cytokines. BAL indicated a significant, dose-related respectively), and corrected body weights, minus the influx of neutrophils in the lungs, and the Northern blot gravid uterine weight, were also significantly reduced analysis demonstrated increased mRNA expression of (88%, 84%, and 83% of controls, respectively). There macrophage inflammatory protein-2 and another cyto- were no differences in the mean numbers of total kine, KC. The results demonstrate an inflammatory implants per dam, live fetuses per dam, late resorptions response in the lungs associated with exposure to per dam, or dead fetuses per dam. Fetal body weight was vanadium pentoxide. significantly reduced at all dose levels (87%, 87%, and 79% of control values, respectively), as was fetal body Groups of 10 male Wistar rats received vanadium length (97%, 85%, and 82% of control values, respec- pentoxide in drinking-water for a period of 6 months at tively). The major dose-related effects externally were concentrations of 0, 1, or 100 mg vanadium/litre. Simi- increased incidence of cleft palate (an abnormality with a larly, 10 male and 10 female ICR mice were given 0 or significant background incidence in mice) at 75 and

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6 mg vanadium pentoxide/kg body weight by gavage, (Pierce et al., 1996). Procedures were as with the work on 5 days/week for 6 weeks. The study focused on vanadium pentoxide (section 8.9.1). assessing the immunotoxicity of vanadium and recorded the weight of the spleen and thymus, spleen cellularity, Results were similar to those obtained with vana- leukocyte count in peripheral blood, indicators of non- dium pentoxide, but occurred earlier and lasted longer. specific immunity (phagocytosis, natural killer cell The results demonstrate an inflammatory response, more activity), and humoral as well as cell-mediated immunity potent than with vanadium pentoxide, associated with (Mravcova et al., 1993). exposure to sodium metavanadate.

The study demonstrated an enlargement of the There are no data specifically relating to neuro- spleen in rats exposed to vanadium at a concentration of logical end-points. 100 mg/litre, the same finding as in mice, although with diminished spleen cellularity in mice. Thymus weight 8.9.3 Tetravalent vanadium compounds was not influenced. The leukocyte count in peripheral blood was increased significantly in both rats and mice. As part of the study summarized above (sections In rats and mice, a decrease in phagocytosis, which was 8.9.1 and 8.9.2), groups of 6–8 female rats received a dose-dependent in rats, was found. In exposed mice, solution of 0, 0.021, or 0.21 mg vanadyl sulfate in there appeared signs of intense response to mitogens phosphate-buffered saline by single intratracheal and high stimulation of B-cells in the plaque-forming administration (Pierce et al., 1996). Procedures were as cells assay. Activation of T- and B-cells and the with the work on vanadium pentoxide (section 8.9.1). magnitude of the response to concanavalin A indicate potential vanadium-related hypersensitivity. Results were similar to those obtained with vana- dium pentoxide, but occurred earlier and lasted longer There are no data specifically relating to neuro- than with either vanadium pentoxide or sodium meta- logical end-points. vanadate, indicating that, in this assay, this substance was the most potent in an inflammatory response. 8.9.2 Other pentavalent vanadium compounds There are no data specifically relating to neuro- Male rats (numbers not given) were exposed nose logical end-points. only 8 h/day for 4 days to atmospheres containing either filtered air or approximately 2 mg vanadium/m3 in the form of ammonium metavanadate aerosol (0.32 µm MMAD) (Cohen et al., 1996a,b). Twenty-four hours after 9. EFFECTS ON HUMANS the final exposure, BAL was performed on the rats. Cells gathered in this process were used to assess the effects of vanadium on tumour necrosis factor alpha (TNF-") 9.1 Studies on volunteers production, radical oxygen ion production, interferon-(- induced Class II/I-A antigen expression, and phagocytic 9.1.1 Vanadium pentoxide activity. Nine healthy volunteers were exposed to vanadium There was no significant difference in the numbers pentoxide dust (98% <5 µm) in an exposure chamber of alveolar macrophages in the BAL fluid taken from (Zenz & Berg, 1967). Each subject underwent a complete exposed and control animals. Induced production of physical evaluation, chest X-ray, haematological and TNF-" by these macrophages was decreased following urine analysis, and pulmonary function tests prior to and vanadium exposure, as was the ability to increase cell immediately after exposure.Two volunteers were exposed surface Class II/I-A antigen expression induced by to 0.1 mg/m3 for 8 h. No symptoms occurred during or interferon-(. The ability of the macrophages to produce immediately after exposure. Within 24 h, considerable radical oxygen anions in response to stimulation was mucus had formed. This was easily cleared by slight also reduced following vanadium exposure. The report coughing, increased after 48 h, subsided within 72 h, and suggests that vanadium exposure could alter host completely disappeared after 4 days. Five volunteers immunocompetence through an inhibitory effect on were exposed to 0.25 mg/m3 for 8 h. All developed a macrophage function. loose, productive cough the following morning. All subjects had stopped coughing by the tenth day. Groups of 6–8 female rats received a solution of 0, Physical examination revealed nothing of clinical 0.021, or 0.21 mg sodium metavanadate in phosphate- significance, and pulmonary function tests showed no buffered saline by single intratracheal administration change compared with pre-exposure values. Two volunteers were exposed to 1 mg vanadium pentoxide

26 Vanadium pentoxide and other inorganic vanadium compounds

dust/m3 for 8 h. Sporadic coughing developed after 5 h, abdominal pain, anorexia, nausea, and weight loss. and more frequent coughing developed by the end of These symptoms improved when dosing was stopped or the 7th hour. Persistent cough remained for 8 days. reduced. Five men developed “green tongue” and one Chest examinations revealed clear lung fields, and no other pharyngitis with marginal ulceration of the tongue. differences were reported in pulmonary function tests performed before, immediately after, or once weekly for A group of six subjects was administered 50– 3 weeks after exposure. Three weeks after the initial 125 mg ammonium vanadyl tartrate/day orally for 45– exposure, the same volunteers were accidentally exposed 94 days (Dimond et al., 1963). No haematological or to a heavy cloud of vanadium pentoxide dust (unknown biochemical indication of toxicity and no effect on concentration) for a 5-min period while waiting for circulating lipids were reported. There were no other another test, resulting in marked coughing (which per- investigations conducted. sisted for about 1 week), production of sputum, rales, and expiratory wheezes. Pulmonary function was alleged 9.2 Clinical and epidemiological studies to be normal, although the reliability of this claim is for occupational exposure considered doubtful in view of the severity of the clinical observations. 9.2.1 Vanadium pentoxide

9.1.2 Other pentavalent vanadium compounds Eye irritation has been reported in studies in vana- dium workers (see Lewis, 1959; Zenz et al., 1962; Lees, Five male medical students received an oral 1980; Musk & Tees, 1982). Patch testing in workforces administration of 100 or 125 mg diammonium oxy- has produced two isolated reactions, although no skin tartratovanadate/day (approximately 1.7 mg/kg body irritation was reported in 100 human volunteers following weight per day, assuming 70 kg body weight) for skin patch testing with 10% vanadium pentoxide in 6 weeks (Curran et al., 1959). No overt evidence of petrolatum. The underlying reason for the skin toxicity was reported in any of the men. No change in responses in workers is unclear (Motolese et al., 1993). complete blood counts, including platelets, routine urinalyses, blood urea nitrogen, blood glucose, serum Zenz et al. (1962) reported on 18 workers exposed cholesterol esters, serum alkaline phosphatase, serum to varying degrees to vanadium pentoxide dust (mean transaminase, or serum bilirubin was reported particle size <5 µm) in excess of 0.5 mg/m3 (apparently throughout the study. No further investigations were measured over a 24-h period) during a pelletizing conducted. process. Three of the most heavily exposed men devel- oped symptoms, including sore throat and dry cough. 9.1.3 Tetravalent vanadium compounds Examination of each on the third day revealed markedly inflamed throats and signs of intense persistent Vanadyl sulfate is apparently used by some coughing, but no evidence of wheezing or rales. The weight-training athletes in an attempt to improve three men also reported “burning eyes,” and physical performance, as it has been claimed to lower blood examination revealed slight conjunctivitis. Upon cholesterol levels. A double-blind trial by Fawcett et al. resumption of work after a 3-day exposure-free period, (1996, 1997) investigated the effects of administration of the symptoms returned within 0.5–4 h, with greater vanadyl sulfate on haematological indices, blood intensity than before, despite the use of respiratory viscosity, and biochemistry in weight-training athletes. protective equipment. After 2 weeks of the process, all 18 The treatment group (11 males; 4 females) was orally workers, including those primarily assigned to office and administered 0.5 mg/kg body weight per day for 12 laboratory duties, developed symptoms and signs of weeks, and a control group (12 males; 4 females) received varying degrees, including nasopharyngitis, hacking placebo capsules. At the end of the study, there were no cough, and wheezing. This study confirms that significant differences between the groups in terms of vanadium pentoxide exposure can produce respiratory body weight, blood pressure, standard haematological and also eye irritation. indices, blood viscosity, or standard blood biochemistry measurements. Lees (1980) reported signs of respiratory irritation (cough, respiratory wheeze, sore throat, rhinitis, and A group of 12 volunteers received 75 mg diammo- nosebleed) and eye irritation in a group of 17 boiler nium vanadotartrate/day orally for 2 weeks, followed by cleaners. However, as there was no control group and it 125 mg/day for the remaining 5.5 months (Somerville & was unclear whether other compounds were present, no Davies, 1962). Two subjects withdrew due to “toxic conclusions can be drawn regarding the cause or signifi- gastrointestinal effects.” cance of these symptoms. However, the findings are compatible with other studies on inhalation of vanadium There was no significant effect on serum choles- pentoxide. terol levels. However, five patients had persistent upper

27 Concise International Chemical Assessment Document 29

A study by Kiviluoto (1980), using a respiratory controls), injection (i.e., hyperaemia) of the pharynx and questionnaire, chest radiography, and tests of nasal mucosa in 41.5% (4.4% in controls), and “green ventilatory function (FVC and FEV1), investigated 63 tongue” in 37.5% (0% in controls). men who had worked at a factory refining vanadium pentoxide from magnetite ore for at least 4 months. It is not clear what levels or duration of exposure These men were matched for age and smoking habit with were experienced by the workers who presented with 63 workers at a magnetite ore mine in the same area, symptoms. However, the findings reinforce the picture of presumably not exposed or negligibly exposed to exposure to vanadium pentoxide causing eye and vanadium pentoxide. respiratory tract effects.

Overall, on the basis of pulmonary function tests A group of 69 workers in the Czech Republic was and a questionnaire of respiratory symptomatology, exposed for periods ranging from 0.5 to 33 years (mean there were no indications of vanadium-induced ill-health duration of exposure 9.2 years) in the manufacture of in this workforce. vanadium pentoxide from slag rich in vanadium (Kucera et al., 1994). The concentration of vanadium in the A further study, in which haematological and ambient air at the work sites was 0.016–4.8 mg/m3. For biochemical analyses were performed, is reported in the comparison, a group of 33 adult subjects not exposed to same group of workers as above by Kiviluoto et al. vanadium was investigated to assess the influence of (1981b). All the haematological results were within such exposure. The authors stated that there were no reference values, and there were no statistical differences symptoms of adverse health effects related to vanadium between the groups. Although there were significant reported in the workers, although it was unclear what differences between control and exposed groups in investigations had been conducted to support this serum concentrations of albumin, chloride ions, bilirubin, assertion. conjugated bilirubin, and urea, these were not clinically significant, as the magnitude of change was small, Huang et al. (1989) conducted a clinical and radio- subject to interindividual variation, and liable to have logical investigation of 76 workers in a ferrovanadium arisen by chance. works, who had worked in the plant between 2 and 28 years. In the exposed group, out of 71 examined, 89% Levy et al. (1984) studied respiratory tract irritation had a cough (10% in controls), expectoration was seen in in a group of 74 boilermakers. Vanadium pentoxide fume 53% (15% in controls), 38% were short of breath (0% in in air was measured from various parts of the boiler and controls), and 44% had respiratory harshness or dry ranged between 0.05 and 5.3 mg/m3 (time period of sibilant rale (0% in controls). Of 66 of the exposed group measurement not stated). The boilermakers worked examined, hyposmia or anosmia was reported in 23% (5% 10 h/day, 6 days/week, and reported symptoms after in controls), congested nasal mucosa in 80% (13% in only a couple of days. controls), erosion or ulceration of the nasal septum in 9% (0% in controls), and perforation of the nasal septum The incidence of respiratory tract symptomatology in 1 subject (0 in controls). Chest X-rays of all 76 was high, a finding that is compatible with other studies exposed subjects revealed 68% with increased, coars- on inhalation of vanadium pentoxide. However, it is ened, and contorted bronchovascular shadowing (23% difficult to draw firm conclusions from this study due to in controls). the potential for mixed exposures to have occurred (e.g., especially sulfur dioxide, but also chromium, nickel, While exposure to vanadium compounds may have copper, iron oxide, and carbon monoxide), and also no contributed to the clinical findings and symptoms control group was utilized for comparison. reported, no firm conclusion can be drawn from this study in this regard, as mixed exposures are likely to A study by Lewis (1959) investigated 24 men have occurred, including possibly to hexavalent chro- exposed to vanadium pentoxide for at least 6 months mium used in alloy production or chromium plating from two different centres. These were age-matched with (some of the effects described, particularly nasal septum 45 control subjects from the same areas. The level of perforation, are consistent with chromium toxicity). exposure to vanadium pentoxide was between 0.2 and 0.92 mg/m3 (0.11 and 0.52 mg vanadium/m3; time period of The case histories of four men were reported by measurement not stated). In the exposed group, 62.5% Musk & Tees (1982). One worker was exposed to large complained of eye, nose, and throat irritation (6.6% in amounts of dry ammonium vanadate dust over a 6-h control), 83.4% had a cough (33.3% in control), 41.5% period while shovelling powder into a bin. Within 2 h of produced sputum (13.3% in control), and 16.6% com- commencing work, retro-orbital headache, epiphora plained of wheezing (0% in control). Physical findings (tears), dry mouth, and green discoloration of the tongue included wheezes, rales, or rhonchi in 20.8% (0% in

28 Vanadium pentoxide and other inorganic vanadium compounds

were reported. There was a marked green discoloration of A link between workers exposed to vanadium and the skin of the fingers (despite the use of gloves), asthma/bronchial hyperresponsiveness has been claimed scrotum, and upper legs. His nose was reported to be (Irsigler et al., 1999). However, less than 1% of workers stuffy, and he was lethargic. The next day, his testicles showed bronchial hyperresponsiveness. Although it were swollen and tender, and, on the third day after was reported that some of these worked in a part of the exposure, he developed wheezing, dyspnoea, and a factory with the highest vanadium exposures, it is cough productive of green sputum. He had several small unclear how many other men also worked there but were haemoptyses over the following 2 weeks. Wheezing and unaffected by exposure. Indeed, details of the numbers dyspnoea persisted for about 1 month; chest symptoms of men in various parts of the factory were not given. were at their worst 3 weeks after the incident. On Also, the previous medical histories of the affected men examination 6 weeks after the last exposure, he was are unclear. There does not appear to be a comparison asymptomatic, with the exception of a partially blocked with a suitably matched control group. Thus, no mean- left nostril and the reddened appearance of nasal ingful conclusions can be drawn from this study. mucosa. Chest examination revealed no abnormality. Pulmonary function assessment showed normal lung 9.2.2 Tetravalent vanadium compounds volume, forced expiratory flow rate, and gas transfer. He had a mild eosinophilia of the peripheral blood. There are no data available.

The other three workers also reported broadly 9.3 Epidemiological studies for general similar findings (e.g., green discoloration of the tongue population exposure and skin, respiratory difficulties) associated with exposure to vanadium pentoxide. Early correlational studies relating general concen- trations of vanadium in the environment to mortality In a further study of workers exposed to vanadium figures are summarized in IPCS (1988); no cause–effect pentoxide, one worker exposed to up to 0.1 mg/m3 for relationships can be established from these studies, 30 min/day on a regular basis displayed the which give conflicting results. A single epidemiological characteristic “green tongue” associated with vanadium study, where individual exposure could be assessed, has exposure (Kawai et al., 1989). This effect was not been conducted of general population exposure to dusts observed in the two other workers regularly working generated by a plant processing vanadium-rich slag. It is with vanadium pentoxide (albeit at much lower levels). estimated that an area with a radius of 3 km was exposed The limited number of samples and people in this study to the dust from a plant in Mnisek in the Czech Republic; precluded any assessment of a dose–response the population in this area was 4850. The study concen- relationship for “green tongue.” trated on children aged between 10 and 12 years, with sampling conducted over 2 years. Venous blood, saliva, A similar, but slight, impairment of pulmonary hair, and fingernail clippings were collected from the function (FEV1 reduced by less than 4%) was observed children. Dust aerosol, ambient air, soil, and drinking- over a 4-week work period in a prospective study of a water were analysed from the local environment. Health group of 26 boilermakers with personal exposures to status was assessed based on haematological around 0.0016–0.032 mg/m3 “vanadium” (form unspec- parameters (blood cell and platelet counts, haematocrit, ified) (Hauser et al., 1995). However, no firm conclusions mean corpuscular volume, and haemoglobin), specific can be drawn owing to the mixed exposures that were immunity (IgA, IgE, IgG, secretory IgA, IgM, transferrin, likely to have been encountered and the small magnitude "-1-antitrypsin, $-2-microglobulin), cellular immunity of the reported change. There was also a lack of (phagocytosis of peripheral leukocytes, stimulation of T- exposure–response relationship. lymphocyte mitogenic activity), cytogenic analysis (frequency of chromosome aberrations in peripheral Similarly, green tongue and irritation of the upper lymphocytes, sister chromatid exchange), and serum respiratory tract were reported in a group of 10 boiler lipids (cholesterol, triglycerides). Children from the maintenance workers (Todaro et al., 1991). Urinary exposed groups had lower red blood cell counts than vanadium levels were recorded, but there was no report- controls, a decrease in levels of serum and secretory ing of air monitoring values or indication of other IgA, and a seasonal decrease in IgG. Marked differences substances that may have been present. A small range of between groups were seen in natural cell-mediated blood biochemistry parameters was recorded for up to immunity, with significantly higher mitotic activity of T- 2 years after a change in the work (which presumably led lymphocytes in children from the immediate vicinity of to reduced exposure), but no changes were observed. the plant. A higher incidence of viral and bacterial Overall, no useful conclusions can be drawn from this infections was registered in children from the exposed study. locality. However, the study could not control for

29 Concise International Chemical Assessment Document 29

confounding by exposures to compounds other than Stendahl & Sprague (1982) reported weight- vanadium. Cytogenetic analysis revealed no genotoxic adjusted 7-day LC50s ranging from 1.9 to 6 mg vanadium/ effects. Vanadium levels in hair were elevated in children litre in tests at various levels of total hardness (30, 100, living close to the plant. In another group living farther and 355 mg/litre) and pH (5.5–8.8). Toxicity decreased away, those with parent(s) working at the plant had from low to high hardness by an average factor of 1.8. higher levels in hair than those whose parent(s) did not, Toxicity was greatest at pH 7.7, and the predominating – indicating exposure in the home from dust transferred on ion H2VO4 was apparently the most toxic one. working clothes (Kucera et al., 1992). The overall conclusion reached was that long-term exposure to Hilton & Bettger (1988) fed juvenile rainbow trout vanadium had no negative impact on health; differences (Oncorhynchus mykiss) a diet containing sodium ortho- observed were within the range of normal values in all vanadate at concentrations ranging from 10.2 to 8960 mg cases (Lener et al., 1998). vanadium/kg diet for 12 weeks. All levels of supple- mented vanadium significantly reduced growth and feeding response in the trout. Feed avoidance and significantly increased mortality were reported at 10. EFFECTS ON OTHER ORGANISMS IN >493 mg/kg diet. THE LABORATORY AND FIELD 10.2 Terrestrial environment

10.1 Aquatic environment Cannon (1963) reported detrimental effects on plants at aqueous vanadium concentrations of 10– The toxicity of vanadium to aquatic organisms is 20 mg/litre; however, higher concentrations can be summarized in Table 5. tolerated by legumes that use vanadium in the nitrogen fixation process. In six of seven lakes studied, the addition of vanadium at concentrations in the 2–165 ×10–7 mol/litre The growth of flax and cabbage was reduced at a range decreased photosynthetic rates of phytoplankton. vanadium concentration of 0.5 mg/litre (nutrient solu- Simple correlation analysis revealed that only biomass tion), especially under conditions of low iron and phos- and proportion of cyanobacteria were significantly phorus (Warington, 1954; Hara et al., 1976). correlated (P < 0.05) with the response to vanadium. The authors concluded that lakes characterized by high Vanadium can induce iron deficiency chlorosis phytoplankton biomass, high proportion of cyano- (Cannon, 1963) and affect trace element nutrition bacteria, and low proportion of Bacillariophyta and (Warington, 1954; Wallace et al., 1977). Hewitt (1953) Chrysophyta are most vulnerable to inhibition of found that 5 mg vanadium/litre in hydroponic medium photosynthesis by vanadium (Nalewajko et al., 1995). caused iron deficiency chlorosis in sugar beet plants, and growth was reduced by 30–50%. Ringelband & Karbe (1996) found that population growth in the brackish water hydroid Cordylophora In soil, the concentration of vanadium causing caspia was significantly impaired at 2 mg vanadium/litre toxic effects in plants may range between 10 and over a 10-day exposure period. 1300 mg/kg, depending on plant species, the form of vanadium, and soil type (Hopkins et al., 1977). Kaplan et Fichet & Miramand (1998) observed a significant al. (1990) found that vanadium concentrations of reduction in the development of normal oyster (Crassos- 80 mg/kg caused significant reductions in Brassica trea gigas) larvae exposed to 0.05 mg vanadium/litre for biomass in sandy soil; however, concentrations of up to 48 h. A significant reduction in pluteus development in 100 mg/kg had no effect in loamy sand. The differential urchin (Paracentrotus lividus) larvae was found at response was attributed to greater accumulation of 0.1 mg/litre, but not at 0.05 mg/litre, over the same time vanadium by plants grown in sand. Similarly, significant period. In 8-day exposures, significant mortality was reductions in dry matter yield of shoots and roots of observed in brine shrimp (Artemia salina) larvae at soybean were observed at 30 mg/kg in fluvo-aquic soil, 0.25 mg/litre. whereas no effect was found at 75 mg/kg in oxisols derived from red sandstones in China (Wang & Liu, Van der Hoeven (1991) found a 21-day no- 1999). observed-effect concentration (NOEC), based on off- spring production in Daphnia magna, of 1.13 mg vanadium/litre.

30 Vanadium pentoxide and other inorganic vanadium compounds

Table 5: Toxicity of vanadium compounds to aquatic organisms.

Organism End-point Concentration (mg/litre) Reference Marine algae

Green alga Dunaliella marina 15-day LC50 0.5 Miramand & Ünsal, 1978

Marine diatom

Diatom Asterionella japonica 15-day LC50 2 Miramand & Ünsal, 1978

Freshwater invertebrates

Water flea Daphnia magna 48-h LC50 3.1 Allen et al., 1995

48-h LC50 4.1 Beusen & Neven, 1987

23-day LC50 2 Beusen & Neven, 1987

Naidid oligochaete Pristina leidyi 48-h LC50 30.8 Smith et al., 1991

Marine invertebrates

Hydroid Cordylophora caspia 10-day LC50 5.8 Ringelband & Karbe, 1996

Worm Nereis diversicolor 9-day LC50 10 Miramand & Ünsal, 1978

Mussel Mytilus galloprovincialis 9-day LC50 35 Miramand & Ünsal, 1978

Crab Carcinus maenus 9-day LC50 65 Miramand & Ünsal, 1978

Brine shrimp Artemia salina (larvae) 9-day LC50 0.2–0.3 Miramand & Fowler, 1998

Sea urchin Arbaccia lixula (pluteus) 72-h LC100 0.5 Miramand & Fowler, 1998

Freshwater fish

Rainbow trout Oncorhynchus mykiss 96-h LC50 6.4–22 Giles et al., 1979

(juvenile) 96-h LC50 11.4 Giles & Klaverkamp, 1982

(eyed egg) 96-h LC50 118 Giles & Klaverkamp, 1982

96-h LC50 5.2–13.2 Stendahl & Sprague, 1982

7-day LC50 2.4–5.6 Sprague et al., 1978

11-day LC50 1.99 Sprague et al., 1978

14-day LC50 1.95 Giles et al., 1979

Chinook salmon Oncorhynchus tshawytscha 96-h LC50 16.5 Hamilton & Buhl, 1990

Brook trout Salvelinus fontinalis 96-h LC50 7–24 Ernst & Garside, 1987

Flag fish Jordanella floridae (adult) 96-h LC50 11.2 Holdway & Sprague, 1979

(larvae) 28-day LC50 1.1–1.9 Holdway & Sprague, 1979

Colorado squawfish Ptychocheilus lucius (fry) 96-h LC50 7.8 Hamilton, 1995

(juvenile) 96-h LC50 3.8–4.3 Hamilton, 1995

Razorback sucker Xyrauchen texanus (fry) 96-h LC50 8.8 Hamilton, 1995

(juvenile) 96-h LC50 3.0–4.0 Hamilton, 1995

Bonytail Gila elegans (fry) 96-h LC50 5.3 Hamilton, 1995

(juvenile) 96-h LC50 2.2–5.1 Hamilton, 1995

Flannelmouth sucker Catostomus latipinnis 96-h LC50 11.5 Hamilton & Buhl, 1997 (larvae)

Goldfish Carassius auratus 144-h LC50 2.5–8.1 Knudtson, 1979

Guppy Poecilia reticulata 96-h LC50 8 Beusen & Neven, 1987

144-h LC50 0.4–1.1 Knudtson, 1979

Zebrafish Brachydanio rerio 96-h LC50 4 Beusen & Neven, 1987

Freshwater teleost Nuria denricus 96-h LC50 2.6 Abbasi, 1998

Marine fish

Dab Limanda limanda 96-h LC50 27.8 Taylor et al., 1985

31 Concise International Chemical Assessment Document 29

11. EFFECTS EVALUATION to pentavalent vanadium compounds have been investigated or reported in animals and humans. The data are of variable quality. No studies are available on 11.1 Evaluation of health effects tetravalent forms of vanadium.

11.1.1 Hazard identification and dose–response Inhalation studies in primates reported changes in assessment pulmonary function and inflammatory cell parameters following a 6-h exposure to 3 or 5 mg vanadium pentox- In animals, pentavalent vanadium has been shown ide aerosol/m3 (1.7 or 2.8 mg vanadium/m3). Subchronic to accumulate in the lung following repeated exposure. exposure did not lead to an exacerbation of this acute There is information suggesting that inorganic vanadium responsivity or to a cellular immune response as mea- compounds are absorbed following inhalation and sured in BAL fluid and also in serum. Furthermore, subsequently excreted via the urine with an initial rapid subchronic exposure to up to 0.5 mg/m3 (0.28 mg phase of elimination, followed by a slower phase, which vanadium/m3) did not enhance bronchial reactivity to presumably reflects the gradual release of vanadium from vanadium pentoxide or methacholine. Respiratory body tissues. distress developed in three animals from a group of nine exposed to the intermittent peaks of 1.1 mg vanadium Oral studies indicate that vanadium compounds pentoxide/m3 (0.62 mg/m3 vanadium) for 2 days/week. are poorly absorbed from the gastrointestinal tract. No A concentration of 1.0 mg vanadium pentoxide/m3 dermal studies are available. (0.56 mg vanadium/m3) did not produce respiratory tract toxicity in rats and mice following exposure for 6 h/day, 5 Absorbed vanadium in either pentavalent or days/week, for 13 weeks. At 2 mg vanadium pentoxide/ tetravalent states is distributed mainly to the bone, liver, m3 (1 mg vanadium/m3) and above, dose-related toxicity kidney, and spleen, and it is also detected in the testes. to the respiratory tract has been observed in rodents, The main route of vanadium excretion is via the urine. including hyperplasia and metaplasia of the respiratory The pattern of vanadium distribution and excretion epithelium and lung fibrosis and inflammation. indicates that there is potential for accumulation and retention of absorbed vanadium, particularly in the bone. A study in human volunteers showed that a single One oral study indicates that tetravalent vanadium has 8-h exposure to 0.1 mg vanadium pentoxide dust/m3 the ability to cross the placental barrier to the fetus. leads to delayed but prolonged bronchial effects involv- ing excessive production of mucus. The mechanism 3 3 An LC67 of 1440 mg/m (800 mg vanadium/m ) has underlying this response is uncertain, as no subjective been reported following 1-h inhalation exposure of rats irritant symptoms were reported during exposure. At 0.25 to vanadium pentoxide dust. Oral studies in rats and mg/m3, a similar pattern of response was seen, with the mice produced LD50 values in the range 10–160 mg/kg addition of cough for some days post-exposure. Expo- body weight (6–90 mg/kg body weight as vanadium) for sure to 1.0 mg/m3 produced persistent and prolonged vanadium pentoxide and other pentavalent vanadium coughing after 5 h. A no-effect level for bronchial effects compounds, whereas tetravalent vanadium compounds was not identified in this study. have LD50 values in the range 448–467 mg/kg body weight (90–94 mg/kg body weight as vanadium). No The workplace studies available lack information information is available concerning dermal toxicity. on the nature and extent of past occupational exposure and provide only limited information on exposures at the Eye irritation has been reported in studies in time of the study. There is the likelihood that mixed vanadium workers. Patch testing in workforces has exposures may have occurred, although the appearance produced two isolated reactions. No skin irritation was of green coloration of the tongue indicates that exposure reported in 100 human volunteers following skin patch to vanadium pentoxide is likely. The generally poor- testing with 10% vanadium pentoxide. No information is quality data available indicate that repeated inhalation available from animal studies with regard to the potential exposure to the dust and fume of vanadium pentoxide is of vanadium compounds to produce skin or eye irrita- associated with irritation of the eyes, nose, and throat. tion. Overall, the potential for vanadium and vanadium Wheeze and dyspnoea are commonly reported in work- compounds to produce skin irritation on direct contact is ers exposed to vanadium pentoxide dust and fume. unclear. No conventional animal skin sensitization Overall, there are insufficient data to reliably describe the studies have been reported. exposure–response relationship for the respiratory effects of vanadium pentoxide dust and fume in humans. The effects on the respiratory tract of single and repeated inhalation exposure (and combinations thereof)

32 Vanadium pentoxide and other inorganic vanadium compounds

Oral studies involving repeated exposure, although The potential for vanadium compounds to exert of poor quality, are available for both pentavalent and effects on fertility has been very poorly investigated. A tetravalent forms of vanadium in both humans and fertility study in male mice involving exposure to sodium animals, although vanadium pentoxide has not been metavanadate in drinking-water suggests the possibility studied. No dermal studies are available, although it is that oral exposure of male mice to sodium metavanadate not expected that vanadium will be absorbed across the at 60 and 80 mg/kg body weight directly caused a skin to any significant extent. The limitations of the decrease in spermatid/spermatozoal count and in the repeated oral dosing studies are such that it is not pos- number of pregnancies produced in subsequent matings. sible to characterize a dose–response relationship for the However, significant general toxicity, reflected in toxicity of any form of vanadium in animals or in decreased body weight gain, was also evident at humans; one study in rats produced evidence of spleen 80 mg/kg body weight. and kidney toxicity with a drinking-water intake of 2.1 ppm (mg/litre) vanadium and above, as sodium There are a number of developmental studies on metavanadate. pentavalent and tetravalent vanadium compounds, and a consistent observation is that of skeletal anomalies. Pentavalent and tetravalent forms of vanadium Interpretation of these studies is difficult because of have produced aneugenic effects in vitro. There is evi- unconventional routes of exposure and evidence of dence that these forms of vanadium as well as trivalent maternal toxicity that may itself contribute to the effects vanadium can also produce DNA/chromosome damage seen in pups. in vitro, both positive and negative results having emerged from the available studies. The weight of evi- 11.1.2 Criteria for setting tolerable intakes or dence from the available data suggests that vanadium guidance values for vanadium pentoxide compounds do not produce gene mutations in standard in vitro tests in bacterial or mammalian cells. The toxicological end-points of concern are genotoxicity and respiratory tract irritation. Vanadium In vivo, both pentavalent and tetravalent vanadium pentoxide is considered to be a somatic and germ cell compounds have produced clear evidence of aneuploidy mutagen, and there is some, although not conclusive, in somatic cells. There is some limited evidence for evidence to indicate the involvement, at least in part, of vanadium compounds also being able to express clasto- aneugenicity. It is not possible to clearly identify the genic effects. Only one study is available on the threshold level, for any route of exposure relevant to potential of vanadium compounds to produce germ cell humans, below which there would be no concern for mutagenicity. A positive result was obtained in mice potential genotoxic activity. In addition, repeated receiving vanadium pentoxide by intraperitoneal inhalation exposure to the dust and fume of vanadium injection, indicating the potential for vanadium to act as pentoxide is associated with irritation of the eyes, nose, a germ cell mutagen. However, the underlying and throat and impaired pulmonary function. Similarly, mechanism for this effect (aneugenicity; clastogenicity) there are insufficient data to reliably describe the is uncertain. It is also unclear how these findings can be exposure–response relationship for the respiratory generalized to more realistic routes of exposure or to effects of vanadium pentoxide dust and fume in humans. other vanadium compounds. Since it is not possible to identify a level of exposure that is without adverse effect, it is recommended that Although aneugenicity is, in principle, a form of levels be reduced to the extent possible. genotoxicity that can have an identifiable threshold, the nature of the mutagenicity database on vanadium com- 11.1.3 Sample risk characterization pounds is such that it is not possible to clearly identify the threshold level, for any route of exposure relevant to Risks to human health and the environment will humans, below which there would be no concern for vary considerably depending upon the type and extent potential mutagenic activity. of exposure. Responsible authorities are strongly encouraged to characterize risk on the basis of locally No useful information is available regarding the measured or predicted exposure scenarios. To assist the carcinogenic potential of any form of vanadium via any reader, examples of exposure estimation and risk route of exposure in animals1 or in humans. characterization are provided in CICADs, whenever possible. These examples cannot be considered as representing all possible exposure situations, but are provided as guidance only. The reader is referred to EHC 1 The authors of this document are aware that a 2-year 170 (IPCS, 1994) for advice on the derivation of health- inhalation bioassay in rodents has recently been based tolerable intakes and guidance values. completed at the US National Toxicology Program. However, results are not available at this time.

33 Concise International Chemical Assessment Document 29

The scenario chosen as a specific example is occu- term effects as a result of sequestration in body tissues pational exposure in the United Kingdom. There are only such as bone. Furthermore, the significance of effects two forms of vanadium of occupational significance in seen in developmental toxicity studies using vanadium the United Kingdom — vanadium metal (impure and pentoxide is not well understood. At present, studies are alloyed forms) and vanadium pentoxide. No toxicology generally poorly reported or poorly conducted. Skeletal data are available on metallic vanadium (valency state 0). anomalies have been seen in a number of studies with There is no means of extrapolating data from vanadium pentavalent and tetravalent vanadium compounds, compounds to predict the properties of vanadium metal. although it is difficult to ascertain the role of the severe Therefore, in the absence of a hazard assessment on maternal toxicity that has also been evident. It is plaus- vanadium metal, no risk assessment can be performed. ible that the skeletal anomalies in pups may be related to the disturbance of calcium balance (Younes & Strubelt, The other occupationally relevant form is vana- 1991) and interference with phosphate metabolism. dium pentoxide. Vanadium pentoxide is a demonstrable somatic and presumed germ cell mutagen and produces 11.2 Evaluation of environmental effects an unusual profile of respiratory tract effects. Delayed and persistent respiratory effects (production of mucus Vanadium is found in both fresh water and sea- and cough) have been reported following human expo- water in a natural background range of approximately sure to 0.1 mg vanadium pentoxide dust/m3, although no 1–3 µg/litre. Locally high concentrations of the metal, up threshold was established for these effects. Impaired to about 70 µg/litre, have been reported in fresh waters, pulmonary function is reported following repeated often associated with leaching from volcanic lava flows exposure to vanadium pentoxide dust and fume, and and uranium deposits. Data on concentrations in surface there are insufficient data to reliably describe the waters influenced by industrial waste are few, but mainly exposure–response relationship for the respiratory fall within the natural range (up to about 65 µg/litre). A effects in humans. Thus, toxicity to the respiratory tract single early reported concentration in surface waters will be a concern at all levels of occupational exposure. receiving industrial waste of 2 mg/litre may be unreliable.

Inhalation is the dominant route of concern for Vanadium is an essential trace element in some vanadium pentoxide exposure. There is substantial organisms (e.g., nitrogen-fixing bacteria). Its essentiality absorption of inorganic vanadium compounds following in other organisms (e.g., for humans and other mammals) inhalation exposure. Given the genotoxic properties of remains an open question. vanadium and the inability to identify a threshold, there is concern at every level of exposure. Vanadium is bioaccumulated by a few species of biota, notably ascidians and some polychaete annelids. There are no oral exposure data on vanadium Most organisms show low concentrations of the metal. pentoxide. There is no evidence for biomagnification in food chains in marine organisms; there are no data for freshwater Following dermal exposure, it is unlikely that skin organisms. irritation or sensitization will be of concern in humans. Given the green staining of the skin that is occasionally Toxicity values for vanadium in freshwater and seen as a result of excessive exposure to vanadium marine organisms generally range between 0.2 and pentoxide, it would seem that there is potential for some, 120 mg/litre. Reports of sublethal effects at around perhaps limited, dermal absorption. However, there are 10 µg/litre for algal photosynthesis, 50 µg/litre for oyster no data relating to potential systemic toxicity via dermal larval development, and 1130 µg/litre for Daphnia exposure. Given the overall lack of information in relation reproduction have been reported. to dermal exposure, it is not possible to assess the risks to human health following exposure by this route. For natural waters, most toxic effects of vanadium occur only at concentrations substantially higher than 11.1.4 Uncertainties those reported in the field. Most reported concentration in industrial areas are also substantially lower than those Overall, the toxicokinetic and toxicological data- required to produce adverse effects. A single, possibly base on vanadium and vanadium pentoxide is limited, unreliable, older high value for an industrial scenario and attempts to utilize information from other inorganic does exceed toxic concentrations (Fig. 1). vanadium compounds are not entirely satisfactory. Of particular concern is the limited understanding of the potential for dermal absorption and the potential long-

34 Vanadium pentoxide and other inorganic vanadium compounds

6 10

5 10

4 Single reported 10 concentration for industrial waters (reliability uncertain) 3 10 Highest reported 2 concentration in natural 10 water

1 10 Normal range for surface waters Log concentration of vanadium (µg/litre) 0 10

-1 10 Figure 1. Range of reported toxic concentrations of vanadium compared with concentrations in water. Triangles represent reported LC50 values for a range of organisms in seawater and fresh water, squares represent the 21-day NOEC for Daphnia magna reproduction, and circles represent the LOEC for the development of oyster larvae.

There are insufficient data on toxicity to terrestrial organisms to draw risk conclusions.

There are too few data to assess risk in specific industrial contexts.

12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

A published review of vanadium is available (IPCS, 1988). Information on international hazard classification and labelling is included in the International Chemical Safety Cards (ICSCs 0455 and 0596) reproduced in this document. The World Health Organization’s air quality guideline for vanadium is 1 µg/m3, which is based on a lowest-observed-adverse-effect level (LOAEL) of 20 µg/m3 from studies on occupationally exposed individuals, using an overall uncertainty factor of 20 (WHO, 1987).

35 Concise International Chemical Assessment Document 29

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Tsukamoto Y, Saka S, Kumano K, Iwanami S, Ishida O, Marumo mice and Kunming albino mice. Dukou Sanitary and Anti- F (1990) Abnormal accumulation of vanadium in patients on Epidemic Station [cited in Sun, 1987]. chronic hemodialysis. Nephron, 56:368–373. Yao D, Li S, et al. (1986a) A long-term study on the chronic US EPA (1983) Methods for chemical analysis of water and toxicity and carcinogenicity of the inhalation of vanadium wastes. Washington, DC, US Environmental Protection Agency; pentoxide dust on mice. Dukou Sanitary and Anti-Epidemic Springfield, VA, US Department of Commerce, National Station [cited in Sun, 1987]. Technical Information Service. Yao D, Zhang B, et al. (1986b) Study on the acute and US EPA (1986) Test methods for evaluating solid waste. Vol. subchronic toxicity of vanadium pentoxide. Dukou Sanitary and 1A: Laboratory manual for physical/chemical methods. Anti-Epidemic Station [cited in Sun, 1987]. Washington, DC, US Environmental Protection Agency, Office of Solid Waste and Emergency Response (Document No. 7910.1- Yen TF (1975) Vanadium and its bonding in petroleum. In: Yen 7911.3). TF, ed. The role of trace metals in petroleum. Ann Arbor, MI, Ann Arbor Science Publishers, pp. 167–181. US EPA (1992) Support: Dust inhalation toxicity studies with cover letter dated 081992. Washington, DC, US Environmental Younes M, Strubelt O (1991) Vanadate-induced toxicity towards Protection Agency, Office of Toxic Substances (Doc #89- isolated perfused rat livers: The role of lipid peroxidation. 940000275; see also Doc #88-920000666, initial submission). Toxicology, 66:63–74. van der Hoeven N (1991) Proceedings of the 2nd workshop on Zaporowska H, Wasilewski W (1992) Haematological results of sources of variation in ecotoxicological tests with Daphnia vanadium intoxication in Wistar rats. Comparative biochemistry magna. Sheffield, University of Sheffield [cited in Allen et al., and physiology, 101C(1):57–61. 1995]. Zaporowska H, Wasilewski W, Slotwinska M (1993) Effect of Wallace A, Alexander G, Chadhury F (1977) Phytotoxicity of chronic vanadium administration in drinking water to rats. cobalt, vanadium, titanium, silver, and chromium. Biometals, 6:3–10. Communications in soil science and plant analysis, 8(9):751–756. Zenz C, Berg B (1967) Human responses to controlled vanadium pentoxide exposure. Archives of environmental health, Wang J, Liu Z (1999) Effect of vanadium on the growth of 14:709–712. soybean seedlings. Plant and soil, 216:47–51. Zenz C, Bartlett J, Thiede W (1962) Acute vanadium pentoxide Warington K (1954) The influence of iron supply on toxic effects intoxication. Archives of environmental health, 5:542–546. of manganese, molybdenum and vanadium in soybeans, peas, and flax. Annals of applied biology, 41(1):1–22. Zhang L, Zhou K (1992) Background values of trace elements in the source area of the Yangtze River. The science of the total Wever R, Hemrika W (1998) Vanadium in enzymes. In: Nriagu J, environment, 125:391–404. ed. Vanadium in the environment. Part 1: Chemistry and biochemistry. New York, NY, John Wiley & Sons, pp. 285–305. Zhang T, Gou X, Yang Z (1991) A study on developmental toxicity of vanadium pentoxide in NIH mice. Hua Hsi I Ko Ta White MA, Reeves GD, Moore S, Chandler HA, Holden HJ Hsueh Hsueh Pao, 22:192–195. (1987) Sensitive determination of urinary vanadium as a measure of occupational exposure during cleaning of oil fired Zhang T, Gou X, Yang Z (1993a) Study of teratogenicity and boilers. Annals of occupational hygiene, 31(3):339–343. sensitive period of vanadium pentoxide in Wistar rats. Hua Hsi I Ko Ta Hsueh Hsueh Pao, 24:202–205. WHO (1987) Air quality guidelines for Europe. Copenhagen, World Health Organization, Regional Office for Europe, 426 pp. Zhang T, Yang Z, Zeng C, Gou X (1993b) A study on develop- mental toxicity of vanadium pentoxide in Wistar rats. Hua Hsi I Wide M (1984) Effect of short-term exposure to five industrial Ko Ta Hsueh Hsueh Pao, 24:92–96. metals on the embryonic and fetal development of the mouse. Environmental research, 33:47–53. Zhong B, Gu Z, Wallace W, Whong W, Ong T (1994) Genotoxicity of vanadium pentoxide in Chinese hamster V79 Wrbitsky R, Goen T, Frank F, Angerer J (1995) Internal exposure cells. Mutation research, 321:35–42. of waste incineration workers to organic and inorganic substances. International archives of occupational and environmental health, 68:13–21.

Yang H, Yao D, Feng S, Qin J, Chen Y (1986a) [A study of the teratogenicity of vanadium pentoxide.] Dukou Sanitary and Anti- Epidemic Station, pp. 35–43 (internal report) [cited in Sun, 1987].

Yang H et al. (1986b) A study on the effect of inhaling vanadium pentoxide dust on the frequencies of micronucleus of PCE in mice. Dukou Sanitary and Anti-Epidemic Station, pp. 48–50 (internal report) [cited in Sun, 1987].

Yang H, Zhang B, et al. (1986c) Studies on the effect of vanadium pentoxide on the micronucleus of PCE in 615 strain

41 Concise International Chemical Assessment Document 29

APPENDIX 1 — SOURCE DOCUMENTS APPENDIX 2 — CICAD PEER REVIEW

HSE (in press) Vanadium pentoxide. Health and The draft CICAD on vanadium pentoxide and other Safety Executive. Sudbury, Suffolk, HSE Books inorganic vanadium compounds was sent for review to institutions and organizations identified by IPCS after contact (Risk Assessment Document EH72/XX) with IPCS national contact points and Participating Institutions, as well as to identified experts. Comments were received from: The author’s draft version is initially reviewed internally by a group of approximately 10 Health and Safety Executive M. Baril, International Programme on Chemical Safety/ experts, mainly toxicologists, but also involving other relevant Institut de Recherche en Santé et en Sécurité du disciplines, such as epidemiology and occupational hygiene. Travail du Québec, Montreal, Quebec, Canada The toxicology section of the amended draft is then reviewed by R. Benson, Drinking Water Program, US Environmental toxicologists from the United Kingdom Department of Health. Protection Agency, Denver, CO, USA Subsequently, the entire Risk Assessment Document is reviewed T. Berzins, National Chemicals Inspectorate, Solna, by a tripartite advisory committee to the United Kingdom Health Sweden and Safety Commission, the Working Group for the Assessment R. Chhabra, Department of Health and Human Services, of Toxic Chemicals (WATCH). This committee comprises experts Research Triangle Park, NC, USA in toxicology, occupational health, and hygiene from industry, P. Edwards, Protection of Health Division, Department of trade unions, and academia. Health, London, United Kingdom R. Hertel, Federal Institute for Health Protection of The members of the WATCH committee at the time of the Consumers and Veterinary Medicine, Berlin, peer review were: Germany M. Kiilunen, Finnish Institute of Occupational Health, Mr Steve Bailey (Independent Consultant) Helsinki, Finland Professor Jim Bridges (Robens Institute, Guildford) J. Lener, National Institute of Public Health, Prague, Mr Robin Chapman (Chemical Industries Association) Czech Republic Dr Hilary Cross (Trade Unions Congress) I. Mangelsdorf, Fraunhofer Institute, Hanover, Germany Mr David Farrar (Independent Consultant) H. Nagy, National Institute for Occupational Safety and Dr Tony Fletcher (Trade Unions Congress) Health, Washington, DC, USA Dr Ian Guest (Chemical Industries Association) E. Ohanian, Office of Water, US Environmental Dr Alastair Hay (Trade Unions Congress) Protection Agency, Washington, DC, USA Dr Len Levy (Institute for Environment and Health, S.A. Soliman, Alexandria University, El-Shatby, Leicester) Alexandria, Egypt Dr Tony Mallet (Chemical Industries Association) M. Sun, School of Public Health, West China University of Mr Alan Moses (Chemical Industries Association) Medical Sciences, Chengdu, Sichuan, People’s Mr Jim Sanderson (Independent Consultant) Republic of China Dr Anne Spurgeon (Institute of Occupational Health, W.F. ten Berge, DSM, Heerlen, The Netherlands Birmingham) P. Yao, Institute of Occupational Medicine, Chinese Academy of Preventive Medicine, Ministry of Health, Beijing, People’s Republic of China K. Ziegler-Skylakakis, GSF-Forschungszentrum für Umvelt IPCS (1988) Vanadium. Geneva, World Health und Gesundheit, Neuherberg, Oberschleissheim, Organization, International Programme on Germany Chemical Safety, 170 pp. (Environmental Health Criteria 81)

A WHO Task Group on Environmental Health Criteria for Vanadium met in Moscow, USSR, from 30 March to 3 April 1987. The Task Group reviewed and revised the draft criteria document and made an evaluation of the risks for human health and the environment from exposure to vanadium

Copies of this document may be obtained from:

International Programme on Chemical Safety World Health Organization Geneva, Switzerland

42 Vanadium pentoxide and other inorganic vanadium compounds

APPENDIX 3 — CICAD FINAL REVIEW BOARD Observer Helsinki, Finland, 26–29 June 2000 Dr R.J. Lewis (representative of European Centre for Ecotoxicology and Toxicology of Chemicals), Epidemiology and Health Surveillance, ExxonMobil Biomedical Sciences, Inc., Members Annandale, NJ, USA

Mr H. Ahlers, Education and Information Division, National Institute for Occupational Safety and Health, Cincinnati, OH, USA Secretariat

Dr T. Berzins, National Chemicals Inspectorate (KEMI), Solna, Dr A. Aitio, International Programme on Chemical Safety, World Sweden Health Organization, Geneva, Switzerland (Secretary)

Dr R.M. Bruce, Office of Research and Development, National Dr P.G. Jenkins, International Programme on Chemical Safety, Center for Environmental Assessment, US Environmental World Health Organization, Geneva, Switzerland Protection Agency, Cincinnati, OH, USA Dr M. Younes, International Programme on Chemical Safety, Mr R. Cary, Health and Safety Executive, Liverpool, United World Health Organization, Geneva, Switzerland Kingdom (Rapporteur)

Dr R.S. Chhabra, General Toxicology Group, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA

Dr H. Choudhury, National Center for Environmental Assessment, US Environmental Protection Agency, Cincinnati, OH, USA

Dr S. Dobson, Centre for Ecology and Hydrology, Monks Wood, Abbots Ripton, United Kingdom (Chairman)

Dr H. Gibb, National Center for Environmental Assessment, US Environmental Protection Agency, Washington, DC, USA

Dr R.F. Hertel, Federal Institute for Health Protection of Consumers and Veterinary Medicine, Berlin, Germany

Ms K. Hughes, Priority Substances Section, Environmental Health Directorate, Health Canada, Ottawa, Ontario, Canada

Dr G. Koennecker, Chemical Risk Assessment, Fraunhofer Institute for Toxicology and Aerosol Research, Hanover, Germany

Ms M. Meek, Existing Substances Division, Environmental Health Directorate, Health Canada, Ottawa, Ontario, Canada

Dr A. Nishikawa, Division of Pathology, Biological Safety Research Centre, National Institute of Health Sciences, Tokyo, Japan

Dr V. Riihimäki, Finnish Institute of Occupational Health, Helsinki, Finland

Dr J. Risher, Agency for Toxic Substances and Disease Registry, Division of Toxicology, US Department of Health and Human Services, Atlanta, GA, USA

Professor K. Savolainen, Finnish Institute of Occupational Health, Helsinki, Finland (Vice-Chairman)

Dr J. Sekizawa, Division of Chem-Bio Informatics, National Institute of Health Sciences, Tokyo, Japan

Dr S. Soliman, Department of Pesticide Chemistry, Faculty of Agriculture, Alexandria University, Alexandria, Egypt

Ms D. Willcocks, National Industrial Chemicals Notification and Assessment Scheme, Sydney, NSW, Australia

43 VANADIUM TRIOXIDE 0455 March 1998 CAS No: 1314-34-7 Divanadium trioxide RTECS No: YW3050000 Vanadium sesquioxide UN No: 3285 Vanadic oxide EC No: Vanadium(III) oxide

V2O3 Molecular mass: 149.9

TYPES OF HAZARD/ ACUTE HAZARDS/SYMPTOMS PREVENTION FIRST AID/FIRE FIGHTING EXPOSURE

FIRE Combustible under specific NO open flames. In case of fire in the surroundings: conditions. Gives off irritating or all extinguishing agents allowed. toxic fumes (or gases) in a fire.

EXPLOSION

EXPOSURE PREVENT DISPERSION OF DUST!

Inhalation Sore throat. Cough. Laboured Local exhaust or breathing Fresh air, rest. Half-upright breathing. Weakness. protection. position. Refer for medical attention.

Skin Dry skin. Redness. Protective gloves. Remove contaminated clothes. Rinse skin with plenty of water or shower.

Eyes Redness. Safety goggles, or eye protection in First rinse with plenty of water for combination with breathing several minutes (remove contact protection if powder. lenses if easily possible), then take to a doctor.

Ingestion Headache. Vomiting. Weakness. Do not eat, drink, or smoke during Induce vomiting (ONLY IN work. CONSCIOUS PERSONS!). Give plenty of water to drink. Refer for medical attention.

SPILLAGE DISPOSAL PACKAGING & LABELLING

Sweep spilled substance into containers; if Symbol Do not transport with food and appropriate, moisten first to prevent dusting. R: feedstuffs. Carefully collect remainder, then remove to safe S: place (extra personal protection: P3 filter respirator UN Hazard Class: 6.1 for toxic particles). UN Pack Group: III

EMERGENCY RESPONSE STORAGE

Transport Emergency Card: TEC (R)-61G65c Separated from food and feedstuffs.

Prepared in the context of cooperation between the International IPCS Programme on Chemical Safety and the European Commission International © IPCS 1999 Programme on Chemical Safety SEE IMPORTANT INFORMATION ON THE BACK. 0455 VANADIUM TRIOXIDE

IMPORTANT DATA

Physical State; Appearance Routes of Exposure BLACK POWDER, TURNS GRADUALLY INTO INDIGO-BLUE The substance can be absorbed into the body by inhalation of

CRYSTALS OF VANADIUM TETROXIDE (V2O4) ON its aerosol and by ingestion. EXPOSURE TO AIR. Inhalation Risk Chemical Dangers Evaporation at 20
C is negligible; a harmful concentration of The substance decomposes on heating or on burning airborne particles can, however, be reached quickly. producing irritating and toxic fumes (vanadium oxides). Effects of Short-term Exposure Occupational Exposure Limits The aerosol irritates the eyes, the skin and the respiratory tract. TLV not established. MAK not established. Inhalation of high concentrations of aerosol of this substance may cause conjunctivitis, rhinitis and bronchitis. The effects may be delayed. See Notes.

Effects of Long-term or Repeated Exposure The substance may have effects on the respiratory tract, resulting in chronic rhinitis and chronic bronchitis.

PHYSICAL PROPERTIES

Melting point: 1970
C Solubility in water: poor Density: 4.87 g/cm3 at 18
C

ENVIRONMENTAL DATA

NOTES Depending on the degree of exposure, periodic medical examination is indicated. The symptoms of acute exposure do not become manifest until 1-6 days. Also consult ICSC # 0596 Vanadium pentoxide.

ADDITIONAL INFORMATION

LEGAL NOTICE Neither the EC nor the IPCS nor any person acting on behalf of the EC or the IPCS is responsible for the use which might be made of this information

© IPCS 1999 VANADIUM PENTOXIDE 0596 October 1999 CAS No: 1314-62-1 Divanadium pentoxide RTECS No: YW2450000 (dust) Vanadic anhydride UN No: 2862 Vanadium(V)oxide

EC No: 023-001-00-8 V2O5 Molecular mass: 181.9

TYPES OF HAZARD/ ACUTE HAZARDS/SYMPTOMS PREVENTION FIRST AID/FIRE FIGHTING EXPOSURE

FIRE Not combustible. In case of fire in the surroundings: all extinguishing agents allowed.

EXPLOSION

EXPOSURE PREVENT DISPERSION OF DUST! STRICT HYGIENE!

Inhalation Sore throat. Cough. Burning Ventilation, local exhaust, or Fresh air, rest. Half-upright position. sensation. Shortness of breath. breathing protection. Refer for medical attention. Laboured breathing. Wheezing.

Skin Redness. Burning sensation. Pain. Protective gloves. Remove contaminated clothes. Rinse skin with plenty of water or shower.

Eyes Pain. Redness. Conjunctivitis. Safety goggles, or eye protection in First rinse with plenty of water for combination with breathing several minutes (remove contact protection if powder. lenses if easily possible), then take to a doctor.

Ingestion Abdominal cramps. Diarrhoea. Do not eat, drink, or smoke during Induce vomiting (ONLY IN Drowsiness. Nausea. work. Wash hands before eating. CONSCIOUS PERSONS!). Give Unconsciousness. Vomiting. plenty of water to drink. Refer for medical attention.

SPILLAGE DISPOSAL PACKAGING & LABELLING

Sweep spilled substance into containers; if T Symbol Do not transport with food and appropriate, moisten first to prevent dusting. N Symbol feedstuffs. Carefully collect remainder, then remove to safe R: 20/22-37-40-48/23-51/53-63 place. (Extra personal protection: P3 filter respirator S: (1/2-)36/37-38-45-61 for toxic particles). Do NOT let this chemical enter UN Hazard Class: 6.1 the environment. UN Pack Group: III

EMERGENCY RESPONSE STORAGE

Transport Emergency Card: TEC (R)-61G64c Separated from food and feedstuffs.

Prepared in the context of cooperation between the International IPCS Programme on Chemical Safety and the European Commission International © IPCS 2000 Programme on Chemical Safety SEE IMPORTANT INFORMATION ON THE BACK. 0596 VANADIUM PENTOXIDE

IMPORTANT DATA Physical State; Appearance Routes of exposure YELLOW TO RED CRYSTALLINE POWDER OR SOLID IN The substance can be absorbed into the body by inhalation of VARIOUS FORMS. its aerosol and by ingestion.

Chemical dangers Inhalation risk Upon heating, toxic fumes are formed. Reacts with combustible Evaporation at 20°C is negligible; a harmful concentration of substances. airborne particles can, however, be reached quickly when dispersed. Occupational exposure limits 3 TLV (respirable dust or fume, as V2O5): 0.05 mg/m (TWA) Effects of short-term exposure (ACGIH 1999). The aerosol of this substance irritates the eyes, the skin and MAK: 0.05 mg/m3; (1996). the respiratory tract. Inhalation of high concentrations may cause lung oedema, bronchitis, bronchospasm. The effects may be delayed.

Effects of long-term or repeated exposure Lungs may be affected by inhalation of high concentrations of dust or fumes. The substance may cause greenish-black discolouration of the tongue.

PHYSICAL PROPERTIES

Boiling point (decomposes): 1750°C Relative density (water = 1): 3.4 Melting point: 690°C Solubility in water, g/100 ml: 0.8

ENVIRONMENTAL DATA The substance is harmful to aquatic organisms.

NOTES Depending on the degree of exposure, periodic medical examination is indicated. The symptoms of lung oedema often do not become manifest until a few hours have passed and they are aggravated by physical effort. Rest and medical observation are therefore essential. Immediate administration of an appropriate spray, by a doctor or a person authorized by him/her, should be considered.

ADDITIONAL INFORMATION

LEGAL NOTICE Neither the EC nor the IPCS nor any person acting on behalf of the EC or the IPCS is responsible for the use which might be made of this information

©IPCS 2000 Concise International Chemical Assessment Document 29

RÉSUMÉ D’ORIENTATION On estime que chaque année, quelque 8,4 tonnes de vanadium sont libérées dans l’atmosphère à partir de sources naturelles (valeurs extrêmes : 1,5-49,2 tonnes). La Ce CICAD consacré au pentoxyde de vanadium et source de pollution de l’environnement par le vanadium à d’autres dérivés minéraux du vanadium repose sur un qui est de loin la plus importante est constituée par la bilan des problèmes sanitaires (principalement en milieu combustion du pétrole et du charbon; environ 90 % des professionnel) préparé par le Health and Safety quelque 64 000 tonnes de vanadium libérées dans Executive du Royaume-Uni (HSE, sous presse). Ce l’atmosphère chaque année par des phénomènes document vise principalement les voies d’exposition à naturels ou par l’activité humaine ont en effet cette prendre en considération sur les lieux de travail, mais source pour origine. contient également des informations relatives à l’environnement. La bibliographie utilisée va jusqu’à Dans l’environnement, le vanadium offre une novembre 1998. Un dépouillement complémentaire de la chimie complexe. Dans les minéraux, le degré d’oxydation litterature à été effectué jusqu’à mai 1999 afin de recueillir du vanadium peut être de +3, +4 ou +5. Par dissolution toutes données supplémentaires publiées après dans l’eau, V3+ et V4+ sont rapidement oxydés au degré l’achèvement de ce document. En ce qui concerne les +5, qui constitue la forme la plus commune du vanadium données environnementales, on a utilisé la monographie dans l’environnement. En solution, cette forme publiée dans la série Critères d’hygiène de l’environne- correspond aux vanadates, qui peuvent se polymériser ment (IPCS, 1988). Comme on ne disposait d’aucun (pour donner principalement des dimères et des document plus récent sur le devenir et les effets trimères), en particulier en solution concentrée. Dans les environnementaux de ces composés, il a été procédé à tissus, ce sont les formes V3+ et V4+ qui prédominent, du une recherche bibliographique afin d’obtenir un fait que le milieu est largement réducteur; dans le plasma, complément d’information. Des renseignements sur la c’est V5+ qui prédomine. nature de l’examen par des pairs et sur les sources documentaires existantes sont données à l’appendice 1. Le vanadium est probablement essentiel pour les L’appendice 2 contient des informations sur l’examen par systèmes enzymatiques qui fixent l’azote atmosphérique des pairs du présent CICAD. Ce CICAD a été approuvé (bactéries) et il est concentré par certains organismes en tant qu’évaluation internationale lors de la réunion du comme les tuniciers, quelques annélidés de la classe des Comité d’évaluation finale qui s’est tenue à Helsinki polychètes et certaines algues microscopiques. On ne (Finlande) du 26 au 29 juin 2000. La liste des participants sait cependant pas avec certitude quelle est sa fonction à cette réunion figure à l’appendice 3. Les fiches chez ces organismes. La question de savoir si le internationales sur la sécurité chimique du trioxyde vanadium est essentiel pour d’autres organismes reste (ICSC 0455) et du pentoxyde de vanadium (ICSC 0596) posée. Rien n’indique qu’il s’accumule ou subisse une établies par le Programme international sur la sécurité bioamplification dans la chaîne alimentaire des chimique (IPCS, 1999a,b) sont également reproduites organismes marins, qui constituent le groupe le mieux dans le présent CICAD. étudié.

Le vanadium (No CAS 7440-62-2) est un métal Le lessivage du vanadium dans les différents ductile, de couleur gris-argent, qui peut exister sous profils pédologiques est très limité. divers degrés d’oxydation : !1, 0, +2, +3, +4 et +5. Sa forme commerciale la plus courante est le pentoxyde On a signalé la présence de fortes concentrations V2O5 (No CAS 1314-62-1) correspondant à la valence +5 de vanadium dans l’air à proximité de sources indus- et qui se présente sous la forme d’une poudre cristalline trielles et de feux d’hydrocarbures. En ce qui concerne qui peut être jaune, rouge ou verte. les dépôts, des valeurs annuelles de 0,1 à 10 kg/ha sont caractéristiques des zones urbaines où sont implantées Le vanadium est un élément abondant et très des sources importantes de vanadium; ces valeurs vont largement répandu. Le minerai est extrait en Afrique du de 0,01 à 0,1 kg/ha par an dans les zones rurales ou Sud, en Russie et en Chine. Lors de la fusion du minerai urbaines où n’existent pas de sources de vanadium et de fer, il se forme un laitier contenant du pentoxyde de s’abaissent à <0,001-0,01 kg/ha par an dans les régions vanadium que l’on utilise pour la production du métal. reculées. On prépare également le pentoxyde de vanadium en l’extrayant par solvant des minerais d’uranium ou par Dans la plupart des eaux douces de surface, la grillage des sels présents dans les résidus de chaudières concentration du vanadium est inférieure à 3 µg/litre; des ou dans ceux des usines de production de phosphore valeurs plus élevées, pouvant atteindre 70 µg/litre ont élémentaire. La combustion des huiles lourdes dans les été relevées dans des zones où existent d’importantes chaudières et les fours conduit à la formation de résidus sources géochimiques. On ne possède guère de données solides, de suie, de tartre et de cendres volantes qui sur la teneur en vanadium des eaux proches de sites contiennent du pentoxyde de vanadium. industriels; la plupart des publications font état de

48 Vanadium pentoxide and other inorganic vanadium compounds

valeurs correspondant sensiblement aux concentrations Des études sur des travailleurs de l’industrie du naturelles les plus fortes. Les concentrations pélagiques vanadium ont mis en évidence des cas d’irritation vont de 1 à 3 mg/litre, dans les sédiments, la concen- oculaire. Chez 100 volontaires à qui on avait posé un tration va de 20 à 200 mg/g, les valeurs les plus élevées timbre cutané contenant 10 % de pentoxyde de étant relevées dans la zone littorale. vanadium, on n’a pas constaté d’irritation cutanée, mais un test analogue effectué sur des travailleurs a donné Quelques organismes concentrent le vanadium, et lieu a deux réactions isolées. L’expérimentation animale la concentration de ce métal peut atteindre 10 000 µg/g n’a permis de dégager aucun résultat clair concernant le chez les ascidies et 786 µg/g chez les polychètes. Chez la pouvoir irritant oculaire ou cutané des composés du plupart des êtres vivants, la concentration est, d’une vanadium ou leur action sensibilisatrice au niveau de façon générale, inférieure à 50 mg/g et habituellement l’épiderme. beaucoup plus faible. Dans un groupe de volontaires exposés pendant 8 L’exposition par la voie alimentaire est estimée h à de la poussière contenant 0,1 mg de vanadium par m3, chez l’Homme à 11-30 µg par jour. Dans l’eau de boisson, on a observé des effets retardés mais prolongés sur les la concentration va jusqu’à 100 µg/litre. Dans certaines bronches qui se manifestaient notamment par une nappes souterraines qui alimentent les sources d’eau production excessive de mucus. A la concentration de potable, on a relevé des concentrations de vanadium 0,25 mg/m3, la réaction était analogue, avec en plus de la supérieures à 50 µg/litre. L’eau minérale en bouteille peut toux qui s’est prolongée pendant les quelques jours en contenir davantage. suivant l’exposition. A la concentration de 1,0 mg/m3, la toux est devenue permanente au bout de cinq heures et On possède des données toxicocinétiques limitées s’est maintenue longtemps. Il ne ressort de cette étude selon lesquelles chez l’Homme, le vanadium est résorbé aucune valeur de la dose maximale sans effet après inhalation puis excrété dans l’urine, l’élimination se bronchique. faisant en deux phases, une phase initiale rapide puis une phase plus lente qui correspond vraisemblablement L’inhalation répétée de vapeurs et de poussières à la libération progressive du vanadium retenu dans les de pentoxyde de vanadium entraîne une irritation des tissus. Après administration par voie orale, le vanadium yeux, du nez et de la gorge. Chez les travailleurs exposés IV est mal résorbé dans les voies digestives. On ne à ces vapeurs et à ces poussières, on observe dispose pas d’études sur l’absorption percutanée. couramment une respiration sifflante et de la dyspnée. Globalement , on ne dispose pas de données suffisantes L’expérimentation animale montre qu’après pour établir de façon fiable une relation exposition- exposition par la voie respiratoire ou orale le vanadium réponse relative aux effets respiratoires des poussières et absorbé sous des formes correspondant aux degrés des vapeurs de vanadium chez l’Homme. d’oxydation IV ou V se répartit principalement dans les os, le foie, les reins et la rate. On en a également décelé la Les dérivés correspondant aux valences 4 et 5 du présence dans les testicules. La principale voie vanadium ont des effets aneugènes in vitro en présence d’excrétion est la voie urinaire. Le mode de distribution ou en l’absence d’activation métabolique. On est fondé à et d’excrétion du vanadium montre qu’une fois résorbé, penser que ces dérivés ainsi que ceux du vanadium III le métal peut s’accumuler et être retenu, notamment dans sont capables de provoquer des lésions de l’ADN et des les os. Il a également été montré que le vanadium chromosomes in vitro, mais les études existantes tétravalent est capable de franchir la barrière foeto- donnent à cet égard des résultats qui sont tantôt placentaire. positifs, tantôt négatifs. Il semble, à la lumière des données disponibles, que les composés du vanadium ne Dans la seule étude de toxicité aiguë par inhalation soient pas mutagènes , à en juger par les tests classiques 3 qui soit disponible, on a obtenu une CL67 de 1440 mg/m de mutagénicité in vitro sur des cellules bactériennes ou (800 mg de vanadium par m3) pour des rats exposés mammaliennes. pendant 1 h à de la poussière de pentoxyde de vanadium. L’exposition de rats et de souris par la voie In vivo, une aneuploïdie des cellules somatiques orale a permis d’obtenir une DL50 qui se situait entre 10 s’observe clairement après exposition à des dérivés du et 160 mg/kg de poids corporel dans le cas du pentoxyde vanadium IV et du vanadium V selon différentes voies. et d’autres dérivés du vanadium V, alors qu’avec les Comme dans le cas des études in vitro, les tests destinés dérivés du vanadium IV, les valeurs étaient comprises à mettre en évidence des effets clastogènes donnent des entre 448 et 467 mg/kg de poids corporel. On ne dispose résultats mitigés et dans l’ensemble, on reste dans d’aucune donnée sur la toxicité du vanadium par la voie l’incertitude quand au pouvoir clastogène du vanadium percutanée. vis-à-vis des cellules somatiques. Par contre, on a obtenu un résultat positif dans le cas des cellules germinales de souris à qui on avait injecté du pentoxyde

49 Concise International Chemical Assessment Document 29

de vanadium par voie intrapéritonéale. Le mécanisme qui de vue écotoxicologique, il serait plus judicieux de est à la base de ces effets (aneugènes et clastogènes) prendre en considération l’action sur le développement n’est pas connu avec certitude. On ignore également des huîtres (sensiblement réduit à 0,05 mg de vanadium dans quelle mesure ces résultats peuvent être étendus à par litre) et sur la reproduction des daphnies (concen- d’autres voies d’exposition et à d’autres dérivés du tration sans effet observable à 21 jours : 1,13 mg/litre). vanadium. Peu d’études ont été consacrés aux organismes terrestres. La plupart de celles qui portent sur des Etant donné la nature de la base de données sur la végétaux concernent des cultures hydroponiques sur génotoxicité du pentoxyde de vanadium et d’autres lesquelles on observe des effets à partir de 5 mg/litre. dérivés de cet élément, il n’est pas possible de définir Les résultats de ces études sont difficiles à transposer sans ambiguité le seuil au-dessous duquel, quelle que aux plantes cultivées en pleine terre. soit la voie d’exposition à prendre en considération chez l’Homme, il n’y aurait pas lieu de craindre un risque Dans les divers compartiments de l’environnement, d’activité génotoxique. la concentration est sensiblement inférieure aux valeurs toxiques. On ne possède que peu de données sur la On ne possède aucune information utile sur le concentration au voisinage des sites industriels et il pouvoir cancérogène du vanadium chez l’Homme ou n’est pas possible de procéder à une évaluation du l’animal, sous quelque forme et par quelque voie risque sur cette base. Quoi qu’il en soit, les valeurs dont d’exposition que ce soit.1 il est fait état semble correspondre aux concentrations naturelles les plus fortes, ce qui indique que le risque Une étude de fécondité sur des souris mâles dont devrait être faible. Des mesures sur les lieux mêmes l’eau de boisson contenait du métavanadate de sodium, s’imposent dans chaque cas particulier. incite à penser que l’exposition des animaux à ce composé aux doses de 60 et 80 mg/kg de poids corporel a été la cause directe d’une diminution du nombre de spermatides et de spermatozoïdes ainsi que du nombre de grossesses consécutives à l’accouplement de ces mâles avec des souris femelles. Il est vrai toutefois, qu’à la dose de 80 mg/kg p.c., la toxicité générale du composé était également évidente (diminution du gain de poids).

Un certain nombre d’études ont été consacrées à l’action des composés du vanadium IV et V sur le développement. Elles révèlent systématiquement la présence d’anomalies du squelette. Les résultats de ces études sont difficiles à interpréter car les voies d’exposition étaient inhabituelles et la toxicité manifeste des composés pour les mères a pu influer sur les effets constatés dans la progéniture.

Chez l’Homme les points d’aboutissement de l’action toxique à prendre en considération sont la génotoxicité et l’irritation des voies respiratoires. Comme il n’est pas possible de définir le seuil de concentration à partir duquel il n’y a plus d’effets toxiques, il est recommandé de réduire le plus possible le niveau d’exposition.

Pour les organismes aquatiques, les valeurs de la

CL50 vont de 0,2 à environ 120 mg/litre, la majorité des valeurs se situant entre 1 et 12 mg par litre. D’une point

1 Les auteurs de ce document ont connaissance d’une étude au cours de laquelle on a fait inhaler pendant 2 ans des dérivés du vanadium à des rongeurs. Cette étude vient de s’achever aux Etats-Unis dans le cadre du National Toxicology Program et les résultats n’en sont pas encore disponibles.

50 Vanadium pentoxide and other inorganic vanadium compounds

RESUMEN DE ORIENTACIÓN Las emisiones atmosféricas a partir de fuentes naturales en todo el mundo se han estimado en 8,4 tone- ladas al año (gama de 1,5-49,2 toneladas). La fuente más Este CICAD sobre el pentóxido de vanadio y otros importante de contaminación ambiental por vanadio es compuestos inorgánicos de vanadio se basó en un con diferencia la combustión de petróleo y de carbón; examen de los problemas relativos a la salud humana alrededor del 90% de las aproximadamente 64 000 tone- (fundamentalmente profesionales) preparado por la ladas de vanadio que se liberan en la atmósfera cada año Dirección de Salud y Seguridad del Reino Unido (HSE, a partir de fuentes tanto naturales como antropogénicas en prensa). Este examen se concentra en las vías de procede de la combustión del petróleo. exposición de interés para el entorno ocupacional, pero contiene también información sobre el medio ambiente. La química del vanadio en el medio ambiente es Figuran los datos identificados hasta noviembre de 1998. compleja. En los minerales, el estado de oxidación del Se realizó una ulterior búsqueda bibliográfica hasta mayo vanadio puede ser +3, +4 ó +5. La disolución en agua de 1999 para localizar cualquier información nueva que oxida rápidamente el V3+ y el V4+ al estado pentavalente, se hubiera publicado desde la terminación del examen. Se que es la forma más común del metal en el medio utilizó una monografía de los Criterios de Salud ambiente. El vanadato, compuesto pentavalente en Ambiental (IPCS, 1988) como documento original para la solución, se puede polimerizar (principalmente a las información ambiental. Puesto que no se disponía de formas diméricas o triméricas), en particular a concen- documentos originales más recientes sobre el destino y traciones más altas de las sales. En los tejidos de los los efectos en el medio ambiente, se realizó una organismos predominan el V3+ y el V4+, debido en gran búsqueda bibliográfica para obtener más información. La parte a las condiciones de reducción; en el plasma información acerca del carácter del examen colegiado y la predomina el V5+. disponibilidad de los documentos originales figura en el apéndice 1. La información sobre el examen colegiado de El vanadio es probablemente esencial para los este CICAD aparece en el apéndice 2. Este CICAD se sistemas enzimáticos que fijan el nitrógeno de la atmós- aprobó como evaluación internacional en una reunión de fera (bacterias) y lo concentran algunos organismos la Junta de Evaluación Final celebrada en Helsinki (tunicados, algunos anélidos poliquetos, algunas micro- (Finlandia) del 26 al 29 de junio de 2000. La lista de algas), pero no se conoce bien su función en estos participantes en esta reunión figura en el apéndice 3. Las organismos. Sigue siendo una cuestión abierta si el Fichas internacionales de seguridad química sobre el vanadio es o no esencial para otros organismos. No hay trióxido de vanadio (ICSC 0455) y el pentóxido de pruebas de acumulación o bioamplificación en las vanadio (ICSC 0596), preparadas por el Programa cadenas alimentarias de los organismos marinos, que Internacional de Seguridad de las Sustancias Químicas forman el grupo mejor estudiado. (IPCS, 1999a,b), también se reproducen en el presente documento. Hay una lixiviación muy limitada del vanadio a través de los perfiles del suelo. El vanadio (CAS Nº 7440-62-2) es un metal gris plateado suave que puede existir en varios estados de Se han notificado niveles más altos de vanadio en oxidación diferentes: !1, 0, +2, +3, +4 y +5. La forma el aire próximo a fuentes industriales e incendios de comercial más común es el pentóxido de vanadio (V2O5; hidrocarburos. Las tasas de deposición representativas CAS Nº 1314-62-1) y en este estado pentavalente es un son de 0,1-10 kg/ha al año para zonas urbanas afectadas polvo cristalino rojo-amarillento o verde. por fuentes locales importantes, de 0,01-0,1 kg/ha al año para las zonas rurales y urbanas que no tienen una El vanadio es un elemento abundante, con una fuente local importante y <0,001-0,01 kg/ha al año para distribución muy amplia; se extrae en Sudáfrica, Rusia y las zonas remotas. China. Durante la fusión de la mena de hierro se forma escoria de vanadio con pentóxido de vanadio, que se La mayor parte de las aguas superficiales dulces utiliza para la producción de vanadio metálico. El contienen menos de 3 µg de vanadio/litro; se han pentóxido de vanadio se obtiene también por extracción notificado niveles más altos, de hasta unos 70 µg/litro, con disolventes a partir de menas de uranio y mediante en zonas con fuentes geoquímicas grandes. Los datos un proceso de calcinación de las sales de los residuos de sobre los niveles de vanadio en aguas superficiales las calderas o de los residuos de las instalaciones de próximas a actividades industriales son escasos; la fosfato elemental. Durante la combustión de fueloil en mayoría de los informes parecen indicar niveles calderas y hornos, hay pentóxido de vanadio en los aproximadamente iguales a los naturales más elevados. residuos sólidos, el hollín, las incrustaciones de las Las concentraciones en el agua marina en mar abierta calderas y las cenizas volátiles. oscilan entre 1 y 3 µg/litro y en los sedimentos van de 20 a 200 µg/g; los niveles más altos se observan en los sedimentos costeros.

51 Concise International Chemical Assessment Document 29

Algunos organismos concentran vanadio en can- En un grupo de voluntarios humanos, una expo- tidades que ascienden hasta 10 000 µg/g en las ascidias sición aislada de ocho horas a 0,1 mg de polvo de y 786 µg/g en los anélidos poliquetos. La mayoría de los pentóxido de vanadio/m3 produjo efectos bronquiales organismos suelen contener menos de 50 µg/g y normal- retardados, pero prolongados, con una producción mente concentraciones mucho más bajas. excesiva de moco. Con 0,25 mg/m3 se observó una pauta de respuesta semejante, con la adición de tos durante Las estimaciones de la exposición total de las algunos días después de la exposición. La exposición a personas en los alimentos oscilan entre 11 y 30 µg/día. 1,0 mg/m3 produjo una tos persistente y prolongada Los niveles en el agua de bebida ascienden hasta después de cinco horas. En este estudio no se identificó 100 µg/litro. Algunas fuentes de agua freática que un nivel sin efectos para los trastornos bronquiales. abastecen de agua potable muestran concentraciones superiores a 50 µg/litro. Los niveles en el agua de La exposición por inhalación repetida al polvo y el manantial embotellada pueden ser más altos. humo de pentóxido de vanadio está asociada con la irritación de los ojos, la nariz y la garganta. En los En las personas, la limitada información tóxico- trabajadores expuestos al polvo y el humo de pentóxido cinetica disponible parece indicar que se absorbe de vanadio se suelen notificar jadeo y disnea. En con- vanadio tras la inhalación y luego se excreta en la orina junto, no hay datos suficientes que permitan describir de con una fase inicial de eliminación rápida, seguida de manera fidedigna la relación exposición-respuesta para una fase más lenta, que posiblemente se debe a la los efectos respiratorios del polvo y el humo de pen- eliminación gradual de vanadio de los tejidos del tóxido de vanadio en las personas. organismo. Tras la administración oral, la absorción de vanadio tetravalente a partir del sistema gastrointestinal Las formas pentavalentes y tetravelentes del es escasa. No se disponía de estudios cutáneos. vanadio han provocado efectos aneugénicos in vitro con activación metabólica y sin ella. Hay pruebas de que En estudios de inhalación y de administración oral estas formas de vanadio, así como el vanadio trivalente, en animales de laboratorio, el vanadio absorbido en los también pueden producir in vitro daños en el ADN/ estados pentavalente o tetravalente se distribuye funda- cromosomas, habiéndose obtenido en los estudios mentalmente en los huesos, el hígado, el riñón y el bazo, disponibles resultados tanto positivos como negativos. y también se detecta en los testículos. La vía principal de El valor probatorio de los datos disponibles parece excreción del vanadio es a través de la orina. Su pauta de indicar que los compuestos de vanadio no producen distribución y excreción indica que es posible la mutaciones genéticas en pruebas normalizadas in vitro acumulación y retención del vanadio absorbido, sobre en células de bacterias o de mamíferos. todo en los huesos. Hay pruebas de que el vanadio tetravalente puede atravesar la barrera placentaría y In vivo, tanto los compuestos de vanadio penta- llegar al feto. valentes como los tetravalentes han dado pruebas manifiestas de aneuploidía de las células somáticas tras En el único estudio de inhalación aguda disponible la exposición mediante varias vías diferentes. Las 3 se notificó una CL67 de 1440 mg/m (800 mg de vanadio/ pruebas de que los compuestos de vanadio también m3) tras la exposición de ratas a polvo de pentóxido de pueden producir efectos clastogénicos son desiguales, vanadio durante una hora. En estudios de administración al igual que en los estudios in vitro, y la posición global oral en ratas y ratones se obtuvieron valores de la DL50 sobre la clastogenicidad en las células somáticas es del orden de 10-160 mg/kg de peso corporal para el incierta. Se obtuvo un resultado positivo en células pentóxido de vanadio y otros compuestos de vanadio germinales de ratones a los que se administró pentóxido pentavalente, mientras que para los compuestos de de vanadio por inyección intraperitoneal. Sin embargo, vanadio tetravalente los valores de la DL50 son del orden hay dudas acerca del mecanismo en el que se basa este de 448-467 mg/kg de peso corporal. No hay información efecto (aneugenicidad; clastogenicidad). Tampoco está relativa a la toxicidad cutánea. claro cómo se pueden generalizar estos resultados a vías de exposición más realistas o a otros compuestos de En estudios realizados con trabajadores del vana- vanadio. dio se ha notificado irritación ocular. No se informó de irritación cutánea en 100 voluntarios humanos tras la Las características de la base de datos sobre la prueba del parche cutáneo con un 10% de pentóxido de genotoxicidad del pentóxido de vanadio y otros com- vanadio, aunque la prueba del parche realizada en los puestos de vanadio son tales que no es posible identi- trabajadores produjo dos reacciones aisladas. No hay ficar claramente el nivel umbral para ninguna vía de información clara disponible de estudios en animales con exposición de interés para el ser humano por debajo del respecto al potencial de los compuestos de vanadio para cual no habría que preocuparse por la posible actividad producir irritación cutánea u ocular o bien sensibilización genotóxica. cutánea.

52 Vanadium pentoxide and other inorganic vanadium compounds

No se dispone de información útil sobre el pocos datos sobre las concentraciones en lugares potencial carcinogénico de ninguna de las formas de industriales específicos y no es posible realizar una vanadio por ninguna de las vías de exposición para los evaluación del riesgo sobre esta base. Sin embargo, las animales1 o las personas. concentraciones notificadas parecen ser semejantes a las naturales más altas, lo que parece indicar que el riesgo Un estudio de la fecundidad en ratones machos, sería bajo. Se deben realizar mediciones locales para con exposición al metavanadato de sodio en el agua de evaluar el riesgo en cualquier circunstancia determinada. bebida, parece indicar la posibilidad de que la exposición oral de los ratones machos a este compuesto a concentraciones de 60 y 80 mg/kg de peso corporal causara directamente una disminución del recuento de espermátidas/espermatozoides y del número de gesta- ciones tras el apareamiento. Sin embargo, también se pudo observar una toxicidad general significativa (disminución del aumento del peso corporal) a 80 mg/kg de peso corporal).

Hay algunos estudios sobre los efectos de los compuestos de vanadio pentavalente o tetravalente en el desarrollo, con una observación sistemática de anoma- lías esqueléticas. La interpretación de estos estudios es difícil, debido a las vías de exposición no tradicionales utilizadas y a que hay pruebas de toxicidad materna, la cual podría contribuir por sí misma a los efectos detec- tados en las crías.

Los efectos toxicológicos finales motivo de pre- ocupación para las personas son la genotoxicidad y la irritación de las vías respiratorias. Puesto que no es posible determinar un nivel de exposición sin efectos adversos, se recomienda reducir los niveles en la medida de lo posible.

Los valores de la CL50 para la toxicidad aguda de organismos acuáticos oscila entre 0,2 y unos 120 mg/li- tro, aunque para la mayoría están entre 1 y 12 mg/litro. Otros efectos finales importantes desde el punto de vista ecotoxicológico se observaron en el desarrollo de las larvas de ostras (reducción significativa con 0,05 mg de vanadio/litro) y en la reproducción de Daphnia (con- centración sin efectos observados en 21 días con 1,13 mg/litro). Son pocos los estudios terrestres. La mayoría de los estudios en plantas se han realizado en cultivos hidropónicos, donde se detectaron efectos a concentraciones de 5 mg/litro y superiores; estos estudios son difíciles de interpretar en relación con las plantas cultivadas en el suelo.

Las concentraciones en los compartimentos del medio ambiente son notablemente inferiores a las concentraciones tóxicas notificadas. Se dispone de

1 Los autores de este documento tienen conocimiento de que recientemente se ha completado en el Programa Nacional de Toxicología de los Estados Unidos una biovaloración por inhalación de dos años en roedores. Sin embargo, en este momento no están disponibles todavía los resultados.

53 THE CONCISE INTERNATIONAL CHEMICAL ASSESSMENT DOCUMENT SERIES

Azodicarbonamide (No. 16, 1999) Benzoic acid and sodium benzoate (No. 26, 2000) Benzyl butyl phthalate (No. 17, 1999) Biphenyl (No. 6, 1999) 2-Butoxyethanol (No. 10, 1998) Chloral hydrate (No. 25, 2000) Crystalline silica, Quartz (No. 24, 2000) Cumene (No. 18, 1999) 1,2-Diaminoethane (No. 15, 1999) 3,3'-Dichlorobenzidine (No. 2, 1998) 1,2-Dichloroethane (No. 1, 1998) 2,2-Dichloro-1,1,1-trifluoroethane (HCFC-123) (No. 23, 2000) Diphenylmethane diisocyanate (MDI) (No. 27, 2000) Ethylenediamine (No. 15, 1999) Ethylene glycol: environmental aspects (No. 22, 2000) 2-Furaldehyde (No. 21, 2000) HCFC-123 (No. 23, 2000) Limonene (No. 5, 1998) Manganese and its compounds (No. 12, 1999) Methyl chloride (No. 28, 2000) Methyl methacrylate (No. 4, 1998) Mononitrophenols (No. 20, 2000) Phenylhydrazine (No. 19, 2000) N-Phenyl-1-naphthylamine (No. 9, 1998) 1,1,2,2-Tetrachloroethane (No. 3, 1998) 1,1,1,2-Tetrafluoroethane (No. 11, 1998) o-Toluidine (No. 7, 1998) Tributyltin oxide (No. 14, 1999) Triglycidyl isocyanurate (No. 8, 1998) Triphenyltin compounds (No. 13, 1999)

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