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IPCS
International Programme on Chemical Safety
REPORT OF THE IPCS ELEVENTH FINAL REVIEW BOARDMEETING ON CONCISE INTERNATIONAL CHEMICAL
ASSESSMENT DOCUMENTS (CICADs)
Varna, Bulgaria: 8 - 11 September 2003
Programme international sur la Sécurite des Substances Chimiques
Internal Technical ReportRapport Technique Interne
United Nations Environment ProgrammeProgramme des Nations Unies pour
l'Environnement
International Labour OrganizationBureau International du Travail
World Health OrganizationOrganisation mondiale de la Santé
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UNITED NATIONS ENVIRONMENT PROGRAMME IPCS/CICAD/03.01INTERNATIONAL LABOUR ORGANIZATION English onlyWORLD HEALTH ORGANIZATION
REPORT OF THE IPCS ELEVENTH FINAL REVIEW BOARDMEETING ON CONCISE INTERNATIONAL CHEMICAL
ASSESSMENT DOCUMENTS (CICADs)
Varna, Bulgaria: 8 - 11 September 2003
The issue of this document does not constitute formal publication. It should not bereviewed, abstracted, or quoted without the written permission of the Coordinator,Programme for the Promotion of Chemical Safety, WHO, Geneva, Switzerland.
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CONTENTS
Introduction ....................................................................................................................................... 7Background ........................................................................................................................................ 7Document evaluation......................................................................................................................... 7
Asphalt ........................................................................................................................................... 7Chlorobenzenes other than hexachlorobenzene: Environmental aspects ...................................... 8Chloroform..................................................................................................................................... 8Creosote ......................................................................................................................................... 8Glyoxal........................................................................................................................................... 8Hydrogen cyanide and cyanides: Human health aspects ............................................................... 8Manganese and manganese compounds: Environmental aspects .................................................. 8
General issues to be considered by the Steering Group................................................................. 9Other business.................................................................................................................................... 9
Distribution of CICADs for peer review and FRB ........................................................................ 912th Final Review Board meeting .................................................................................................. 9
Acknowledgements ............................................................................................................................ 9Appendix I: Participants of the FRB Meeting .............................................................................. 11
Members ...................................................................................................................................... 11Observers ..................................................................................................................................... 12Secretariat .................................................................................................................................... 12
Appendix II: AGENDA................................................................................................................... 13Appendix III: Terms of reference for a final review board......................................................... 14Appendix IV: Final review board comments on draft CICADs ................................................. 15
Asphalt ......................................................................................................................................... 15Chlorobenzenes other than hexachlorobenzene: environmental aspects .................................... 17Chloroform................................................................................................................................... 18Creosote ....................................................................................................................................... 20Glyoxal......................................................................................................................................... 22Hydrogen Cyanide and Cyanides: Human health aspects ........................................................... 24Manganese and manganese compounds: Environmental aspects ................................................ 26
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Introduction
Dr N. Rizov on behalf of the National Center of Hygiene, Sofia, Bulgaria, and Dr. A. Aitio,on behalf of the Programme for the Promotion of Chemical Safety, World HealthOrganization, opened the meeting and welcomed the participants.
The meeting opened with the election of officers: Dr R Chhabra was elected as Chair and DrRF Hertel as Vice-Chair and Mr. P Howe and Dr G Dura as Rapporteurs. Following a briefintroduction of each participant (List of participants, Appendix I), the agenda was adopted asproposed (Appendix II).
None of the members of the 11th Final Review Board (FRB) declared any conflict of interestswith the subject matter of the meeting, and the potential conflicts of interest of two memberswith tobacco production/tobacco industry were considered not to present an impediment fortheir full participation in the meeting. The declaration of interest forms for each peer reviewerwere considered in the context of separate CICAD drafts.
Background
Dr A. Aitio outlined the Terms of Reference for the meeting (Appendix III), and described theinternational peer-review process for the production of CICADs. He clarified the roles ofMembers and Observers, namely that Members are responsible for taking the formaldecisions on the CICADs, whereas Observers are restricted to commenting on the factualcontent of the documents. Members were reminded that they are selected to serve on the FRBfor their individual scientific expertise and not, in any way, as representatives of theirgovernments.
Document evaluation
After an introduction to and discussion of the key items brought up by the peer review processby the Discussion Leader, the FRB systematically reviewed responses of the authors to thecomments submitted during the peer-review phase. Areas where additional changes wererecommended are noted in Appendix IV. All other comments were considered to have beenadequately addressed by the authors. The tables of peer-review comments are to be held bythe Secretariat and made available, upon request.
Asphalt
The CICAD on Asphalt was approved by the Final Review Board as an internationalassessment and recommended it for publication subject to the requested changes being madeas noted in Appendix 4. The FRB further recommended that the IPCS Risk AssessmentSteering Group consider whether it is possible and useful to derive tolerable concentration forinhalation exposure for non-cancer endpoints on the base of animal experiments (taking intoaccount difficulties of experimental generation of fumes) and that the approval of the peer-review-induced changes be sought from the meeting Chair, Vice-Chair and DiscussionLeader.
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Chlorobenzenes other than hexachlorobenzene: Environmental aspects
The CICAD on Chlorobenzenes (other than hexa-); Environmental aspects was approved bythe Final Review Board as an international assessment and recommended for publicationsubject to the requested changes being made as noted in Appendix 4, as approved by theChair.
Chloroform
The CICAD on Chloroform was approved by the Final Review Board as an internationalassessment and recommended for publication subject to the requested changes being made asnoted in Appendix 4, as approved by the Chair.
Creosote
The CICAD on Creosote was approved by the Final Review Board as an internationalassessment and recommended for publication subject to the requested changes being made asnoted in Appendix 4, as approved by the Chair. Advice to be sought from the Steering Groupon the title of de novo CICAD documents, as exemplified by the draft on Creosote.
Glyoxal
The CICAD on Glyoxal was approved by the Final Review Board as an internationalassessment and recommended for publication subject to the requested changes being made asnoted in Appendix 4, as approved by the Chair.
Hydrogen cyanide and cyanides: Human health aspects
The FRB approved the main text of the document subject to requested changes being made asnoted in Appendix 4. The FRB revised the Section 10 of the document to better accommodatethe peer review comments received and recommended that advice be sought from the RiskAssessment Steering Group on the optimal way of finalising the draft CICAD specifically visa vis the need to involve further review of the revised section: are the changes proposed bythe FRB within the purview of the FRB, or are the changes performed of such importance thatfurther peer review is needed.
Manganese and manganese compounds: Environmental aspects
The CICAD on Manganese was approved by the Final Review Board as an internationalassessment and recommended for publication subject to the requested changes being made asnoted in Appendix 4, as approved by the Chair.
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General issues to be considered by the Steering Group
1. Whether guidelines are needed on the particular sensitivity of children and moregenerally, to especially sensitive life stages.
2. How we go about publishing responses to peer-review comments.3. Specific guidelines on discussion leaders approaching authors before FRB.4. The presentation of the Evaluation section (references to original studies)5. The presentation of the literature searches performed to update the source document
Other business
Distribution of CICADs for peer review and FRB
The FRB considered that the distribution of the documents via the world wide web, using auser name and pass word-protected entry, a step forward. After some initial difficulties ofaccess had been removed by technical changes, there had been no problems with the access.The FRB considered this way of distribution a better alternative than email because of theincreasing uncertainties of the safety of the email attachments.
12th Final Review Board meeting
The 12th FRB is planned to take place in June 2004. The closing date for the receipt of firstdraft of CICADs is January 31, 2004. Chemicals likely to be considered includealkoxyethanols (methoxy-, ethoxy-, propoxy- and butoxyethanol), heptachlor, tin andinorganic tin compounds, and butyl acetate isomers.
Acknowledgements
The International Programme on Chemical Safety (IPCS) wishes to express its gratitudeto the Japanese Ministry of Health and Welfare and the United States EnvironmentalProtection Agency, and European Commission for their generosity in providing financialsupport for the CICADs Project, which enabled the IPCS to convene this 11th Final ReviewBoard. Thanks are also due to local organizing committee, chaired by Dr Fina PetrovaSimeonova the for providing the meeting facilities and the practical arrangements of themeeting. Finally, appreciation is extended to the authors of the first draft documents, peerreviewers and FRB members, especially those who agreed to fulfil the roles of Chairman,Vice-Chairman and Rapporteurs, i.e., Drs Chhabra, Hertel, Dura, and Mr. Howe, respectively,as well as to those participants who acted as discussion leaders. They gave generously of theirtime and their expertise. The commitment of all the aforementioned has contributed to thesuccess of the IPCS CICADs chemical risk assessment activity.
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APPENDIX I
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Appendix I: Participants of the FRB Meeting
Members
Dr Ivan Benchev, Complex Lulin 5, Block 508 vhodA, Apart.31, Sofia, Bulgaria, fax: 359 2 9541277Dr Raj Chhabra, National Institute of Environmental Health Sciences, P.O. Box 12233, ResearchTriangle Park, North Carolina 27709, United States of America, tel: 1 919 541 3386, fax: 1 919 5414704, e-mail: [email protected] Christopher De Rosa, Agency for Toxic Substance and Disease Registry (ATSDR), Centres forDisease Control (MS-29), Atlanta, Georgia 30333, United States of America, tel: 1 404 498 0160, fax:1 404 498 0094, e-mail: [email protected] Stuart Dobson, Centre for Ecology and Hydrology, Monks Wood, Abbots Ripton, Huntingdon,Cambridgeshire, PE28 2LS, United Kingdom, tel: 44 1387 772 494, fax: 44 1487 773 467, e-mail:[email protected] Gyula Dura, Acting Director, National Institute of Environmental of József Fodor Public HealthCentre, Gyáli út 2-6, Budapest 1097, Hungary, tel: 361 218 3158, fax: 361 215 0148, e-mail:[email protected] Lawrence Fishbein, 4320 Ashford Lane, Fairfax, Virginia 22032, United States of America, tel: 1703 764 5232, fax: 1 703 764 7281, email: [email protected] Herman Gibb, National Center for Environmental Assessment (8601D), US EnvironmentalProtection Agency, Ariel Rios Building, 1200 Pennsylvania Avenue NW, Washington, DC 20460,United States of America, tel: 1 202 564 3334, fax: 1 202 565 0090, e-mail:[email protected] Rolf F. Hertel, Federal Institute for Risk Assessment (BfR), FG82, Thielallee 88-92, 14195Berlin, Germany, tel: 49 188 8412 3931, fax: 49 188 8412 3003, e-mail: [email protected] Paul Howe, Centre for Ecology and Hydrology, Monks Wood, Abbots Ripton, Huntingdon,Cambridgeshire, PE28 2LS, United Kingdom, tel: 44 1487 772 499, fax: 44 1487 773 467, e-mail:[email protected] Susumu Ishimitsu, Chief, Division of Safety Information on Drug, Food and Chemicals, NationalInstitute of Hygienic Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan, tel: 813 37001482, fax: 813 3700 1483, e-mail: [email protected] Debabrata Kanungo, Central Insecticides Board, Directorate of Plant Protection, Quarantine &Storage, Ministry of Agriculture, Government of India, NH IV, Faridabad-121 001, Haryana, India,tel: 91 98 183 94 894, fax: 91 129 241 2125, e-mail: [email protected] Janet Kielhorn, Fraunhofer Institute for Toxicology and Experimental Medicine, Nikolai-Fuchs-Strasse 1, D-30625 Hannover, Germany, tel: 49 511 5350 329, fax: 49 511 5350 335, e-mail:[email protected] Bette Meek, Environmental Health Directorate, Health Canada, Tunney's Pasture (AddressLocator 0801C2), Ottawa, Ontario K1A OL2, Canada, tel: 1 613 957 3129, fax: 1 613 954 2486, e-mail: [email protected] Takeshi Morita, Senior Researcher, Division of Safety Information on Drug, Food andChemicals, National Institute of Hygienic Sciences, 1.18-1 Kamiyoga, Setagaya-ku, Tokyo 158 8501,Japan, tel: 813 3700 1482, fax: 813 3700 1483, e-mail: [email protected] Frank K. Muchiri, Acting Director, Directorate of Occupational Health and Safety Services, P.O.Box 34120 - 00100, Nairobi, Kenya, tel:254 20 555 178, fax: 254 20 550825, e-mail:[email protected] Edward Ohanian 1, Director, Health & Ecological Criteria Division, USEPA1200 Pennsylvania Avenue, NW Washington DC 20460, USA, tel: +1 202 566 1117, fax: +1 202566 1140, email: [email protected]
1 invited but unable to attend
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Dr Larry Olsen, Research Chemist, Biological Monitoring & Health Assessment Branch, Division ofApplied Research & Technology, NIOSH Mailstop C26, 4676 Columbia Parkway, Cincinnati, OH45226, United States of America, tel: 1 513 533 8543, fax: 1 513 533 8494, e-mail: [email protected] Nikolai Rizov, Associate Professor, Director, National Center of Hygiene, Medical Ecology andNutrition, 15 Dimitar Nestorov Blvd., Sofia 1431, Bulgaria, tel: 359 2 954 1300, fax: 359 2 954 1277,e-mail: [email protected] Paul Schulte, Director, Education and Information Division, NIOSH Mailstop C32, 4676Columbia Parkway, Cincinnati, OH 45226, United States of America, tel: 1 513 533 8339, fax: 1 513533 8588, e-mail: [email protected] Jun Sekizawa, Professor, Faculty of Integrated Arts and Sciences Tokushima University, 1-1Minami-josanjima, Tokushima 770-8502, Japan, tel/fax: 81 88 656 7263 e-mail:[email protected] Fina Petrova Simeonova, Professor, Bul. Zarigradsko shosse 4a block 2a, Sofia 1113, Bulgaria,tel: 359 2172 6587, fax: 359 295 41277, e-mail: [email protected] Salah Soliman, Professor, Alexandria University, Faculty of Agriculture, El Shatby, Alexandria21545, Egypt, tel: 203 592 0067, fax: 203 592 2780, e-mail: [email protected] Jennifer Stauber, CSIRO Energy Technology, Centre for Advanced Analytical Chemistry,Private Mail Bag 7, Bangor, NSW 2234, Australia, e-mail: [email protected] Peter Watts, Toxicology Advice & Consulting Ltd., Westmead House, 123 Westmead Road,Surrey SM1 4JH, United Kingdom, tel: 44 208 722 4701, fax: 44 208 770 0544, e-mail:[email protected] Deborah Willcocks, GPO Box 58, Sydney, NSW 2001, Australia, tel: 612 8577 8890, fax: 61 28577 8888, e-mail: [email protected] Yuxin Zheng 1, Professor and Deputy Director, National Institute for Occupational Health andPoison Control, Chinese Center for Disease Control and Prevention, 29 Nan Wei Road,Beijing 10050,P.R. China, tel: +86-10-63047639, fax: +86-10-63014323, e-mail [email protected] Kyriakoula Ziegler-Skylakakis, European Commission, DG Employment & Social Affairs, RueAlcide de Gasperi, 2920 Luxembourg, tel: 352 4301 34424, fax: 352 4301 43259, e-mail:[email protected]
Observers
Dr Sylvia Jacobi, Degussa AG, Fine Chemicals, Chemicals Safety Management, FC-TME-CSM,Postcode 266-001, Rodenbacher Chaussee 4, D-63457 Hanau-Wolfgang, Germany, tel: 49 6181 593900, fax: 49 6181 59 2083, e-mail: [email protected]. Mike Southern, Shell International Petroleum Company Limited, Shell Centre, London SE17NA, United Kingdom, e-mail: [email protected]. Wil ten Berge, DSM, Corporate SHE & M, P:O: Box 6500, NL 6401 JH Heerlen, theNetherlands, tel: 31 45 578 7128, fax: 31 45 578 7112, e-mail: [email protected]
Secretariat
Dr A. Aitio, International Programme on Chemical Safety, World Health Organization, 20 AvenueAppia, 1211 Geneva 22, Switzerland, tel: 41 22 791 3592, fax: 41 22 791 4848, e-mail:[email protected] T. Ehara, International Programme on Chemical Safety, World Health Organization, 20 AvenueAppia, 1211 Geneva 22, Switzerland, tel: 41 22 791 4334, fax: 41 22 791 4848, e-mail:[email protected]
1 invited but unable to attend
APPENDIX II
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Appendix II: AGENDA
1. Opening of the meeting, election of officers and adoption of the agenda
2. Introduction to the Terms of Reference for Final Review Board members
3. Discussion of conflicts of interest
4. Draft CICAD on Chloroform1
5. Draft CICAD on Hydrogen cyanide and cyanides: Human health aspects
6. Draft CICAD on Creosote
7. Draft CICAD on Chlorobenzenes (other than hexa-), environmental aspects
8. Draft CICAD on Asphalt
9. Draft CICAD on Glyoxal
10. Draft CICAD on Manganese and compounds: Environmental aspects
11. Future CICADs
12. Any other business
• Distribution of CICAD draft documents
13. Closure of the meeting= = =
1 Consideration of each draft CICAD will be lead by the discussion leader
APPENDIX III
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Appendix III: Terms of reference for a final review board
The Final Review Board is responsible for the following functions:
ensuring that each CICAD has been subjected to an appropriate and thoroughpeer review;
verifying that peer reviewers’ comments have been addressed appropriately;
providing guidance to authors on how to resolve any remaining issues if, in theopinion of the Board, all comments of the reviewers have not been adequatelyaddressed;
approving CICADs as international assessments.
The Final Review Board conducts most of its business at meetings, but when needed, also bycorrespondence after and before the meetings. It is guided in its work by the IPCS ProgrammeAdvisory Committee, and functions in collaboration with the IPCS Steering Group on RiskAssessment.
APPENDIX IV
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Appendix IV: Final review board comments on draft CICADs
For all CICAD drafts, the changes in the text to be reflected in the Executive summary.
Asphalt
Discussion leader: Dr H.Gibb
It was agreed to modify title to Asphalt (Bitumen).
Dr Gibb emphasized three main areas from the peer-review comments which warranted furtherdiscussion:
• Is the risk of cancer understated? Yes – make modifications to section 11 and the summary.• Should the Boffetta et al. study be described as finding no ‘causal link’ between bitumen
fume and lung cancer? Yes – in both section 11 and the summary. However, the main textshould avoid making an assessment of individual studies, and the wording causal link(usually restricted to describe the totality of the studies rather than a single study) shouldtherefore be deleted from the text. Assessment of the studied should be performed in Section11.
• Should there be more discussion of the difference in chemical composition, physicalcharacteristics and biological activity between asphalt fumes collected in the field and thosein the laboratory? No.
Specific points
Section 2Add comparative description of different bitumens from CEN, and reference to CONCAWEhttp://www.concawe.be/Download/Reports/Rpt_92-104.pdf. Editorial change: Move the bullet pointsfrom Chapter 4 to Chapter 2 as they describe asphalts (and not sources of exposure)
Section 3.1, para 2Add a sentence to clarify that the earlier NIOSH method is comparable to the published 1998 NIOSHmethod.Indicate how samples should be taken and if possible make a statement on particle size.
Section 4, para 4Standardise tons and tonnes.
Section 5, para 2First part dealing with toxicity to be moved to Section 10 (retain degradation information in section 5).
Section 6, para 3Remove table 6-1 and details of analysis.
Section 6.2, para 5Check the original paper on 5 mg/L of PAC concentration in water. Is this an experiment? If thefigure is correct state that ‘significance unclear’.
Section 6.2, para 9Clarify so that whole body burden can be calculated
APPENDIX IV
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Section 6.2, para 10Move information on DNA strand breaks to section 9.
Section 7Para 1: Editorial changes to indicate that mixtures do not rend themselves to kinetic analyses; there areseveral studies on the kinetics of different components of bitumen/asphalt, and it is not known whetherthe kinetics of the components is similar when presented in mixture = if there are interactions. Addadditional data/article from Dr.Ziegler-Skylakakis on toxicokinetics of Asphalt, if helpfull ininterpretation of the information on disposition of asphalt (The MAK document). Clarify ‘radicalcations’.
Section 8, para 1Delete ‘generated during paving and roofing operations’ from end of first sentence.
Section 8.1To the extent possible rearrange irritation of skin followed by irritation of the respiratory tract
Section 8.1, para 2Add clinical signs of irritation
Section 8.1, para 6After the first line add ‘The generation of the asphalt fumes was mimicked to be similar to humanexposure during road paving in Germany (Pohlmann et al., 2001 and one other reference provided byDr Kielhorn).Add ‘nose only’The whole paragraph to be moved (editorial decision on placement - only partially irritation).
Section 8.2.2, para 7Delete penultimate sentence. Ma et al. (2002) paper to be checked ("absence of positive findings").
Section 8.4Add footnote to the effect that the FRB is aware of a two- year nose only inhalation carcinogenicitystudy in rats on asphalt (Fraunhofer).
Section 8.4, para 16Check the number of animals in the text relative to the following table. Delete last sentence.
Section 9Two articles on human DNA-adducts should be included (from Dr.Ziegler-Skylakakis [Fuchs et al1996, Jarvholm et al 1999); to go together with the article of Toraasson from Section 6) and cross-referenced to section 6.2 (biomarker information in 6 and strand breaks in 9).
Section 10Reinstate original title. Move para 2 to section 5.
Section 11 Para 2Check the wording "raw asphalt"
Section 11.1.1, para 3Shorten paragraph and remove references.
Section 11.1.1, para 5The lowest exposure (0.02 mg/m3) which caused respiratory tract problems should be added.
APPENDIX IV
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Section 11.1.2Delete paragraph 7.
Section 11.1.3Delete paragraphs 9 & 10. Use some of the material in the uncertainties section.
Section 11.1.5To be deleted. Information to be made available to the steering group.
Chlorobenzenes other than hexachlorobenzene: Environmental aspects
Discussion leader: Dr J. Stauber
Section 1Extra sentence to be added outlining the reasoning for producing a CICAD on environmental aspectsonly.Extra paragraph to be added summarising the evaluation section following modification.
Section 2, table 1Authors to check the original source of the solubility data used in the WHO EHC on chlorobenzenes.
Section 2, table 2The number of significant figures used to be reduced.
Section 4.2, para 4Authors to check IUCLID for production figures.
Section 4.2Dr Sekizawa to provide more production figures for Japan.The production of lindane as a possible source of chlorobenzenes to be added.
Section 4, table 2The number of significant figures used to be reduced.
Section 5.2.2, para 18Authors to check spelling of My(c)obacterium.
Section 5.2.2 paras 23 & 25bAuthors to check if there are any exposure figures for these studies.
Section 6, para 5Extra text on whether chlorobenzenes were dissolved or not provided by authors in response to aquestion by a peer-reviewer.
Section 6, para 9Authors to reduce the number of significant figures used in the last sentence.
APPENDIX IV
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Section 7, table 3If no further details are available regarding the endpoints cellular changes in the toxicity tests on greenalgae and diatoms then these should be deleted from the table.All 72h EC50s on algae to be moved to table 4.
Section 7, table 4All short-term LC50s on fish survival should be moved to table 3.Add extra study on 40 day NOEC for marine crabs (Dr Stauber to provide).
Section 7.2Add a statement that toxicity information on other terrestrial organisms was not found.
Section 8Evaluation to be modified taking into account that some of the algal studies have been reclassified aschronic tests and that an extra marine study on crabs is now available.Figures to remain in Section 8 as modified by authors.
Chloroform
Discussion Leader: Dr R. S. Chhabra
Section 1Remove reference to Canada throughout summary except where this is necessary.
Section 1, para 6The TDI is not corrected in the text and should read 0.015.Results of the short-term test should be clarified. More details on histopathology to be added.Section 3Dr Rizov to provide information on extra analytical techniques.
Section 4, para 1Change the units Gg to metric tonnes throughout paragraph.Delete last two sentences.
Section 5.5, para 5Change Lustry to Lusty.
Section 5.6, para 6Change 99.1 to 90.1.
Section 6, para 5Large number of non -detected in this study making the means unreliable. Remove reference to meansand just quote the highest recorded and the detection limits in addition to the percentage of results >det. limits.Is chloroform in tobacco smoke? Authors to check.Authors should check the original source to see if there is a significant difference between smokingand non-smoking households.
APPENDIX IV
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Section 6, para 22 (level of exposure): Tables 3 & 4Clarify how the statistical analysis was performed and identify number of samples for the differentcategories in table 3 and 4 which form the basis for the Monte Carlo analysis.
Section 7The metabolic pathway figure to be edited to specify the key role of CYP2E1 and cross-reference tosection 8.8 to emphasise the same point.
Section 7.2, para 9Refer to the source document for detail of PBPK model though some expansion in the text. Explain infootnote the “hybrid” animal or cross-reference to the source document.
Section 8.1, para 1bMove the 13-week material into short-term exposure.
Section 8.2.1, para 13Possible move to long-term (IPCS to decide). Add personal communication from NTP veterinarypathologist about his opinion that the liver effects seen in dog study were treatment-related.Add some extra information from table 6 into the text to support treatment-related conclusion.
Section 8.4.3, para 22Yamamoto study does not need further information (5 ppm low concentration to be added).
Section 8.5Detail on genotoxicity adequate as it is; refer to table in source document for detail.
Section 8.7, para 41The paragraph is deleted and the material moved to 8.2.1: delete relevant sentences in paras 3 & 4.
Section 8.8Mode of action - insert a short recap of critical information on CYP 2E1, phosgene generation,reaction with lipids - underline metabolism at low exposure with an introductory summary paragraph.
paras 45, 46, 48 & 56The authors to check to make sure all corrections have been made.
Section 10.1 Add marine data from Dr Stauber
Section 11.1.1Remove ‘and dose response assessment’ from the title.
Section 11, para 12Expand with information from appendix 1, para 9 regarding the justification for the uncertaintyfactors.
Section 11.1.2Define VMRATEK and VMRATEL.
Section 11.1.3Clarify method of moving from TDI to tissue dose (Bette Meek to propose text).
APPENDIX IV
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Section 11.1.3, para 31Delete reassuring.
Section 11.1.4, paras 35 & 36PBPK model – mention that human kidney has much less CYP2E1 contents than the laboratoryanimals and that the PBPK model takes this into account. The text should address the uncertainityinstead of the need for further studies.
Section 11.2Give explanation on EEV, PEC, ENEV and PNEC. Compare Canadian and EU approaches. Makeoverall conclusion for both freshwater and marine that toxicity unlikely at typical environmentalconcentrations but possible in worst case (Stuart Dobson to help modify text)
Para 48bExplain or remove marine dilution of 6 to 360.
Creosote
Discussion Leader: Dr C. De Rosa
It was agreed that the title should be changed to COAL TAR CREOSOTE.
Specific pointsParentheses should be used consistently for denoting PAHs (e.g. benzo[a]pyrene) throughout thedocument. Dr Hoeke's comments submitted after the cut-off date on the details of the text to beconsidered by the author during the final revision.
Section 2, table 2.1A range of melting points to be identified and added (emphasise properties are different in variousCreosote preparations (for different application))
Section 2, table 2.2Heikkila (2000) reference not thought to be the most appropriate to use as a source for physico-chemical properties. Dr Olsen suggested other more relevant sources of information.
Section 2, figure 2.2BTEX ethylbenzene, other isomers of xyleneIt would be more informative to present the structure of dibenzofuran since this is mentioned in thetext.
Section 2.3Dr Rizov to provide some text regarding up-to-date analytical techniques.
Section 2.3, para 29Dr Olsen to provide rewording for first two sentences regarding NIOSH analysis.
APPENDIX IV
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Section 3, para4bSource to be defined - add IPCS personal communication
Section 3, para 18Author to check the website of the American Wood Preservers Association for the number of creosotetreatment plants in the USA.
Table 5-13Concerning exposure of children in playground : give footnotes to website (for exposure model, giveinformation of models/model assumptions)
Section 6, para 10Needs to be reworded to improve the clarity.
Section 6, para 13Add to reference list papers in thesis.
Section 7.3, para 13Reinstate paragraph and expand to include dermal exposure. Make explicit statement that creosote is5 times more potent as a carcinogen than its B[a]P content alone would have predicted.Refer to CSTEE (1999) document on website. Add a footnote that a risk assessment was made fromthis study.
7.6.2.1, para 44Sampling time to be added – 24 hours after final treatment.
Table 8-3Dr Gibb to reorganize the table.Footnote needs to be changed from consulting group to consultative group. Information regarding theconsultative group needs to be added in an appendix.
Table 8-4The cohorts National Cancer Registry, Sweden and Finnish Cancer Registry need to be clarified.
Section 9.1.2.2, para 18EC50 expressed in % - ’elutriate equals 100%’ needs to be added in parentheses.
Section 9.1.2.3, para 22Wording to be clarified by Dr Dobson.
Section 10.1.3, para 12Deleted text to be replaced with ”Creosote is considered to be a genotoxic carcinogen for which athreshold level has not been identified”. Please note that this same sentence needs to be added tosection 1.9, para 81.
Section 10.1.3, para 17Reinstate second half of paragraph. Expand to include dermal route, mice, clarify that it is acumulative risk for one type of creosote, that data are insufficient for risk characterization and addfootnote to CSTEE website. Describe the study that was used in more detail. Add to executivesummary.
APPENDIX IV
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Section 10.1.3, para 19Expand paragraph to include the ’potential of being carcinogenic in humans when exposed dermally’.Underline that Creosote, based on the experimental data, seems to be a complete carcinogen beingboth as initiator and promoter.Section 10.1.4Incoporate some of first sentence from section 2.1, paragraph 7 with additional remarks on toxicology.
Glyoxal
Discussion leader: Dr S. Dobson
Section 2Chemical structures and names to be revised to reflect stereochemistry if possible.
Section 2, para 1The reference to “mixtures with air may explode” was added in response to a reviewer’s comment. Itappears that this is the result of a dust explosion rather than any chemical properties of the compound;this should be deleted.
Section 3.4 para 5If the information is available, insert some text to explain why glyoxal concentrations rise in plasma ofuraemic patients or state such information does not exist in the literature.
Section 4.2Dr Sekizawa to provide extra information on Japanese production.
Section 4.3Reword the text on main uses to avoid the apparent contradiction.
Section 5.2The names (formaldehyde and hydroxycarbene) do help to distinguish between H2CO and HCOH[removed in response to a comment] and should be left in.
Section 6.2.1, para 8bChange ‘worst case etc’ to ‘An exposure scenario has been compiled as a hypothesised worst case’Specify that these are the authors’ calculations and say something about the basis of choosing thesefoods/consumption levels (note that these changes must be reflected in section 11).Explain ‘digestive’.
Section 6.2.1, para 9Take highest value for air concentration for this estimate of inhalation intake.Explain origin of the drinking water estimate.
New para 11Insert new text on consumer products.
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Section 6.2.2, para 13replace with text on new example of exposure scenario (nurse cleaning)
Section 8, para 11Second sentence should reflect that effects were seen at maternally toxic doses.
Section 8.5, para 33Question from reviewer 14 on whether cytotoxicity was reported – state that it wasn’t
Section 8.6.2, para 41add OECD guideline number
Section 8.6.2, para 42clarify why the authors of the NTP study chose to ignore apparent developmental effects and/or flagthese in the Evaluation.
Section 8.6.2, para42binsert species (rat) and some more detail of the result.
Section 8.8, para 46It should be stated that this effect has never been shown for glyoxal.
Section 11In responding to reviewers’ comments, the authors have included NOELs for routes other thaninhalation in Section 11. They have also developed and explained estimates of daily intake from foodin the text. However, this exposure side of the oral argument is not included in Section 11. This leavesthe oral effects information somewhat isolated. Some comment in Section 11 of the likely significanceof intake from food would be helpful since both sides of the equation are covered in the document.Extra uncertainties would be needed in 11.1.4 for the oral route.
Section 11.1.1, para 11Last sentence – add ‘a lifetime skin painting study’
Section 11.1.2, para 12Reinstate original text and remove new text.
Section 11.1.2, para 15Clarify that calculations are done as 100% glyoxal. Delete higher NOAEL (>10) and reference tosystemic effects in both sentences.
Section 11.1.2, para 15bThere are short and medium term studies with similar outcomes and evidence that glyoxal is notaccumulated in the body. The use of the lifetime extrapolation uncertainty factor (factor of 5) is alsojustified on the basis of the 125 mg/kg LOAEL with wide dose spacing to NOAEL of 25 mg/kg.
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Section 11.1.3Insert new text on example risk characterisations.Example 1: delete ‘worst case’ replace with ‘An exposure scenario has been compiled as ahypothesised worst case’; delete last sentence.Example 2: delete last sentence and replace with ‘Dermal contact may cause sensitisation.’Compare amount in food with TDI.
State that NOAEL wasn’t established in the studies available; therefore, the highest dose level appliedin the studies was considered as NOAEL, but the values could be higher if the studies wereperformed at the dose levels showing some effects.
Section 11.1.4Add to uncertainties section that glyoxal can be formed endogenously.
Section 11.1.4, para 17adelete ‘and on in vitro’
Section 11.1.4, para 17bDelete.
Hydrogen Cyanide and Cyanides: Human health aspects
Discussion Leader: M.E. Meek
Section 6.1.3Reinstate text on soil
Section 6.1.5Delete last part of sentence “for health …although previously banned”. Following sentence needseditorial change (not sentence).CN- radical – delete the minus and add a raised period CN.
Section 6.2.1Check the figures on levels in food against the revision of Chapter 10 to inform risk assessment
Section 7.1, para 3Skin absorption … can lead to harmful effects.
Section 7.2, para 5Insert “known occupational” between ‘without’ and ‘cyanide exposure’.
Para 6Move to beginning of 7.2 and make sure that there are no inconsistencies.
Section 8.1, para 1bInsert units mg/m3
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Section 8.1, para 4Harmonise the text in the Summary with respect to the information on irritation presented here.State that there is incomplete information on the exposure regime in the dermal study on rabbits.
Para 8Give some explanation of why the difference between the bolus dose and dietary exposure. Specifythat both mg/kg values are expressed as body weight.
Section 8.3.1, para 31Check if the ‘decrease’ was reported to be statistically significant
Para 16Insert ‘daily’ for 15 months. Cross reference to 8.7 or copy text into both sections
Section 8.4, para 25Check the NOAEL of 11.2 mg/kg. Is this a female dose? If so, reinstate the text on the females or statesomething about female effects.
Section 8.5.1Subheadings “in vivo” and “in vitro studies” to be removed
Section 8.6.1, para 33’After 21 weeks’ to be corrected to ’After 2 weeks’
Section 8.7, para 49Insert extra text from Dr Fishbein
Section 9, para 6Delete para; verify that the acute lethal doses are consistent in the different paras
Section 9.2, para 28Remove ’adequate engineering devices......’.
Section 10
FRB partly revised the Section 11 (and in consequence modified the Section 1) to better accomodatethe peer reviewers' comments and to reflect the high acute toxicity of cyanides. The authors andsecretariat to verify the accuracy of the new draft against the main text and the original papers andconsult with the Risk Assessment Steering Group on whether the modified texts represent a changethat requires a new peer review or other steps before acceptance of the whole document as aninternational assessment.
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Manganese and manganese compounds: Environmental aspects
Discussion leader: Dr J. Stauber
The main area of discussion that was highlighted was the risk evaluation section and whether someform of quantitative risk assessment could be carried out.
Sections 1 & 8To be compared with section 4.2 for consistency with regard to statements on anthropogenic releases.
Section 2, Table 1Information on water solubility to be added; the CAS no of mancozeb (8018-01-7) to be corrected.
Section 4.1, para 2Clarify the meaning of ‘black smokers’.
Section 4.1, para 8Dr Willcocks to provide information to revise the first sentence.Loranger & Zayed (1995) should be deleted from this paragraph because the information ismisleading.Replace last sentence of paragraph 8 with revised text.
Section 4, para 9After para 9: Add the following: It is clear that the contribution of MMT to overall manganese levelsin the environment is complex. The contribution of MMT to atmospheric manganese concentrations isdifficult to establish since it may be masked by more substantial variation associated with otherindustrial activities as well as road dust and windblown dust (Bankovitch et al. 2003). However, eventhough manganese may be a small percentage of total suspended particulate measured in cities, such asMontreal, the contribution of MMT to air manganese levels could be significant in that it may accountfor stable manganese levels in the face of declining total suspended particulate concentrations. Factorssuch as unfavourable meteorological conditions and high traffic density could lead to an increase inthe annual fine manganese levels attributable to MMT (Wallace & Slonecker, 1997; Davis et al.,1998).
Section 5.2, para 12Add paragraph on Biotransformation by micro-organisms after this paragraph.
Section 6, para 5Add the following to paragraph:During the late summer Horsetooth Reservoir, CO, USA is fully stratified and exhibits seasonally highfluxes of iron, manganese and metal-rich particles into the water column. Stein et al. (2002)monitored manganese concentrations during August 1999. Total manganese concentration in waterprior to filtration and measured by AAS was 93 µg/litre; after sedimentation of particles the totalmanganese concentration was 213 µg/litre measured by ICP-AES.However, check the values.
Section 6, Table 2aThe year of the study to be added
Section 7.2Dr Stauber to provide extra references.
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Section 7.2, Table 3Bogaerts et al. (1998) to be checked.
Section 8It was agreed to carry out a semi-quantitative risk assessment. The authors to carry out an assessmentwhich will be checked by Drs Stauber, Chhabra and Aitio. The assessment will be peer-reviewed byat least two independent reviewers.
ICSCs:The card on Mancozeb (0754) to be added