IPCS
International Programme on Chemical Safety
REPORT OF THE IPCS ELEVENTH FINAL REVIEW BOARD
MEETING ON CONCISE INTERNATIONAL CHEMICAL
ASSESSMENT DOCUMENTS (CICADs)
Varna, Bulgaria: 8 - 11 September 2003
Programme international sur la Sécurite des Substances Chimiques
Internal Technical Report
Rapport Technique Interne
United Nations Environment Programme
Programme des Nations Unies pour
l'Environnement
International Labour Organization
Bureau International du Travail
World Health Organization
Organisation mondiale de la Santé
2
UNITED NATIONS ENVIRONMENT PROGRAMME
INTERNATIONAL LABOUR ORGANIZATION
WORLD HEALTH ORGANIZATION
IPCS/CICAD/03.01
English only
REPORT OF THE IPCS ELEVENTH FINAL REVIEW BOARD
MEETING 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 be
reviewed, 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 ....................................................................................................................................... 7
Background ........................................................................................................................................ 7
Document evaluation......................................................................................................................... 7
Asphalt ........................................................................................................................................... 7
Chlorobenzenes other than hexachlorobenzene: Environmental aspects ...................................... 8
Chloroform..................................................................................................................................... 8
Creosote ......................................................................................................................................... 8
Glyoxal........................................................................................................................................... 8
Hydrogen cyanide and cyanides: Human health aspects ............................................................... 8
Manganese and manganese compounds: Environmental aspects .................................................. 8
General issues to be considered by the Steering Group................................................................. 9
Other business.................................................................................................................................... 9
Distribution of CICADs for peer review and FRB ........................................................................ 9
12th Final Review Board meeting .................................................................................................. 9
Acknowledgements ............................................................................................................................ 9
Appendix I: Participants of the FRB Meeting .............................................................................. 11
Members ...................................................................................................................................... 11
Observers ..................................................................................................................................... 12
Secretariat .................................................................................................................................... 12
Appendix II: AGENDA................................................................................................................... 13
Appendix III: Terms of reference for a final review board......................................................... 14
Appendix IV: Final review board comments on draft CICADs ................................................. 15
Asphalt ......................................................................................................................................... 15
Chlorobenzenes other than hexachlorobenzene: environmental aspects .................................... 17
Chloroform................................................................................................................................... 18
Creosote ....................................................................................................................................... 20
Glyoxal......................................................................................................................................... 22
Hydrogen Cyanide and Cyanides: Human health aspects ........................................................... 24
Manganese 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 Health
Organization, opened the meeting and welcomed the participants.
The meeting opened with the election of officers: Dr R Chhabra was elected as Chair and Dr
RF Hertel as Vice-Chair and Mr. P Howe and Dr G Dura as Rapporteurs. Following a brief
introduction of each participant (List of participants, Appendix I), the agenda was adopted as
proposed (Appendix II).
None of the members of the 11th Final Review Board (FRB) declared any conflict of interests
with the subject matter of the meeting, and the potential conflicts of interest of two members
with tobacco production/tobacco industry were considered not to present an impediment for
their full participation in the meeting. The declaration of interest forms for each peer reviewer
were considered in the context of separate CICAD drafts.
Background
Dr A. Aitio outlined the Terms of Reference for the meeting (Appendix III), and described the
international peer-review process for the production of CICADs. He clarified the roles of
Members and Observers, namely that Members are responsible for taking the formal
decisions on the CICADs, whereas Observers are restricted to commenting on the factual
content of the documents. Members were reminded that they are selected to serve on the FRB
for their individual scientific expertise and not, in any way, as representatives of their
governments.
Document evaluation
After an introduction to and discussion of the key items brought up by the peer review process
by the Discussion Leader, the FRB systematically reviewed responses of the authors to the
comments submitted during the peer-review phase. Areas where additional changes were
recommended are noted in Appendix IV. All other comments were considered to have been
adequately addressed by the authors. The tables of peer-review comments are to be held by
the Secretariat and made available, upon request.
Asphalt
The CICAD on Asphalt was approved by the Final Review Board as an international
assessment and recommended it for publication subject to the requested changes being made
as noted in Appendix 4. The FRB further recommended that the IPCS Risk Assessment
Steering Group consider whether it is possible and useful to derive tolerable concentration for
inhalation exposure for non-cancer endpoints on the base of animal experiments (taking into
account difficulties of experimental generation of fumes) and that the approval of the peerreview-induced changes be sought from the meeting Chair, Vice-Chair and Discussion
Leader.
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Chlorobenzenes other than hexachlorobenzene: Environmental aspects
The CICAD on Chlorobenzenes (other than hexa-); Environmental aspects was approved by
the Final Review Board as an international assessment and recommended for publication
subject to the requested changes being made as noted in Appendix 4, as approved by the
Chair.
Chloroform
The CICAD on Chloroform was approved by the Final Review Board as an international
assessment and recommended for publication subject to the requested changes being made as
noted in Appendix 4, as approved by the Chair.
Creosote
The CICAD on Creosote was approved by the Final Review Board as an international
assessment and recommended for publication subject to the requested changes being made as
noted in Appendix 4, as approved by the Chair. Advice to be sought from the Steering Group
on 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 international
assessment and recommended for publication subject to the requested changes being made as
noted 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 as
noted in Appendix 4. The FRB revised the Section 10 of the document to better accommodate
the peer review comments received and recommended that advice be sought from the Risk
Assessment Steering Group on the optimal way of finalising the draft CICAD specifically vis
a vis the need to involve further review of the revised section: are the changes proposed by
the FRB within the purview of the FRB, or are the changes performed of such importance that
further peer review is needed.
Manganese and manganese compounds: Environmental aspects
The CICAD on Manganese was approved by the Final Review Board as an international
assessment and recommended for publication subject to the requested changes being made as
noted 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 more
generally, 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 a
user name and pass word-protected entry, a step forward. After some initial difficulties of
access 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 the
increasing 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 first
draft of CICADs is January 31, 2004. Chemicals likely to be considered include
alkoxyethanols (methoxy-, ethoxy-, propoxy- and butoxyethanol), heptachlor, tin and
inorganic tin compounds, and butyl acetate isomers.
Acknowledgements
The International Programme on Chemical Safety (IPCS) wishes to express its gratitude
to the Japanese Ministry of Health and Welfare and the United States Environmental
Protection Agency, and European Commission for their generosity in providing financial
support for the CICADs Project, which enabled the IPCS to convene this 11th Final Review
Board. Thanks are also due to local organizing committee, chaired by Dr Fina Petrova
Simeonova the for providing the meeting facilities and the practical arrangements of the
meeting. Finally, appreciation is extended to the authors of the first draft documents, peer
reviewers 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 their
time and their expertise. The commitment of all the aforementioned has contributed to the
success of the IPCS CICADs chemical risk assessment activity.
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APPENDIX I
Appendix I: Participants of the FRB Meeting
Members
Dr Ivan Benchev, Complex Lulin 5, Block 508 vhodA, Apart.31, Sofia, Bulgaria, fax: 359 2 954
1277
Dr Raj Chhabra, National Institute of Environmental Health Sciences, P.O. Box 12233, Research
Triangle Park, North Carolina 27709, United States of America, tel: 1 919 541 3386, fax: 1 919 541
4704, e-mail: [email protected]
Dr Christopher De Rosa, Agency for Toxic Substance and Disease Registry (ATSDR), Centres for
Disease Control (MS-29), Atlanta, Georgia 30333, United States of America, tel: 1 404 498 0160, fax:
1 404 498 0094, e-mail: [email protected]
Dr 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]
Dr Gyula Dura, Acting Director, National Institute of Environmental of József Fodor Public Health
Centre, Gyáli út 2-6, Budapest 1097, Hungary, tel: 361 218 3158, fax: 361 215 0148, e-mail:
[email protected]
Dr Lawrence Fishbein, 4320 Ashford Lane, Fairfax, Virginia 22032, United States of America, tel: 1
703 764 5232, fax: 1 703 764 7281, email: [email protected]
Dr Herman Gibb, National Center for Environmental Assessment (8601D), US Environmental
Protection 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]
Dr Rolf F. Hertel, Federal Institute for Risk Assessment (BfR), FG82, Thielallee 88-92, 14195
Berlin, Germany, tel: 49 188 8412 3931, fax: 49 188 8412 3003, e-mail: [email protected]
Mr 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]
Dr Susumu Ishimitsu, Chief, Division of Safety Information on Drug, Food and Chemicals, 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]
Dr 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]
Dr Janet Kielhorn, Fraunhofer Institute for Toxicology and Experimental Medicine, Nikolai-FuchsStrasse 1, D-30625 Hannover, Germany, tel: 49 511 5350 329, fax: 49 511 5350 335, e-mail:
[email protected]
Ms Bette Meek, Environmental Health Directorate, Health Canada, Tunney's Pasture (Address
Locator 0801C2), Ottawa, Ontario K1A OL2, Canada, tel: 1 613 957 3129, fax: 1 613 954 2486, email: [email protected]
Dr Takeshi Morita, Senior Researcher, Division of Safety Information on Drug, Food and
Chemicals, 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]
Mr 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]
Dr Edward Ohanian 1, Director, Health & Ecological Criteria Division, USEPA
1200 Pennsylvania Avenue, NW Washington DC 20460, USA, tel: +1 202 566 1117, fax: +1 202
566 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 of
Applied Research & Technology, NIOSH Mailstop C26, 4676 Columbia Parkway, Cincinnati, OH
45226, United States of America, tel: 1 513 533 8543, fax: 1 513 533 8494, e-mail: [email protected]
Dr Nikolai Rizov, Associate Professor, Director, National Center of Hygiene, Medical Ecology and
Nutrition, 15 Dimitar Nestorov Blvd., Sofia 1431, Bulgaria, tel: 359 2 954 1300, fax: 359 2 954 1277,
e-mail: [email protected]
Dr Paul Schulte, Director, Education and Information Division, NIOSH Mailstop C32, 4676
Columbia Parkway, Cincinnati, OH 45226, United States of America, tel: 1 513 533 8339, fax: 1 513
533 8588, e-mail: [email protected]
Dr Jun Sekizawa, Professor, Faculty of Integrated Arts and Sciences Tokushima University, 1-1
Minami-josanjima, Tokushima 770-8502, Japan, tel/fax: 81 88 656 7263 e-mail:
[email protected]
Dr 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]
Dr Salah Soliman, Professor, Alexandria University, Faculty of Agriculture, El Shatby, Alexandria
21545, Egypt, tel: 203 592 0067, fax: 203 592 2780, e-mail: [email protected]
Dr Jennifer Stauber, CSIRO Energy Technology, Centre for Advanced Analytical Chemistry,
Private Mail Bag 7, Bangor, NSW 2234, Australia, e-mail: [email protected]
Dr 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]
Ms Deborah Willcocks, GPO Box 58, Sydney, NSW 2001, Australia, tel: 612 8577 8890, fax: 61 2
8577 8888, e-mail: [email protected]
Dr Yuxin Zheng 1, Professor and Deputy Director, National Institute for Occupational Health and
Poison 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]
Dr Kyriakoula Ziegler-Skylakakis, European Commission, DG Employment & Social Affairs, Rue
Alcide 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 59
3900, fax: 49 6181 59 2083, e-mail: [email protected]
Mr. Mike Southern, Shell International Petroleum Company Limited, Shell Centre, London SE1
7NA, United Kingdom, e-mail: [email protected]
Dr. Wil ten Berge, DSM, Corporate SHE & M, P:O: Box 6500, NL 6401 JH Heerlen, the
Netherlands, 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 Avenue
Appia, 1211 Geneva 22, Switzerland, tel: 41 22 791 3592, fax: 41 22 791 4848, e-mail:
[email protected]
Mr T. Ehara, International Programme on Chemical Safety, World Health Organization, 20 Avenue
Appia, 1211 Geneva 22, Switzerland, tel: 41 22 791 4334, fax: 41 22 791 4848, e-mail:
[email protected]
1
invited but unable to attend
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APPENDIX II
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
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Consideration of each draft CICAD will be lead by the discussion leader
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APPENDIX III
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 thorough
peer review;
verifying that peer reviewers’ comments have been addressed appropriately;
providing guidance to authors on how to resolve any remaining issues if, in the
opinion of the Board, all comments of the reviewers have not been adequately
addressed;
approving CICADs as international assessments.
The Final Review Board conducts most of its business at meetings, but when needed, also by
correspondence after and before the meetings. It is guided in its work by the IPCS Programme
Advisory Committee, and functions in collaboration with the IPCS Steering Group on Risk
Assessment.
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APPENDIX IV
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 further
discussion:
• 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 text
should 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) should
therefore be deleted from the text. Assessment of the studied should be performed in Section
11.
• Should there be more discussion of the difference in chemical composition, physical
characteristics and biological activity between asphalt fumes collected in the field and those
in the laboratory? No.
Specific points
Section 2
Add comparative description of different bitumens from CEN, and reference to CONCAWE
http://www.concawe.be/Download/Reports/Rpt_92-104.pdf. Editorial change: Move the bullet points
from Chapter 4 to Chapter 2 as they describe asphalts (and not sources of exposure)
Section 3.1, para 2
Add a sentence to clarify that the earlier NIOSH method is comparable to the published 1998 NIOSH
method.
Indicate how samples should be taken and if possible make a statement on particle size.
Section 4, para 4
Standardise tons and tonnes.
Section 5, para 2
First part dealing with toxicity to be moved to Section 10 (retain degradation information in section 5).
Section 6, para 3
Remove table 6-1 and details of analysis.
Section 6.2, para 5
Check the original paper on 5 mg/L of PAC concentration in water. Is this an experiment? If the
figure is correct state that ‘significance unclear’.
Section 6.2, para 9
Clarify so that whole body burden can be calculated
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APPENDIX IV
Section 6.2, para 10
Move information on DNA strand breaks to section 9.
Section 7
Para 1: Editorial changes to indicate that mixtures do not rend themselves to kinetic analyses; there are
several studies on the kinetics of different components of bitumen/asphalt, and it is not known whether
the kinetics of the components is similar when presented in mixture = if there are interactions. Add
additional data/article from Dr.Ziegler-Skylakakis on toxicokinetics of Asphalt, if helpfull in
interpretation of the information on disposition of asphalt (The MAK document). Clarify ‘radical
cations’.
Section 8, para 1
Delete ‘generated during paving and roofing operations’ from end of first sentence.
Section 8.1
To the extent possible rearrange irritation of skin followed by irritation of the respiratory tract
Section 8.1, para 2
Add clinical signs of irritation
Section 8.1, para 6
After the first line add ‘The generation of the asphalt fumes was mimicked to be similar to human
exposure during road paving in Germany (Pohlmann et al., 2001 and one other reference provided by
Dr Kielhorn).
Add ‘nose only’
The whole paragraph to be moved (editorial decision on placement - only partially irritation).
Section 8.2.2, para 7
Delete penultimate sentence. Ma et al. (2002) paper to be checked ("absence of positive findings").
Section 8.4
Add footnote to the effect that the FRB is aware of a two- year nose only inhalation carcinogenicity
study in rats on asphalt (Fraunhofer).
Section 8.4, para 16
Check the number of animals in the text relative to the following table. Delete last sentence.
Section 9
Two articles on human DNA-adducts should be included (from Dr.Ziegler-Skylakakis [Fuchs et al
1996, Jarvholm et al 1999); to go together with the article of Toraasson from Section 6) and crossreferenced to section 6.2 (biomarker information in 6 and strand breaks in 9).
Section 10
Reinstate original title. Move para 2 to section 5.
Section 11 Para 2
Check the wording "raw asphalt"
Section 11.1.1, para 3
Shorten paragraph and remove references.
Section 11.1.1, para 5
The lowest exposure (0.02 mg/m3) which caused respiratory tract problems should be added.
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APPENDIX IV
Section 11.1.2
Delete paragraph 7.
Section 11.1.3
Delete paragraphs 9 & 10. Use some of the material in the uncertainties section.
Section 11.1.5
To be deleted. Information to be made available to the steering group.
Chlorobenzenes other than hexachlorobenzene: Environmental aspects
Discussion leader: Dr J. Stauber
Section 1
Extra sentence to be added outlining the reasoning for producing a CICAD on environmental aspects
only.
Extra paragraph to be added summarising the evaluation section following modification.
Section 2, table 1
Authors to check the original source of the solubility data used in the WHO EHC on chlorobenzenes.
Section 2, table 2
The number of significant figures used to be reduced.
Section 4.2, para 4
Authors to check IUCLID for production figures.
Section 4.2
Dr Sekizawa to provide more production figures for Japan.
The production of lindane as a possible source of chlorobenzenes to be added.
Section 4, table 2
The number of significant figures used to be reduced.
Section 5.2.2, para 18
Authors to check spelling of My(c)obacterium.
Section 5.2.2 paras 23 & 25b
Authors to check if there are any exposure figures for these studies.
Section 6, para 5
Extra text on whether chlorobenzenes were dissolved or not provided by authors in response to a
question by a peer-reviewer.
Section 6, para 9
Authors to reduce the number of significant figures used in the last sentence.
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APPENDIX IV
Section 7, table 3
If no further details are available regarding the endpoints cellular changes in the toxicity tests on green
algae and diatoms then these should be deleted from the table.
All 72h EC50s on algae to be moved to table 4.
Section 7, table 4
All 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 7.2
Add a statement that toxicity information on other terrestrial organisms was not found.
Section 8
Evaluation to be modified taking into account that some of the algal studies have been reclassified as
chronic 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 1
Remove reference to Canada throughout summary except where this is necessary.
Section 1, para 6
The 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 3
Dr Rizov to provide information on extra analytical techniques.
Section 4, para 1
Change the units Gg to metric tonnes throughout paragraph.
Delete last two sentences.
Section 5.5, para 5
Change Lustry to Lusty.
Section 5.6, para 6
Change 99.1 to 90.1.
Section 6, para 5
Large number of non -detected in this study making the means unreliable. Remove reference to means
and 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 smoking
and non-smoking households.
18
APPENDIX IV
Section 6, para 22 (level of exposure): Tables 3 & 4
Clarify how the statistical analysis was performed and identify number of samples for the different
categories in table 3 and 4 which form the basis for the Monte Carlo analysis.
Section 7
The metabolic pathway figure to be edited to specify the key role of CYP2E1 and cross-reference to
section 8.8 to emphasise the same point.
Section 7.2, para 9
Refer to the source document for detail of PBPK model though some expansion in the text. Explain in
footnote the “hybrid” animal or cross-reference to the source document.
Section 8.1, para 1b
Move the 13-week material into short-term exposure.
Section 8.2.1, para 13
Possible move to long-term (IPCS to decide). Add personal communication from NTP veterinary
pathologist 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 22
Yamamoto study does not need further information (5 ppm low concentration to be added).
Section 8.5
Detail on genotoxicity adequate as it is; refer to table in source document for detail.
Section 8.7, para 41
The paragraph is deleted and the material moved to 8.2.1: delete relevant sentences in paras 3 & 4.
Section 8.8
Mode 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 & 56
The authors to check to make sure all corrections have been made.
Section 10.1 Add marine data from Dr Stauber
Section 11.1.1
Remove ‘and dose response assessment’ from the title.
Section 11, para 12
Expand with information from appendix 1, para 9 regarding the justification for the uncertainty
factors.
Section 11.1.2
Define VMRATEK and VMRATEL.
Section 11.1.3
Clarify method of moving from TDI to tissue dose (Bette Meek to propose text).
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APPENDIX IV
Section 11.1.3, para 31
Delete reassuring.
Section 11.1.4, paras 35 & 36
PBPK model – mention that human kidney has much less CYP2E1 contents than the laboratory
animals and that the PBPK model takes this into account. The text should address the uncertainity
instead of the need for further studies.
Section 11.2
Give explanation on EEV, PEC, ENEV and PNEC. Compare Canadian and EU approaches. Make
overall conclusion for both freshwater and marine that toxicity unlikely at typical environmental
concentrations but possible in worst case (Stuart Dobson to help modify text)
Para 48b
Explain 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 points
Parentheses should be used consistently for denoting PAHs (e.g. benzo[a]pyrene) throughout the
document. Dr Hoeke's comments submitted after the cut-off date on the details of the text to be
considered by the author during the final revision.
Section 2, table 2.1
A range of melting points to be identified and added (emphasise properties are different in various
Creosote preparations (for different application))
Section 2, table 2.2
Heikkila (2000) reference not thought to be the most appropriate to use as a source for physicochemical properties. Dr Olsen suggested other more relevant sources of information.
Section 2, figure 2.2
BTEX ethylbenzene, other isomers of xylene
It would be more informative to present the structure of dibenzofuran since this is mentioned in the
text.
Section 2.3
Dr Rizov to provide some text regarding up-to-date analytical techniques.
Section 2.3, para 29
Dr Olsen to provide rewording for first two sentences regarding NIOSH analysis.
20
APPENDIX IV
Section 3, para4b
Source to be defined - add IPCS personal communication
Section 3, para 18
Author to check the website of the American Wood Preservers Association for the number of creosote
treatment plants in the USA.
Table 5-13
Concerning exposure of children in playground : give footnotes to website (for exposure model, give
information of models/model assumptions)
Section 6, para 10
Needs to be reworded to improve the clarity.
Section 6, para 13
Add to reference list papers in thesis.
Section 7.3, para 13
Reinstate paragraph and expand to include dermal exposure. Make explicit statement that creosote is
5 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 from
this study.
7.6.2.1, para 44
Sampling time to be added – 24 hours after final treatment.
Table 8-3
Dr Gibb to reorganize the table.
Footnote needs to be changed from consulting group to consultative group. Information regarding the
consultative group needs to be added in an appendix.
Table 8-4
The cohorts National Cancer Registry, Sweden and Finnish Cancer Registry need to be clarified.
Section 9.1.2.2, para 18
EC50 expressed in % - ’elutriate equals 100%’ needs to be added in parentheses.
Section 9.1.2.3, para 22
Wording to be clarified by Dr Dobson.
Section 10.1.3, para 12
Deleted text to be replaced with ”Creosote is considered to be a genotoxic carcinogen for which a
threshold level has not been identified”. Please note that this same sentence needs to be added to
section 1.9, para 81.
Section 10.1.3, para 17
Reinstate second half of paragraph. Expand to include dermal route, mice, clarify that it is a
cumulative risk for one type of creosote, that data are insufficient for risk characterization and add
footnote to CSTEE website. Describe the study that was used in more detail. Add to executive
summary.
21
APPENDIX IV
Section 10.1.3, para 19
Expand 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 being
both as initiator and promoter.
Section 10.1.4
Incoporate some of first sentence from section 2.1, paragraph 7 with additional remarks on toxicology.
Glyoxal
Discussion leader: Dr S. Dobson
Section 2
Chemical structures and names to be revised to reflect stereochemistry if possible.
Section 2, para 1
The reference to “mixtures with air may explode” was added in response to a reviewer’s comment. It
appears 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 5
If the information is available, insert some text to explain why glyoxal concentrations rise in plasma of
uraemic patients or state such information does not exist in the literature.
Section 4.2
Dr Sekizawa to provide extra information on Japanese production.
Section 4.3
Reword the text on main uses to avoid the apparent contradiction.
Section 5.2
The 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 8b
Change ‘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 these
foods/consumption levels (note that these changes must be reflected in section 11).
Explain ‘digestive’.
Section 6.2.1, para 9
Take highest value for air concentration for this estimate of inhalation intake.
Explain origin of the drinking water estimate.
New para 11
Insert new text on consumer products.
22
APPENDIX IV
Section 6.2.2, para 13
replace with text on new example of exposure scenario (nurse cleaning)
Section 8, para 11
Second sentence should reflect that effects were seen at maternally toxic doses.
Section 8.5, para 33
Question from reviewer 14 on whether cytotoxicity was reported – state that it wasn’t
Section 8.6.2, para 41
add OECD guideline number
Section 8.6.2, para 42
clarify why the authors of the NTP study chose to ignore apparent developmental effects and/or flag
these in the Evaluation.
Section 8.6.2, para42b
insert species (rat) and some more detail of the result.
Section 8.8, para 46
It should be stated that this effect has never been shown for glyoxal.
Section 11
In responding to reviewers’ comments, the authors have included NOELs for routes other than
inhalation in Section 11. They have also developed and explained estimates of daily intake from food
in the text. However, this exposure side of the oral argument is not included in Section 11. This leaves
the oral effects information somewhat isolated. Some comment in Section 11 of the likely significance
of 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 11
Last sentence – add ‘a lifetime skin painting study’
Section 11.1.2, para 12
Reinstate original text and remove new text.
Section 11.1.2, para 15
Clarify that calculations are done as 100% glyoxal. Delete higher NOAEL (>10) and reference to
systemic effects in both sentences.
Section 11.1.2, para 15b
There are short and medium term studies with similar outcomes and evidence that glyoxal is not
accumulated in the body. The use of the lifetime extrapolation uncertainty factor (factor of 5) is also
justified on the basis of the 125 mg/kg LOAEL with wide dose spacing to NOAEL of 25 mg/kg.
23
APPENDIX IV
Section 11.1.3
Insert new text on example risk characterisations.
Example 1: delete ‘worst case’ replace with ‘An exposure scenario has been compiled as a
hypothesised 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 applied
in the studies was considered as NOAEL, but the values could be higher if the studies were
performed at the dose levels showing some effects.
Section 11.1.4
Add to uncertainties section that glyoxal can be formed endogenously.
Section 11.1.4, para 17a
delete ‘and on in vitro’
Section 11.1.4, para 17b
Delete.
Hydrogen Cyanide and Cyanides: Human health aspects
Discussion Leader: M.E. Meek
Section 6.1.3
Reinstate text on soil
Section 6.1.5
Delete last part of sentence “for health …although previously banned”. Following sentence needs
editorial change (not sentence).
CN- radical – delete the minus and add a raised period CN.
Section 6.2.1
Check the figures on levels in food against the revision of Chapter 10 to inform risk assessment
Section 7.1, para 3
Skin absorption … can lead to harmful effects.
Section 7.2, para 5
Insert “known occupational” between ‘without’ and ‘cyanide exposure’.
Para 6
Move to beginning of 7.2 and make sure that there are no inconsistencies.
Section 8.1, para 1b
Insert units mg/m3
24
APPENDIX IV
Section 8.1, para 4
Harmonise 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 8
Give some explanation of why the difference between the bolus dose and dietary exposure. Specify
that both mg/kg values are expressed as body weight.
Section 8.3.1, para 31
Check if the ‘decrease’ was reported to be statistically significant
Para 16
Insert ‘daily’ for 15 months. Cross reference to 8.7 or copy text into both sections
Section 8.4, para 25
Check the NOAEL of 11.2 mg/kg. Is this a female dose? If so, reinstate the text on the females or state
something about female effects.
Section 8.5.1
Subheadings “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 49
Insert extra text from Dr Fishbein
Section 9, para 6
Delete para; verify that the acute lethal doses are consistent in the different paras
Section 9.2, para 28
Remove ’adequate engineering devices......’.
Section 10
FRB partly revised the Section 11 (and in consequence modified the Section 1) to better accomodate
the peer reviewers' comments and to reflect the high acute toxicity of cyanides. The authors and
secretariat to verify the accuracy of the new draft against the main text and the original papers and
consult with the Risk Assessment Steering Group on whether the modified texts represent a change
that requires a new peer review or other steps before acceptance of the whole document as an
international assessment.
25
APPENDIX IV
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 some
form of quantitative risk assessment could be carried out.
Sections 1 & 8
To be compared with section 4.2 for consistency with regard to statements on anthropogenic releases.
Section 2, Table 1
Information on water solubility to be added; the CAS no of mancozeb (8018-01-7) to be corrected.
Section 4.1, para 2
Clarify the meaning of ‘black smokers’.
Section 4.1, para 8
Dr Willcocks to provide information to revise the first sentence.
Loranger & Zayed (1995) should be deleted from this paragraph because the information is
misleading.
Replace last sentence of paragraph 8 with revised text.
Section 4, para 9
After para 9: Add the following: It is clear that the contribution of MMT to overall manganese levels
in the environment is complex. The contribution of MMT to atmospheric manganese concentrations is
difficult to establish since it may be masked by more substantial variation associated with other
industrial activities as well as road dust and windblown dust (Bankovitch et al. 2003). However, even
though manganese may be a small percentage of total suspended particulate measured in cities, such as
Montreal, the contribution of MMT to air manganese levels could be significant in that it may account
for stable manganese levels in the face of declining total suspended particulate concentrations. Factors
such as unfavourable meteorological conditions and high traffic density could lead to an increase in
the annual fine manganese levels attributable to MMT (Wallace & Slonecker, 1997; Davis et al.,
1998).
Section 5.2, para 12
Add paragraph on Biotransformation by micro-organisms after this paragraph.
Section 6, para 5
Add the following to paragraph:
During the late summer Horsetooth Reservoir, CO, USA is fully stratified and exhibits seasonally high
fluxes 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 water
prior to filtration and measured by AAS was 93 µg/litre; after sedimentation of particles the total
manganese concentration was 213 µg/litre measured by ICP-AES.
However, check the values.
Section 6, Table 2a
The year of the study to be added
Section 7.2
Dr Stauber to provide extra references.
26
APPENDIX IV
Section 7.2, Table 3
Bogaerts et al. (1998) to be checked.
Section 8
It was agreed to carry out a semi-quantitative risk assessment. The authors to carry out an assessment
which will be checked by Drs Stauber, Chhabra and Aitio. The assessment will be peer-reviewed by
at least two independent reviewers.
ICSCs:
The card on Mancozeb (0754) to be added
27