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UNITED NATIONS ENVIRONMENT PROGRAMME IPCS/CICAD/98.19INTERNATIONAL LABOUR ORGANISATIONWORLD HEALTH ORGANISATION
REPORT OF THE IPCS THIRD FINAL REVIEW BOARD MEETING ON CONCISEINTERNATIONAL CHEMICAL ASSESSMENT DOCUMENTS (CICADs)
30 JUNE - 2 JULY 1998TOKYO, JAPAN
The issue of this document does not constitute formal publication. It should not be reviewed,abstracted, or quoted without the written permission of the Director, International Programmeon Chemical Safety, WHO, Geneva, Switzerland.
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TABLE OF CONTENTS
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
2. Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
3. Document Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23.1 Azodicarbonamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23.2 Ethylene diamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23.3 Tributyltin oxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23.4 Triphenyltin compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23.5 Butyl benzyl phthalate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
4. Other Business . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34.1 Meetings for 1998/99 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34.2 Guidelines for authors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34.3 Other issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Appendix I - Agenda . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Appendix II - List of Participants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Appendix III - Terms of Reference for a FRB . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Appendix IV - FRB comments on draft CICADs . . . . . . . . . . . . . . . . . . . . . . . . . 12
Appendix V - Text drafted during the FRB meeting . . . . . . . . . . . . . . . . . . . . . . . 32
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1. Introduction
Dr P Toft Associate Director, International Programme on Chemical Safety (IPCS) openedthe meeting on behalf of IPCS. He expressed thanks to the NIHS for hosting the meeting and theJapanese government for their continued support of IPCS and the CICAD program. Dr TKaminuma Head, Division of Chem-Bio Informatics welcomed participants to the meeting on behalfof the National Institute of Health Sciences, Japan (NIHS). He noted that NIHS has participated inthe work of IPCS since its beginning in 1980, and were pleased to be able to contribute to the new,but important work on Concise International Chemical Assessment Documents (CICADs). Dr STsuda Deputy Director, International Affairs Division also welcomed participants on behalf of theMinistry of Health and Welfare. He noted the importance of chemicals and pesticides, and theincreasing demands from the public for good information and protection for human health and theenvironment. International assessments were important in making use of available resources. Heexpressed the hope that Japan could host more of these meetings.
Ms M E Meek was elected as Chair of the Review Board and Dr J Sekizawa as ViceChair. Ms D Willcocks served as rapporteur.
With slight changes in the order of presentation of various documents, the agenda wasagreed.
Members introduced themselves briefly. The Chair reminded the meeting of the Terms ofReference for the Final Review Board, and in particular its task of ensuring that peer-reviewcomments had been adequately dealt with. Members had to sign a Declaration/Conflict of Intereststatement in order to participate in the meeting. Though the input of observers to factual content ofthe document was welcomed, the Chair reminded them that only Members could participate informal decision making.
The Chair noted that some of the chemicals being considered were of great interest, andthat this had been reflected in the number of comments received. Especially as many of these wereconcerned with presentation rather than substance, she proposed that authors flag up those issuesand comments that were key. In order to facilitate completion after the meeting she proposed that,as far as possible, text be provided for consideration by the meeting to resolve outstanding issues.
2. Background
Dr. Toft outlined the nature of the content of and process for review of CICADs. CICADsare concise summaries of critical data which are based on high quality national SupportingDocuments. Critical studies are presented in sufficient detail to support the conclusions concerningcharacterization of risk. To ensure transparency, the mechanism for preparation and peer review isclearly delineated in each CICAD.
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The first draft prepared by a contributing author is submitted for acceptance review byIPCS. It is then circulated for international peer review by IPCS contact points identified from asurvey and selected experts. A second draft and responses to comments are prepared for reviewby the Final Review Board which is responsible for:
a) ensuring that each CICAD has undergone appropriate and thorough peer review;
b) verifying that peer reviewers comments have been addressed appropriately;
c) 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;
d) approving CICADs as international assessments.
Dr. Toft reminded participants that members of the FRB served as individual experts andnot as representatives of any organization or country.
3. Document Evaluation
The Final Review Board systematically reviewed responses of the authors to each commentsubmitted during the peer review phase. Areas where additional changes were recommended arenoted in Appendix IV. All other comments were considered to be adequately addressed by theauthors. The tables of peer-review comments are to be held by the Secretariat and made available,upon request.
3.1 Azodicarbonamide
Recommendation: The CICAD on Azodicarbonamide was approved by the Final ReviewBoard as an international assessment and recommended for publication subject to the requestedchanges being made as noted in Appendix IV.
3.2 Ethylene diamine
Recommendation: The CICAD on Ethylene diamine was approved by the Final Review Boardas an international assessment and recommended for publication subject to the requested changesbeing made as noted in Appendix IV.
3.3 Tributyltin oxide
Recommendation: The CICAD on Tributyltin oxide was approved by the Final Review Boardas an international assessment and recommended for publication subject to the requested changesbeing made as noted in Appendix IV.
The meeting noted that Butyl Benzyl Phthalate was currently being assessed within the EU1
Existing Substances Regulation Programme.
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3.4 Triphenyltin compounds
Recommendation: The CICAD on Triphenyltin compounds was approved by the Final ReviewBoard as an international assessment and recommended for publication subject to the requestedchanges being made as noted in Appendix IV.
3.5 Butyl benzyl phthalate1
Recommendation: The CICAD on Butyl benzyl phthalate was approved by the Final ReviewBoard as an international assessment and recommended for publication subject to the requestedchanges being made as noted in Appendix IV.
4. Other Business
4.1 Meetings for 1998/99
It was noted that a further FRB meeting was planned for November/December 1998, andthat it was expected that draft CICADs on Cumene, Ethylene Glycol, 2-furaldehyde,o,m,p-nitrophenol and Phenyl hydrazine would be dealt with. Plans were being made fortwo meetings of the FRB during 1999. A meeting of the Steering Group was planned forSeptember 1998 in Hanover, before the IPCS Programme Advisory Committee meeting. Itwas hoped that this meeting could finalise the pilot phase of the CICAD project.
4.2 Guidelines for authors
As there was insufficient time to discuss the draft Guidelines for authors, participants inthe FRB were asked to submit comments to the Secretariat (Mr A. Strawson) by the end ofAugust.
The availability of the source document was raised, and the FRB referred this point to theSteering Group, while asking that the Guidelines for authors make it clear that the ExecutiveSummary of CICADs should reinforce the point that readers should look to the sourcedocument for detail.
4.3 Other issues
The FRB requested that completed comment tables, and the meeting report be sent to reviewers so that they could see how their comments had been dealt with.
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The FRB requested that the Secretariat forward all peer-review comments to the authorseven if they were too late to be included in the table of comments. The author would be responsiblefor deciding how late comments would be dealt with, and for notifying the FRB of any significantissues raised by the comments.
The following general comments were offered during the meeting to facilitate furtherdeliberations of the FRB. Though some of these matters deserve further attention from the SteeringCommittee, immediate adoption of the remainder was encouraged.
(I) The Foreword should be included in all documents circulated for comment.
(ii) To the extent possible, the use of references not available in the public domain, particularlyfor aspects critical to the overall assessment, should be avoided. Citation of data directlyfrom IUCLID is inappropriate: it is suitable only as a source to identify relevant referencesfor review.
(iii) The presentation of national limits is to be avoided in section 11.1.2 (Criteria for settingGuidance Values). Where considered appropriate, national limits and their derivation canbe included in section 11.1.3 (Sample Risk Characterisation).
(iv) It is recognised that all CICADs will not cover all disciplines (i.e., consumer, occupationaland environmental). However, where a CICAD does not address all disciplines, this needsto be clearly stated in the Executive Summary.
(v) To assist in ensuring that the International Chemical Safety Card and the CICAD areconsistent, better co-ordination between the production of the International Chemical SafetyCard and CICADs is required. The Card should be provided to the author as soon as itsavailable and wherever possible included in the draft CICAD circulated for comment.
(vi) All acronyms should be spelt out the first time they appear in the document.
(vii) As general guidance, NOAELs and LOAELs should be included in tables and only theNOAELS and LOAELS for critical studies should be included in the text. In addition,LOAELs and NOAELs should not be calculated for studies where dose response isinadequately characterised.
(viii) Will consider to revise the process to indicate that the process needs to be flexible forconsideration of unresolved issues or late introduction of new information which may impacton risk characterisation.
(ix) Ensure peer reviewers are made aware of the national document and that they can requestcopies.
(x) Consider whether the revised draft CICAD should be marked with the changes.
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(xi) Send table of peer review comments and record of meeting to all peer reviewers.
(xii) Suggest that in table of peer review comments:
! complete 3 column with either “yes” or “no”;rd
! indicate that where “no” is stated, then refer to record of meeting.
(xiii) The requirement that authors respond to each comment, particularly those related topresentation, be reconsidered.
(xiv) In view of the problems experienced with transmitting files in several different formats, theSecretariat should investigate using a common (e.g., .PDF) format.
(xv) The Secretariat should investigate the practicability of distributing the final documents on theInternet.
(xvi) Authors should include paragraph numbers on all draft CICADs to ease referencing ofcomments (these will be removed in the final editing).
(xvi) Detection limits for monitored data should be given in all CICADs.
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Appendix I - Agenda
PROVISIONAL AGENDA
FINAL REVIEW BOARD MEETING ON CONCISE INTERNATIONAL CHEMICALASSESSMENT DOCUMENTS (CICADs)
Diamond Hotel, Tokyo, Japan30 June - 2 July 1998
1. Registration
2. Opening
3. Welcome - Dr T Kaminuma, Head Division of Chemo-Bio Informatics
4. Election of Officers
5. Adoption of the Agenda
6. Brief introduction to the Terms of Reference for FRB members
7. Draft CICAD on Azodicarbonamide
8. Draft CICAD on Triphenyltin compounds (TPT)
9. Draft CICAD on Tributyltin oxide (TBTO)
10. Draft CICAD on Butyl benzyl phthalate
11. Draft CICAD on Ethylene diamine
12. Other Business
13. Close
Coffee Break Tuesday-Thursday 10.30 and 15.30
Consideration of each draft CICAD will begin with a short presentation by theAuthor/Representative and will be followed by an open discussion focusing on the reviewerscomments.
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Appendix II - List of Participants
Members
Dr. R BensonUS EPA Region 8 (8P2-W-MS)999 18th St., Suite 500 Tel: +1 303 312 7070Denver CO 80202-2466 Fax: +1 303 312 6131USA e-mail: [email protected]
Dr T BerzinsNational Chemicals Inspectorate (KEMI)P.O. Box 1384 Tel: +46 8 730 6825S-171 27 Solna Fax: +46 8 735 7698Sweden e-mail: [email protected]
Mr R. CaryHealth and Safety ExecutiveHealth Directorate, Toxicology UnitRoom 153, Magdalen HouseStanley PrecinctBootle Tel: +44 151 951 4820Merseyside, L20 3QZ Fax: +44 151 951 3197UK e-mail: [email protected]
Dr C. DeRosaAgency for Toxic Substances and Disease RegistryCenters for Disease Control16000 Clifton Road, NEAtlanta Tel: + 1 404 639 6300Georgia 30333 Fax: + 1404 639 6315USA e-mail: [email protected]
Dr S. DobsonInstitute of Terrestrial EcologyMonks Wood, Abbots RiptonHuntingdon Tel: +44 1487 773381Cambridgeshire Fax: +44 1487 773467PE17 2LS UK e-mail: [email protected]
Dr H. GibbUS Environmental Protection AgencyNational Centre for Environmental Assessment (8601D)401 M. Street, SW Tel: +1 203 564 3334
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Washington D.C., 20460 Fax: +1 203 565 0059USA e-mail: [email protected]
Dr R. F. HertelFederal Institute for Health Protection of Consumers & Veterinary MedicineBGVV - FG 82Postfach 33 00 13 Tel: +49 30 8412 3931D-14191 Berlin Fax: +49 30 8412 3003Germany e-mail: [email protected]
Dr I. MangelsdorfFraunhofer Institute for Toxicology and Aerosol SciencesDocumentation and Assessment of ChemicalsNikolai-Fuchs-Str 1 Tel: +49 511 535 0303D-30625 Hanover Fax: +49 511 535 0335Germany e-mail: [email protected]
Ms M. MeekEnvironmental Health DirectorateHealth CanadaTunney's PastureAddress Locator 0802B1 Tel: +1 613 957 3129Ottawa, Ontario K1A 0L2 Fax: +1 613 954 2486Canada e-mail: [email protected]
Dr J. SekizawaNational Institute of Health SciencesDivision of Chemo-Bio Informatics1-18-1 Kamiyoga, Setagaya-ku Tel: +81 33 700 9548Tokyo 158 Fax: +81 35 717 7180Japan e-mail: [email protected]
Prof S. A. SolimanAlexandria UniversityFaculty of AgricultureDepartment of Pesticide ChemistryLaboratory of Environmental Chemistry and ToxicologyEl-Shatby Tel: +20 3 597 5405 or +20 3 541 1376Alexandria 21545 Fax: +20 3 597 2780 or +20 3 481 7232Egypt
Ms D. WillcocksWorksafe AustraliaChemical Assessment Division
* Invited, but unable to attend. 9
92 Parramatta RoadCamberdown Tel: +61 2 9577 9415NSW 2050 Fax: +61 2 9577 9465Australia e-mail: [email protected]
Professor P. YaoChinese Academy of Preventive Medicine, MHInstitute of Occupational Medicine29 Nan Wei Road Tel: + 8610 6315 33911Beijing 10050 Fax: + 8610 6301 4323People's Republic of China e-mail: [email protected]
Observers
*Professor F.M.C. CarpaniniSecretary-general,ECETOCAvenue E. Van Nieuwenhuyse 4Boîte 6 Tel: +322 675 3600B-1160 Brussels Fax: +322 675 3625Belgium e-mail:[email protected]
Dr M. EmaNational Institute of Health SciencesOsaka BranchDivision of Biological Evaluation1-1-43 Houenzaka, Chuuoo-ku Tel: +81 6 941 1533Osaka-shi 540 Fax: +81 6 942 0716Japan
*Mr R. GreenHealth, Safety & Environment OfficerInternational Federation of Chemical, Energy,Mine & General Workers' UnionsAve. Emile de Beco 109 Tel: +32 2 626 2020B-1050 Brussels Fax: +32 2 648 4316Belgium e-mail: [email protected]
*Dr B. HansenEuropean CommissionEuropean Chemicals Bureau Tel: +39 332 785 884 orJRC - Environment Institute TP280 +39 332 789 54721010 ISPRA (VA) Fax: +39 332 785 862Italy e-mail: [email protected]
* Invited, but unable to attend. 10
*Mr T. Jacob (Industry)DupontInternational and Industry Affairs1007 Market Street, N 9496 Tel: +1 302 774 6873Washington, D.C., 19898 Fax: +1 302 773 2010USA e-mail: [email protected]
Dr J. Katoh (Industry)Chief Research ScientistYokohama LaboratoryMitsubishikasei Institute ofToxicological and Environmental Sciences1000 Kamoshida-cho, Midori-ku, Tel: +81 45 24 9844Yokohama-shi 227, Fax: +81 45 961 6296Japan
Dr H. KoeterOECD2 rue André Pascal Tel: + 33 1 45 24 98 44Paris Cedex 16 Fax: + 33 1 45 24 16 75F - 75775 E-mail: [email protected]
Mr. H. KondoBasic Industries BureauChemical Safety Policy OfficeMinistry of International Trade and Industry1-3-1 Kasumigaseki, Chiyoda-kuTokyo, 100Japan
Ms J. MatsuiBasic Industries BureauChemical Safety Policy OfficeMinistry of International Trade and Industry1-3-1 Kasumigaseki, Chiyoda-kuTokyo, 100Japan
*Mr R. MontaigneEuropean Chemical Industry Council (CEFIC)Avenue E. Van Nieuwenhuyse 4Bâtiment 1 Tel: +32 2 676 72 77Brussels Fax: +32 2 676 7332B - 1160 e-mail: RMO@CEFIC:BE
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Dr A. NishikawaChief, Division of PathologyBiological Safety Research CentreNational Institute of Health Sciences1-18-1 Kamiyoga, Setagaya-ku Tel: +81 33 700 9819Tokyo, 158 Fax: +81 33 700 2348Japan
Dr H. NishimuraResearch AssociateEnvironmental Health Science LaboratoryNational Institute of Health Sciences3-1-98 Kasugadenaka, Konohanaku Tel: +81 6 466 5360Osaka, 554T Fax: +81 6 466 5440Japan e-mail: [email protected]
chem.co.jp
Ms C. OhtakeResearcher Chem-Bio InformaticsNational Institute of Health Sciences1-18-1 Kamiyoga Setagaya-ku Tel: +81 33 700 9607Tokyo 158 Fax: +81 33 700 7592Japan e-mail: [email protected]
Dr T. SuzukiNational Institute of Health SciencesDivision of Food1-18-1 Kamiyoga, Setagaya-ku Tel: +81 33 700 9359Tokyo 158 Fax: +81 33 707 6950Japan e-mail: [email protected]
Dr K. Takeda (Industry)Chief Research Scientist, Yokohama LaboratoryMitsubishik Chemical Safety1000 Kamoshide-cho, Aoba1000 Kamoshida-cho, Midori –ku Tel: +81 45 963 3550Yokohama-shi 227-003 Fax: +81 45 961 6296Japan e-mail: [email protected]
Dr K. Tasaka (Pesticide Action Network)Dept. of ChemistryInternational Christian University (ICU)3-10-2 Osawa
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Mitaka Tel: + 81 422 333 282Tokyo Fax: + 81 422 331 449Japan e-mail: [email protected]
Dr H. YamadaHead, Environment Conservation DivisionNational Research Institute of Fisheries Science6-31-1 nagai, Yokosuka Tel: +81 46 856 2887Kanagawa, 238-03 Fax: +81 46 857 3075Japan e-mail: [email protected]
Dr M. YamamotoSenior Researcher Chem-Bio InformaticsNational Institute of Health Sciences1-18-1 Kamiyoga, Setagaya-ku Tel: + 8 35 717 7179Tokyo 158 Fax: +8 35 717 7180Japan e-mail: [email protected]
Dr M YasunoProfessor, School of Environmental ScienceThe University of Shiga Prefecture2500 Hassaka, Hikone Tel: +81 74 928 8303522 Fax: +81 74 928 8463Japan e-mail: [email protected]
Dr K. Zeigler-SkylakakisGSF-Forschungszentrum für Umweltund Gesundheit GmbH,Institut fur Toxikologie,Postfach 1129 Tel: +49 89 3187 3133D-85758 Oberschleissheim Fax: +49 89 3187 3377Germany e-mail: [email protected]
Secretariat
Ms L. RegisWorld Health OrganisationInternational Programme on Chemical Safety20 Avenue Appia Tel: +41 22 791 3566CH-1211 Geneva 27 Fax: +41 22 791 4848Switzerland e-mail: [email protected]
Mr A. StrawsonWHO/International Programme on Chemical Safety
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c/o Health and Safety Executive6SW, Rose Court, 2 Southwark Bridge Tel: +44 171 717 6252London SE1 9HS Fax: +44 171 717 6221UK e-mail: [email protected]
Dr P. ToftAssociate DirectorInternational Programme on Chemical Safety20 Avenue Appia Tel: +41 22 791 4289CH-1211 Geneva 27 Fax: +41 22 791 4848Switzerland e-mail: [email protected]
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Appendix III - Terms of Reference for a FRB
The FRB is responsible for the following functions:
! Ensuring that each CICAD has been subjected to an appropriate and thorough peer-review;
! Verifying that peer-reviewer’s comments have been addressed appropriately;
! Providing guidance to CICAD producers on how to resolve and remaining issues if, in theopinion of the Board, the Author has not adequately addressed all comments of thereviewers;
! Approving CICADs as international documents.
The FRB conducts most of its business at meetings, but also by correspondence between meetings.
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Appendix IV - FRB comments on draft CICADs
Those comments provided by peer reviewers and not specifically addressed below areconsidered by FRB members to have been adequately addressed by the author. For alldocuments Section 1 (Executive Summary) will be revised to be consistent with the otherchanges. Where new text was agreed by the FRB, or recommended for consideration bythe author, the new text is given in Appendix V.
Azodicarbonamide
General
1. For relevant studies, include particle size where available, or state “particle size notavailable”.
2. Include footnote in relevant section stating that a reproductive (OECD 421) study and analgal growth study are currently being conducted in Japan.
Section 1
1. Emphasise that the document primarily addresses occupational health and safety andtherefore the emphasis has been inhalation toxicity and exposure.
2. Include a statement indicating that there was insufficient environment data available to drawany conclusions (Dr Dobson provided a draft text which was considered and accepted bythe meeting). This should also be included in Section 11.2.
3. Include statement that information on consumer use and exposure has been included whereavailable, however there was insufficient data to conduct a consumer risk assessment (DrHertel and Dr Gibb provided a draft text which was considered and accepted by the meeting). This statement will also be included in section 11.1.2.
4. Include a short summary on toxicokinetic data, and state that biurea is the major metabolite.
5. Remove the word “significant” from paragraph 4.
Section 2
1. Decomposition products should be included in Section 13 and not in this section.
2. Include all available trade names either in the International Chemical Safety Card or as anappendix.
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3. Include the standard calculation for converting mg/m to ppm.3
Section 4
1. Include US production levels from HSDB.
2. State that the powder was primarily in the respirable range as it is <10 microns.
Section 5
1. Include the references in the reference list.
Section 6.1
1. R. Cary has confirmed that the exposure levels reported in section 9.2 for the Arenholz et al(1985) study are the correct values. Relevant exposure levels in section 6 to be corrected.
2. Include all sampling durations.
Section 8.1
1. Check that information included in CICAD on IRDC (1983 a,b) studies and 1991 study (ifavailable) is correct.
Section 8.3
1. Specify what was examined in Gafford et al (1971) study.
2. Para. 3, 1 sentence (IRDC study) should read 625 (not 1250) mg/kg.st
3. Para 2 (of June 1998 draft CICAD): indicate the duration of the studies i.e., 13 weeks.
Section 8.4
1. In paragraph 1, in the 1-year study include the same qualifications concerning dogs asstated for the 2-year study (para. 2).
2. At the end of the last sentence in para 2 include the word “biurea”.
Section 9.1
1. Para 1: Check whether exposure to control subjects was 15 minutes or 15 seconds in Maloet al (1985) study.
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Section 9.2
1. Add duration of measurements.
2. Author now has a copy of Arenholz et al and will confirm whether statistical analysis hasbeen conducted and amend CICAD as appropriate.
Section 9.3
1. Check to see if the 3 case reports are included in Yates & Dixon (1988). If it is 3 separatereferences include the references.
Section 10
1. Include introductory statement indicating that all studies are unpublished and not peerreviewed and no conclusions can be drawn.
Section 11.1
1. State that a dose-response cannot be characterised and that exposure levels should beminimised as low as practicable (Mr Cary provided a draft text which was considered andaccepted by the meeting).
2. In para. 1, include more discussion on effects observed in short-term and subchronicstudies and not just NOAELs.
3. Clarify that chronic studies were carried out with biurea and that Azodicarbonamide israpidly converted to biurea.
4. Move information on MEL into section 11.1.3 and emphasis this approach by the UK is anexample only of setting an exposure limit based on practicability.
Section 13.1
1. Incorporate changes to paragraph 1 as suggested in comment 1 (peer reviewer 9), andrefer issue to Dr Baril for consideration by ICSC group.
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Ethylenediamine
Secretariat/Editorial
Section 8 The response to reviewer 12 should be modified to indicate that most of theinformation requested is already in the text.
Section 1
1. Changes to the Risk Characterisation need to be reflected in this Section.
2. Paragraph 7 should state that EDA is a skin irritant/sensitiser (although mentioned inparagraph 8 it should be included here as well).
3. Paragraph 7 should end “.....in the occupational environment” to reflect the content of thereport.
4. This section should be expanded to include the overall conclusion of the environmental RiskCharacterisation.
5. The BUA document needs to be added at the beginning as an additional source document.
6. Include conclusion of environmental assessment (Dr Dobson provided a draft text whichwas considered and accepted by the meeting).
Section 2
1. The references for the log P values should be quoted (given in BUA report).ow
2. The reference to the use of EDA in cosmetics in Paragraph 3 needs to be amended toindicate that it has been used, rather than that it is used.
Section 4
1. Add that it has been used in skin creams; however its continued use is unknown.
2. Information from the English version of the BUA report on emissions to waste water will beadded to Paragraph 1.
3. The production volumes in Paragraph will be expanded to give a better world-wide picture(e.g., from the BUA report).
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Section 6.1
1. NIHS have some data on surface water levels, which will be provided by Dr Sekizawa forinclusion.
2. The residue levels quoted need to be checked as they should fall, but do not appear to.
Section 6.2
1. This section is still rather long. The author will try to cut it back.
2. The EASE model needs further explanation. A brief description and reference to thepublished EU Technical Guidance Document should be given in an Annex.
Section 8.5
1. The positive tests need additional detail and explanation. The inadequacy of the testing of EDA for this end-point, the age of the data and the reliability of the positive tests, needs tocome out clearly. (Ms Meek provided a redraft during the meeting for consideration by theauthor)
Section 8.6
1. There is confusion between the tests, and this would be better split into two paragraphs.
2. Price (1993) is an abstract of the NTP study. The NTP study is to be provided to theauthor by Dr Zeigler-Skylakakis, and incorporated if there is sufficient time.
Section 11.1
1. The text needs reworking to reflect the new conclusion on genotoxicity from Section 8.5(see above). Ms Meek provided a draft text for the whole of Section 11.1 which wasconsidered and accepted by the meeting. This captured the points made below.
2. The information on non-neoplastic effects in the liver should be redrafted to show that thereis a spectrum of effects, and that the effects seen at the lowest dose have been used tocharacterise the systemic toxicity.
3. The discussion of dose-response relationship in Paragraph 3 should be moved to 11.1.2,and the reference to thresholds removed.
4. As no MEL has yet been set in the UK, the relevant paragraph can be deleted.
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5. This section to be redrafted to indicate that:
! it’s a risk characterisation for occupational exposure;! the main concern is asthma and it is not possible to do risk characterisation;! a sample risk characterisation for systemic effects has been carried out.
Section 11.2
1. Paragraph , first sentence should be replaced with the correct text from the ExecutiveSummary.
2. Include the term readily biodegradable.
Section 13.1
1. The International Chemical Safety Card may be the right place to address the desire forsome practical information on preventative and protective measures, although therequirements and guidance in ILO Conventions on Chemicals may cover the managementof occupational risks satisfactorily, especially as risk management is not within the remit ofthese documents. The FRB recommended that the ICSC group consider changes to the R-phrases for this substance.
21
Tributyltin oxide
General
1. Remove all reference to Carlsson (1987) as this is an unpublished report, and cite originaldocuments where available.
Secretarial/Editorial
1. Section 2, peer review comment 1 (reviewer 15): amend authors response to indicate thatthe data presented is consistent with other CICADs.
2. Presentation of “E” values to be determined and amended by Secretariat.
Section 1
1. Indicate the sources for the different sections of the document (i.e., EHC for environmentand IRIS for animal and human toxicity) and that more recent studies have been included inthe CICAD.
2. State that:
! where studies were conducted using TBTO, this is specified;! where the data refers to TBT or the identity of the specific compound is not clear,
then the term TBT is used.
3. Highlight that Immunotoxicity is the critical endpoint.
4. Remove the word “appears” from the second sentence of the last paragraph.
5. State that TBTO is a human skin and respiratory irritant.
6. Summarise the risk characterisation, and state that the benchmark dose and NOAEL aresimilar.
Section 2
1. Dr Dobson to check information regarding trade names and information will be included ifinformative.
2. State the following: “where the data refers to TBT or the identity of the specific compoundis not clear, then the term TBT is used”.
22
Section 4
1. Include a sentence stating that the use of TBTO as an antifouling agent of small boats hasdecreased due to government regulations.
Section 6.1
1. Dr Soliman to provide references on seasonal changes of environmental levels of TBTO.
Section 6.2
1. Dr Sekizawa to supply recent data on human daily intake for inclusion.
Section 7
1. Add more data on toxicokinetics (a per comment 1, reviewer 15) if readily available inEHC document (Mr Cary checked EHC document, and provided information to theauthor).
Section 8
1. Include introductory paragraph stating that the critical effect is Immunotoxicity and that thisis addressed in detail in section 8.7. State the source of the data is IRIS document and whyfull details of certain studies were included. State that all studies are summarised in thetable.
2. Include table in this section and include appropriate heading for table.
Section 8.1
1. Include more information of effects seen in acute studies (as per comment 1, reviewer 15) ifreadily available in EHC document (Mr Cary checked EHC document, and providedinformation to the author).
2. State at the beginning of paragraph 2: “In the only inhalation acute study, …”.
Section 8.2
1. Include information on the size and quality of data for skin and eye irritation and skinsensitisation if readily available from EHC document (Mr Cary checked EHC document,and provided information to the author).
23
2. Remove the following: (allergic contact dermatitis).
Section 8.4.2
1. This section to be condensed, focusing on the adequacy of the studies and the majorendpoints (Ms Meek provided redrafted text for consideration by the author).
2. Dr Benson and Dr Skylakakis to check original data for studies by Daly regarding theincreased incidence of hepatocellular carcinomas and adenomas at the highest dose, asreported in the BUA report.
Section 8.5
1. Incorporate more detail on positive mutagenicity studies if available in EHC document (MrCary checked EHC document, and provided information to the author).
2. Check to make sure the conclusions are consistent with WHO.
Section 8.6
1. Expand the first paragraph to include the NOAELs and the effects observed.
2. Delete the detailed descriptions of the studies and include reference to the table.
Section 8.7
1. Author to check whether all the detail needs to be included for both subchronic studies.
2. Include introductory paragraph drawing attention to the fact that significant effects are seenat lower doses in younger animals.
3. Condense the detail on the abstract of Buckiova et al (1992), stating only the majorobservations and highlighting that only the abstract is available.
4. Clarify last sentence on apotosis by reflecting the author’s response to reviewers lastcomment (reviewer 15).
Section 10.1
1. Clearly state that source of data is the EHC document.
2. Include Latin names of the organisms wherever possible.
24
3. Dr Dobson and Dr Berzins to redraft this section, including:
! addition of an introductory paragraph stating that whenever this chemical is releasedinto the aquatic environment, organisms will be affected;
! remove all reference to Karlsson (1997) report;! correct any errors;! indicate that there is a wide range of sensitivities in different organisms.
4. Dr Yasumo has some minor changes which he passed to Dr Dobson for inclusion.
Section 11.1.1
1. Remove first sentence of last paragraph: “There are no data …. TBTO”.
2. Transfer table to section 8 and provide a suitable heading.
Section 11.1.2
1. Include data for the benchmark dose.
2. State that the NOAEL is very conservative in light of the 10-fold difference in testconcentrations.
Section 11.1.3
1. Dr Sekizawa and Dr Benson to draft sample risk characterisations based on both guidancevalues (i.e., derived from NOAEL and benchmark dose) together with the estimated humanexposure levels (using Japanese data).
2. Revise statement on genotoxicity data to reflect revised conclusion included in section 8.5.
Section 11.2
1. Dr Dobson to expand sentence on bioaccumulation to cover possible human exposure.
2. Check original reference for last paragraph i.e., is it TBT or TBTO.
Section 14
1. Secretariat to include information on international regulations.
25
Appendix 1
1. Expand information on peer review process of EPA and EHC documents.
26
TPT compounds
General
1. All information should be given in the tables, and summarised in the text, i.e., that newinformation which does not appear in the table is not to be introduced in the text.
2. Include an introductory paragraph clearly stating that the source is WHO, 1992. For allinformation extracted from WHO 1992, reference the studies in the text and the tables as: (name ofreference, cited in WHO 1992). All proprietary studies cited from FAO/WHO monographs in thisCICAD will be shown as a following example: (Diehl & Leist, 1986a: unpublished paper cited fromWHO monograph).
Secretariat/Editorial
1. In Peer-review Table, alter author’s response for comment 5 (peer reviewer 7), section 1,to state that a higher value has been added.
2. Change author’s response to comment 1 (reviewer 7), section 6.1, to indicate all data hasbeen added.
3. IPCS Secretariat should check for use information in other countries
Section 1
1. State clearly that human and animal toxicological data is based on JMPR document and thatthe CICAD has essentially adopted the human evaluation of JMPR.
2. State that many original references cited in JMPR were not available to the author and peerreviewers, however recent data do not alter the conclusions of JMPR.
3. Revise para 14 as a consequence of changes to 11.2.
4. Para 2: delete “low melting”.
Appendix 1
1. Need to add information on JMPR and HSE ACP peer review processes, members anddates of meetings.
Section 2
1. Add “anionic” back into the text, i.e., ......where X is an anionic group, such as hydroxy,acetate, chloride or others.
27
2. Delete: (soluble in several g/l or higher).
Section 3
1. Dr Soliman provided more information to the author on analytical methods.
Section 4
1. State that information on use was only provided by Japan.
Section 5
1. Provide references for paragraphs 1 and 2.
2. Detection limits for monitored data should be given.
Section 6.1
1. Detection limits will be added in paragraphs 2 and 3.
2. Latin names will be added in paragraph 4.
Section 6.2
1. Move all information on zebra mussels to section 6.1.
2. Remove last 2 sentences of paragraph 4. The sentence “Some contamination in ocean fishsuggest biomagnification...” to section 6.1.
3. In paragraph 4 include range of TPT levels in fish and clams.
4. Include a new paragraph 8 with information from p14 of the national document describingvarious contamination levels in the natural environment.
Section 8
1. Need to ensure that studies discussed in text can be identified in tables.
2. Include paragraph re-emphasising the source of the data.
Section 8.1
1. 1 paragraph: change the words “toxic symptoms” to “clinical signs” throughout thest
paragraph.
28
2. Include in paragraph 1, 1 sentence: (WHO, 1992 - no further information provided).st
3. In para 1 clarify what is meant by delayed effects.
Section 8.3
1. Table 2 – indicate that these are the more critical studies summarised.
2. Present all NOAEL/LOAEL/NOEL/LOEL figures in table, but only those for criticalstudies in the text.
3. Insert citations for cross-references.
4. Insert “Only studies which showed lowest LOAELs for certain species in certain route ofexposure are chosen. Further studies and details are available in the FAO/WHOmonographs.”
Section 8.4
1. If information available, expand paragraph 4 to include why the JMPR concluded tumourswere not significant.
Section 8.5
1. Paragraph 3: delete “for man”.
2. Paragraph 2, 2 sentence: clarify the sentence by stating for which agents TPTCl enhancednd
micronuclei induction.
3. Paragraph 2: move last sentence to the end of paragraph 1.
4. Paragraph 3: state that “there are no new data which impact on the JMPR conclusion thatTPT is not genotoxic. Recent data indicate, however, that TPT potentates the genotoxicityof other substances”.
5. Paragraph 1: include: “based on studies reviewed in WHO (1992) ........”.
Section 8.6
1. Revise para 4 with up-to-date data on maternal toxicity (abstract has been published). Thisdescribes implantation failure possibly being caused by inhibition of progesteron function.
2. Citation must be confirmed.
29
Section 8.7
1. Add results of additional IP study (study provided by Dr Soliman).
2. Add more quantitative details to paragraph 2.
Section 8.8
1. Dr Sekizawa to include information on Mode of Action from Bettin et al. Study.2. Dr Soliman provided additional reference re “mode of action” for TBT and TPT.3. Alter title to “Mode of Action”.4. Add references from EPA comments on induction of calcium release.
Section 9.2
1. Para 2 last sentence remove “but may not be a sensitiser”.2. Remove para 1.
Section 10.1
1. Reference to de Vries paper now given. Author will obtain and check.
Section 11.1.1
1. Para 1: state that there was no quantitative human data.
2. Para 3 indicate duration of studies.
3. Dr Sekizawa to include revised paragraph from executive summary, summarising the animalhealth effects and Mode of Action.
Section 11.1.1 and Section 13.1
1. Check JMPR regarding delayed CNS effects and remove reference to delayed effects onCNS system if appropriate.
Section 11.1.2
1. Indicate that no further information on uncertainty factors was included in JMPR.
Section 11.2
1. Revised paragraph 6 & 7 (Dr Dobson provided a draft text which was considered and
30
accepted by the meeting) to be included.
Section 12
1. Cross reference to Section 11.1.1.
31
Butyl benzyl phthalate
Section 1
1. Ensure that information on skin irritation and sensitisation correctly reflects revisedconclusions.
2. Place the assessment of endocrine disrupting effects in the context of current work on thistopic (Dr Koeter to provide a text, which also needs to be put in the evaluation).
3. State that the CICAD and national document were developed in parallel.
Section 2
1. Need to check the source of the model vapour pressure and ensure reporting of vapourpressure in sections 2, 4, 5 are correct and consistent.
Section 3
1. Dr Soliman and Dr Cary to check if there are additional analytical methods.
Section 4
1. Need to recognise toys as a source of exposure and indicate the data is inadequate toquantify this exposure.
2. Para. 2: delete “though this is believed to be minimal”.
Section 5
1. Add Koc values (references are Staples and Gledhill).
2. Para. 6, last sentence: delete “however, the potential …….. metabolize BBP”.
3. In response to Comment 5 (peer reviewer 15) – need to confirm whether fugacity modelassumes continuous release in water.
Section 6.2
1. Para 2: indicate that the water surveys were predominantly for surface water.
2. Para 6, 4 sentence: Amend “0.4 litres” to “1.4 litres”.th
3. Para. 5: remove reference to Table 6.1 (which has been deleted in the CICAD).
32
4. Para 6: Remove values for infants and indicate only the magnitude of exposure relative toadults.
Section 8.1
1. End of sentence 2, add: “at near lethal doses”.
Section 8.2
1. State that no tests have been conducted according to validated international protocols.
2. Include more detail on Calley et al study.
Section 8.4
1. Move table 11.1 to section 8.4.
Section 8.4.2
1. Para. 6: replace “epithelial” with “cell”.
2. Give reasons why leukaemia data are dismissed
Section 8.5
1. Move last paragraph to hazard identification section.
2. Para 3: clarify what is meant by “across several studies”.
Section 8.6
1. Para 7 3 sentence: remove “there was no clear dose response”rd
2. Para 7 last sentence: quantify the magnitude of changes.
3. Para 8: delete sentence in square bracket.
4. Dr Ema to supply reference and wording (via Dr Sekizawa).
5. Para 11 (Sharpe et al. 1995): clarify what is meant by “the negative control group was notevaluated”.
33
6. Para 11: verify if 1 and 2 litters were investigated.st nd
7. Para 7: last sentence, move information in the square brackets to the hazard evaluationsection.
8. 3 to last para: check if (NTP, 1989) should be included.rd
9. Remove reference to Sharpe and Ashby studies being similar.
Section 10.1
1. Include more information on test results if a “margin of safety” approach is to be used.
Section 10.1.1
1. Add more detail to this paragraph.
Section 10.1.2
1. Para 2: give more detail on what is meant a by sediment quality value.
Section 10.2.2
1. Delete paragraph.
Section 11.1
1. Para 10: delete reference to studies being similar.
Section 11.1.1
1. Para 5: indicate leukaemia data.
2. Include information on the U shaped response observed for endocrine disruptors.
3. Place the assessment of endocrine disrupting effects in the context of current work on thistopic (Dr Koeter to provide a text).
4. Para 4: amend to say “cannot come to any conclusion for skin sensitisation”.
Section 11.1.2
1. Para 2: indicate that benchmark dose is based on 5% effect level and 95% confidence limit.
34
2. Include a reference for THRESH programme (e.g., title of the manual, and how to get holdof it).
Table 11-1
1. Separate Sharpe and Ashby studies.
Table 11.2
1. Check the degrees of freedom are correct.
2. Reintroduce the figures into the CICAD.
3. Indicate which programme was used to develop benchmark dose. Include brief descriptionon what the benchmark dose, what data are needed and the advantages. State whybenchmark dose was used for BBP.
Section 11.2
1. Para 2: clarify wording to indicate that likely sinks will be soil and sediment (as stated insection 5).
2. Para 4: need to state that higher environment exposure values have been reported.
3. Para 2: reflect changes already made in the executive summary.
4. Para 5: expand paragraph to highlight limitations of the data.
35
Appendix V - Text drafted during the FRB meeting
Azodicarbonamide
1. Add to summary and evaluation:
Azodicarbonamide released to surface waters would partition to the hydrosphere with nosignificant sorption to particulates. Half-life for reaction with OH radicals in the atmosphere is 0.4days. It was readily biodegradable in two out of three tests with sewage sludge and degraded in soilby between 20 and 70% over 14 days. NOECs for fish and water flea have been reported at > 50and 5 mg/litre respectively. Lack of information on release to the environment precludes aquantitative risk assessment.
2. In Section 1 and 11.1.3:
Three papers have recently been published, for which can be concluded that the consumermay chronically be exposed to the substance by oral uptake (bread, beer). For a riskcharacterisation concerning general population this exposure has to be taken into consideration.
The lack of exposure and toxicology data is of concern for assessment of risk to consumers.
3. Section 11.1.1 Hazard identification and dose-response assessment
Some of the available toxicological studies have been conducted using biurea rather thanazodicarbonamide. However, azodicarbonamide is readily converted to biurea in vivo. Hence,similar toxicological properties would be expected.
Azodicarbonamide is of low acute toxicity by all routes, and, although the animal studies areof uncertain quality, solid azodicarbonamide would not be regarded as a skin or eye irritant. Withrespect to respiratory tract irritation, no changes of toxicological significance were seen in guineapigs exposed up to 97 mg/m azodicarbonamide aerosol for 1 hour.3
No conclusions could be drawn regarding skin sensitisation potential from the available,poor quality, animal studies. Although there are currently no validated animal studies to investigateasthmagenic potential, there was no evidence of pulmonary irritation or asthmatic type reactions inguinea pigs exposed to up to 200 mg/m azodicarbonamide aerosol 6 hours/day, 5 days/week for 43
weeks.
Similarly, there were no changes of toxicological significance seen amongst rats or miceexposed by inhalation to up to 200 mg/m azodicarbonamide aerosol 6 hours/day. 5 days/week for3
up to 13 weeks.
For repeated dose studies using the oral route data were inconsistent. In two-year studies inwhich rats received up to 450 mg/kg/day biurea there were no adverse effects seen.
36
Unpublished information suggests that no adverse effects were seen in rats exposed to up to 1250mg/kg/day for 13 weeks. However, shorter-term studies (2-weeks, also unpublished) indicatedhistological lesions in the kidneys at 625 mg/kg/day or more. There were no data in relation torepeated dermal exposure.
Azodicarbonamide has been identified as a mutagen in bacteria systems, butazodicarbonamide was not identified as a mutagen in mammalian in vitro test systems or in twomammalian assays in vivo using bone marrow. It is therefore unlikely that the mutagenic propertiesdisplayed by azodicarbonamide in bacterial systems will be expressed in vivo. However, it isconsidered that a confirmatory in vivo study in a second tissue is required for completereassurance.
There are no adequate data available relating to carcinogenic, reproductive ordevelopmental effects hence it is not possible to evaluate the risk to human health for theseendpoints. {Note: Japan is doing tests within the OECD SIDS programme on reproduction(OECD 421) and algae growth - a footnote should be added in Section 8}
Several bronchial challenge studies have been reported but only one provides reasonableevidence that the work-related asthmatic symptoms were due specifically to azodicarbonamide.This report is considered to show an asthmatic response and not an irritant response toazodicarbonamide on challenge; animal studies suggest that airborne concentrations of up to 200mg/m can be tolerated with little or no pulmonary irritation and in the bronchial challenge tests it is3
unlikely that the levels approached those used in animal studies. The delay in response toazodicarbonamide challenge, the magnitude of reduction in FEV accompanied by an increase in1
airway hyperreactivity in one individual and the fact that a control individual with mildlyhyperreactive airways did not respond to a much more prolonged exposure under similar challengeconditions provides further evidence for asthmagenicity. Further evidence of a link betweenazodicarbonamide and respiratory problems is provided by the results of workplace healthevaluations. Although criticisms can be levelled at individual studies, weight of evidence suggeststhat azodicarbonamide can induce asthma in a significant proportion of people exposed.
There are some case reports of individuals with skin reactions to topically appliedazodicarbonamide. For some of these, results are questionable. However, in workplace healthsurveys, the incidence of skin rash was found to be greater amongst workers regularly exposed toazodicarbonamide. Although no firm conclusions could be drawn from the poorly reported animalstudy, but clear evidence of skin sensitisation to azodicarbonamide in one individual and supportingevidence of skin problems from workplace health surveys lead to the conclusion thatazodicarbonamide should be considered as a human skin sensitiser.
In conclusion, the key toxic effect of azodicarbonamide in humans is asthmagenicity.Evidence of this effect has been found from bronchial challenge studies and workplace healthevaluations. From the information available, azodicarbonamide is considered to have a low potentialfor irritancy, thus it is considered that the respiratory symptoms observed in these studies are mostlikely due to an asthmatic type response rather than respiratory tract irritancy. There is no clearinformation on the levels that may have induced or provoked the
{Clarify whether this refers to unhealable dust}2
37
state of asthma.
There is also information to indicate that azodicarbonamide can cause skin sensitisation in humans.
4. Section 11.1.2 Criteria for setting guidance values for azodicarbonamide
The main cause for concern relates to the risk of developing occupational asthma. There is noinformation available relating to dose-response relationships or levels associated with the inductionof a hypersensitive state or provocation of an asthmatic response. Hence it is not possible to reliablyquantify the risk of developing occupational asthma.
5. Section 11.1.3 Sample risk characterisation
Using data obtained from a factory in the UK and published exposure data as an example (section6.1), levels of airborne azodicarbonamide measured over periods of 70 minutes to 4 hours of up to12 mg/m have been observed. Short term peak exposures could rise higher than this level.3
In the United Kingdom occupational setting, it is recommended that a maximum exposure limit(MEL) is assigned to substances for which it has not been possible to identify a level of exposurethat is without adverse effects to health. This is a non health-based standard and in determining themost appropriate level for a MEL, consideration is taken of the level of control that is reasonablypracticable for industry to achieve. The MEL of 1 mg/m (8-hour TWA) was based on a level of3 2
control that was deemed by tripartite agreement, to be reasonably practicable under workplaceconditions within the United Kingdom. There is also a continuing remit for industry to keep onreducing exposure levels as advances in technology make this possible. For substances that areasthmagens, it is also advisable to have a short-term exposure limit (STEL) to restrict peakexposures as they may have a role in the induction and triggering of asthmatic phenomena. In theabsence of any specific data that might advise adequately on the numerical value of the STEL, 3mg/m (15-minute reference period) has been established.3
Since azodicarbonamide is a skin sensitiser, then where skin contact can occur there may be a riskof developing allergic dermatitis if suitable PPE is not used.
(Comment on consumer exposure - bread/beer - to be added)
38
Ethylenediamine
1. Add to summary:
Given the wide range of acute and chronic test results, a predicted no-effect concentration(PNEC) for aquatic organisms was taken as 16 micrograms/litre based on applying an uncertaintyfactor of 10 to the lowest reported NOEC for Daphnia reproduction. Conservative assumptionsfor predicted environmental concentrations (PEC) produce PEC/PNEC ratios indicating someconcern from initial concentrations. However, more refined exposure estimates indicate low risk toaquatic organisms.
2. Section 8.5 Genotoxicity and related endpoints
Additional detail to be provided on the studies described in the second sentence to indicatethe mixed nature of the results (i.e., those in bacteria)Suggested replacement for last two sentences (to be reflected also in Sections 1 and 11):
Though there has been some evidence of mutagenicity in bacterial systems in a few limitedstudies, the weight of evidence indicates that ethylene diamine is not genotoxic, with all results inmammalian cells in vitro and in vivo (dominant lethal assay) being negative. It should be noted thatthe overall database is also limited with there being no assays for clastogenic activity or forgenotoxic potential in somatic cells in vivo.
3. Section 11.1 Evaluation of health effects
11.1.1 Hazard identification and dose-response assessment
Ethylenediamine is of moderate acute toxicity by all routes. In studies in animals,ethylenediamine is a primary skin and eye irritant being corrosive when undiluted. It is also a skinsensitiser. In repeated dose toxicity studies by the oral and inhalation routes, effects on the liver andkidney have been observed, with pleomorphic changes to hepatocytes in rats being reported atlowest oral doses (45 mg/kg bw and above for two years; NOEL, 9 mg/kg bw/day). In inhalationstudies, there were no effects at 60 ppm, though slight depilation was observed at the next higherconcentration (130 ppm) and effects on the liver and kidney at higher concentrations still(approximately 200 ppm and above).
There has been some evidence of mutagenicity in bacterial systems in a few limited studies.However, the weight of evidence is negative, though the overall database is limited, there being noassays for clastogenic activity or for genotoxic potential in somatic cells in vivo. Ethylenediaminewas not carcinogenic in adequate studies in animals.
In humans, ethylenediamine has the potential to induce respiratory tract hypersensitivity andprovocation of asthma is the major health effect of concern in the occupational environment. Themechanism of induction of the hypersensitive state is unknown although the skin sensitising potential
39
of ECA {was this a typing error?} and limited evidence in workers with EDA-provoked asthma issuggestive of an immunological mechanism. There is no clear data on levels which are associatedwith induction or provocation of asthma.
11.1.2 Criteria for setting guidance values
Available data are inadequate to serve as a basis for characterisation of the dose-responserelationship for provocation of an asthmatic response, the effect of greatest concern in theoccupational environment. Since it is not possible to identify a level of exposure that is withoutadverse effect, it is recommended that levels be reduced to the extent possible.
With regard to systemic effects, the lowest NOELs of 60 ppm (inhalation) and 9 mg/kgbw/day can serve as a basis for comparison with estimated exposure for characterisation of risk,either with application of appropriate uncertainty factors or directly. An example of the latter(margin of exposure) approach is presented in section 11.1.3.
11.1.3 Sample risk characterisation
It should be noted that available data are inadequate to serve as a basis for characterisationof the dose-response relationship and hence risk, for provocation of an asthmatic response, theeffect of greatest concern in the occupational environment.
It should also be noted that since diluted ethylenediamine is a skin irritant and sensitiser, ifsuitable personal protective equipment is not used, there is a risk of developing irritant and/orallergic dermatitis.
A sample risk characterisation for systemic effects in the occupational environment in theUK is provided here. Measured data of exposure to ethylenediamine (generally used in closedsystems) indicate that levels in industry in the UK are less than 0.5 ppm for 8-hr time weightedaverages. Modelled data (EASE) is in good agreement predicting comparable values of 0.21 to0.52 ppm. Short-term peak exposures (sampling and hose uncoupling operations) were predictedto be 6.7 to 13.3 ppm, 15-minute TWA. The EASE model predicts dermal exposures in the rangeof 0 to 0.1 mg/cm /day for an operator transferring ethylenediamine into closed systems once a day2
(though coveralls and well maintained plastic gloves will significantly reduce exposure from thissource).
With respect to systemic effects, worst-case estimated and measured exposures of 0.5 ppm8-hour TWAs are substantially less (by 100 fold or greater) than the NOAEL in the inhalation studyin rats. The combined body burden from inhalation and dermal exposure for chemical synthesis canbe estimated to be around 0.3 mg/kg bw/day (70 kg worker breathing 10 m per day containing 0.53
ppm or 1.25 mg/m which is 100% absorbed and 10% absorption from unprotected, undamaged3
skin for standard hand area of 840 cm ). This is 30 fold less than the NOEL for the hepatic effects2
in the oral studies.
40
Available data on indirect exposure in the general environment or from consumer productsare inadequate to serve as a basis for a sample characterisation of risk for these scenarios.
41
Tributyltin oxide
1. Insert to Executive Summary
In this document the term TBTO is used when that specific chemical is intended. In theenvironment, however, organotin compounds are expected to exist mainly as TBT-hydroxide, -chloride, and -carbonate. In these cases or when the identity of the specific chemical is not clear,the general term TBT is used.
Benchmark dose analysis shows that the exposure corresponding to the lower confidence limit(95%) on dose for a 10% decrease in IgE titer in rats is 0.029 mg/kg-day.
Data show that TBTO is a severe respiratory tract and skin irritant.
2. Insert to Section 3
TBT can be separated from samples by capillary supercritical fluid chromotography and determinedby inductively coupled plasma mass spectrometry. A detection limit of 12.5 pg was obtained (Velaand Caruso, 1993).
3. Insert to Section 4
Government restrictions have decreased the use of TBT compounds in antifouling paints on smallboats.
4. Insert to Section 6.1
Recent data also document a seasonal variation in the concentration of TBT in a freshwater marina(Fent and Hunn, 1991). The concentration of TBT was highest in late Spring and showed aprogressive decline until winter. This same study also documented that the TBT concentration insediment decreased progressively with depth.
5. Section 6.2
Market basket studies have shown that daily intake of TBT per person (assumed to weigh 50 kg) inJapan (expressed as TBTCl) were estimated to be 3.7, 9.9, 5.4, 3.6, 2.9. 1.6. 1.5 and 2.3 µg in1990, 1991, 1992, 1993, 1994, 1995, 1996 and 1997, respectively (NIHS, unpublished). TBTcontamination were found mostly in sea foods. More than two fold difference observed in estimatedvalues and variation in estimated data between a local government and the average of 10 localgovernments implies that differences in food intake pattern or some other factor may influenceestimation (NIHS, unpublished; Tsuda et al., 1995).
This fact and coincidental contamination with TPT must be taken into account in risk estimation inoral route exposure.
42
6. Insert to Section 8
Extensive data are available on the toxicity of TBTO. Detailed descriptions of studies critical to theevaluation of TBTO follow; all other studies are described in USEPA (1997) or WHO (1990).Collectively these data establish that immunotoxicity is the critical effect of TBTO. A detailedevaluation of the immunotoxic effects is found in section 8.7. All studies involving repeated oralexposure are listed in the table below.
7. Suggested condensation of text for section 8.4.2
8.4.2 Chronic exposure and carcinogenicityWell conducted studies are available in rats and mice. Due to its inadequacy, an additional study indogs (Schuh, 1992) is not included here. Long-term studies assessing the immune system arereported in section 8.7.
Rats.In a carcinogenicity/chronic toxicity study, groups of 60 male and 60 female Wistar rats
were exposed to dietary tributyltin oxide for 2 years (Wester et al., 1990, 1988, and 1987). Basedon estimates of average body weight and food consumption from reported data, ingested doseswere approximately 0.019, 0.19, or 2.1 mg/kg-day in males and 0.025, 0.25 or 2.5 mg/kg-day infemales. Endpoints that were evaluated included clinical abnormalities, survival, body weight, foosand water consumption, and the incidence of neoplastic lesions. Haematology, urinalysis, clinicalchemistry (including immunoglobulins IgG, IgM and IgA) and endocrinology (thyroxin and freethyroxin, thyrotropin, luteinizing hormone, follicle stimulating hormone, insulin) were evaluated in 10rats/sex/dose after approximately 3, 12 and 24 months (endocrinology not assessed at 3 months).Organ weights and histology were evaluated in 10 rats/sex/dose after 12 and 24 months, andhistology also was evaluated in all moribund rats as well as rats surviving until 24 months.Neoplastic lesions were examined in the control and high-dose groups, and if differences wereobserved, in the intermediate-dose groups.
No treatment-related adverse changes were found in males or females at the lowest dose.Changes in water intake in the mid and high dose groups and urinary indices in the high dose groupswere suggestive of impaired renal concentrating capacity associated with age-related degenerativechanges in the kidney. These changes were consistent with the increased incidence and severity ofage-related degenerative histopathological changes in the kidney in high dose males and femalesafter 24 months.
Other effects occurred predominantly in high-dose rats. Serum immunoglobulin levels weresignificantly increased (p<0.05) in the high dose group. Body weight gain and survival were alsoreduced in both sexes in the high dose group. Absolute liver, kidney, adrenal gland (male only) andheart (male only) weights were increased and thyroid weight (female only) was decreased in highdose rats at study termination; relative organ weights were not reported.
43
Treatment-related nonneoplastic histological changes occurred in the liver, spleen andthyroid of high dose males and females at 12 months though at 24 months, only the thyroidhistologic changes persisted. There were no accompanying significant changes in concentrations ofserum thyroid hormones.
Increased incidences of several benign spontaneously occurring tumours in some endocrinetissues were observed at the high dose, generally in both sexes. these were benign pituitary tumours,pheochromocytomas in the adrenal medulla and parathyriod adenomas (males). Incidence oftumours were as follows:
Concentration of Pituitary Tumours PheochromocytomasTBTO (mg/kgdiet)
Female Male Female Male
0 22/50 34/50 3/50 16/50
0.5 32/50* 39/50* 3/50 13/50
5 22/50 29/50 3/50 14/50
50 35/50** 43/50*** 34*** 33***
Statistical analysis was carried out according to Peto, one tailed. Values marked with asterisksdiffer significantly from the corresponding control values (*P<0.05; **P<0.01; ***P<0.001).
Concentration of AdenomasTBTO (mg/kgdiet)
Female Male
0 0/64 0/39
0.5 0/44 2/50
5 1/40 1/51
50 1/44 6/43**
The value marked with asterisks differs significantly (chi-square test) from the corresponding controlvalue (**P<0.01).
(Was tumour incidence increased significantly in relation to historical controls?) Thesetumours occur in this strain of rats with high and variable background incidence (Kroes et al., 1981;
44
Wester et al., 1985). The reported background occurrence of pituitary tumours in females was32% and 55% and in males was 34% and 66%; the reported background occurrence ofpheochromocytomas in females was 10% and 12% and in males was 26% and 44%. The authorsreported no data on the background occurrence of parathyroid tumours.
There was no significant endocrine imbalance documented in the study. There was,however, a decrease in the free T4: total T5 ratio for both sexes at 12 and 24 months in the highdose group, and after 12 months at the mid dose group. Although the pituitary tumours stained forthe presence of prolactin, there was no correlation between the serum level of prolactin or theoccurrence of hyperplastic or neoplastic mammary tissue and the presence of pituitary tumour.
Based on the constellation of changes observed at the highest dose, the LOAEL is 2.1 mg/kg-dayand the NOAEL is 0.19 mg/kg-day.
Mice
Tributyltin oxide has not been carcinogenic in an adequate study in mice. In this bioassay,TBTO (purity 97.1%) was fed to groups of 50 male and 50 female CD-1 mice in dietaryconcentrations of 0, 5, 25 or 50 ppm for 18 months. Based on food consumption and body weightdata, mean intake was reported to be 0, 0.7, 3.7 or 7.7 mg/kg-day in males and 0, 0.9, 4.8 or 9.2mg/kg-day in females. Other endpoints that were evaluated included clinical observations, limitedhaematology (total and differential WBC counts and RBC morphology in 10 mice/sex/group at 12and 18 months), organ weights, gross pathology and histology. Clinical chemistry and immunologicalassays were not performed.
Statistically significant decreases in survival occurred in treated mice of both sexes. Inmales, survival after 18 months was 67, 52, 42 and 42% in the control, low, mid, and high dosegroup, respectively (p<0.05, all doses). The overall survival of the low dose males (52%) waswithin the range of controls (45-78%). Because the difference in survival between the low dose andcontrol males became apparent late in the study (beginning at 15 months) and was marked attermination (54% versus 71% in controls), it is considered treatment-related. Survival in females at18 months was 59, 48, 40 and 27% in the control, low, mid, and high dose group, respectively(p<0.05 except for low dose group). No information on cause(s) of death was available. Othertreatment-related effects included significantly decreased food consumption and increased absoluteand relative liver weights in females at the high dose. Incidences of gross liver enlargement anddiscolouration were increased in both sexes in all dose groups, though not considered biologicallysignificant because of the slight nature of the changes and absence of histopathological alterations.Incidences of common spontaneous non-neoplastic lesions, particularly glomerular/interstitialamyloidosis of the kidney were increased in females in all dose groups but not in males. Theprogression of this lesion appeared to be more rapid in both sexes at the two highest doses,indicating a compound-related effect. There were no statistically significant increases in theincidence of any tumours or groups of tumours in males or females. The lowest-observed-adverse-effect-level was, therefore, 0.7 mg/kg-day (the lowest dose tested) based on decreased survival.
45
8. Insert to Section 8.5
In aggregate, despite the limited positive findings at cytotoxic concentrations, evaluation of theevidence shows that TBTO is not genotoxic. This conclusion remains consistent with the previousevaluation by WHO (1990).
9. Insert to Section 8.6
The LOAELs for maternal toxicity in rats and mice are approximately 10 mg/kg-day with NOAELsapproximately 5 mg/kg-day.
10. Insert to Section 8.7
The Vos et al. (1990) studies also establish that weanling animals are more sensitive to the effect ofTBTO than are adults. For example, following subchronic exposure the LOAEL in weanling rats is0.25 mg/kg-day; the LOAEL in aged rats is 2.5 mg/kg-day. NOAELs are 0.025 and 0.25 mg/kg-day, respectively. Additional data from Buckiova et al. (1992) and Smialowicz et al. (1989)provide additional evidence that the developing immune system is more sensitive to the effects ofTBTO.
46
Triphenyltin compounds
1. Executive Summary - Paragraph 1
This Concise International Chemical Assessment Document (CICAD) on triphenyltin wasbased on a review for triphenyltin compounds prepared by the National Committee for CICADs,Japan. Many of the critical studies on health effects in this review were cited from the monographsof FAO and WHO on pesticide residues (FAO, 1991a,b; WHO, 1992) which report summaries ofthe many studies submitted to WHO from manufacturers for evaluation. These original reports areproprietary and are not available to either the author of the National Review or CICAD draft or tothe Final Review Board. Therefore, this CICAD inevitably relies on the evaluations made by theFAO/WHO groups on pesticide residues for those studies cited from summaries of proprietarydata. Extensive information on environmental effects ............(rest stays).
2. Insert new paragraph 8 in Executive Summary
TPT shows varieties of health effects in various animal species, including effects on immune system,reproductive/developmental effects at near to maternally toxic levels (most LOAELs are in severalmg/kg range or lower), hyperplasias/adenomas on endocrine organs, apoptosis on thymus cells,Ca release in sarcoplasmic reticulum cells, and eye irritation. Underlying mechanism of these++
effects is under investigation and a certain common mechanism might be elucidated to explain thistoxicity profile.
3. Section 6.2, paragraph 6
Market basket studies have shown that daily intake of TPT per person (assumed to weigh50 kg) in Japan (expressed as TPTCl) were estimated to be 4.3, 10.4, 2.7, 0.6, 1.2, 1.4, 0.7 and2.7 µg in 1990, 1991, 1992, 1993, 1994, 1995, 1996 and 1997 respectively (NIHS, unpublished).TPT contamination were found mostly in sea foods. More than two fold difference observed inestimated values and variation in estimated data between a local government and the average of 10local governments implies that differences in food intake pattern or some other factor may influencesestimation (NIHS, unpublished; Tsuda et al., 1995). This fact and coincidental contamination withTBT must be taken into account in risk estimation in oral route exposure.
4. Section 8.8
Add three new paragraphs:
a) Testosteron addition (500 ng/l) induces faster and more intensive imposex development inNucella lapitus compared to that induced by TBT. Simultaneous exposure to TBT and to theantiandrogen cyproterone acetate which suppresses imposex development completely in N. lapillusand reduced imposex development in Hinia reticula proves the imposex-inducing effects of TBTare mediated by an increasing androgen level and are not caused directly by the organotincompound itself. Furthermore, TBT-induced imposex development can be suppressed in both snails
47
by adding oestrogens to the aquous medium. These observations suggest that TBT causes aninhibition of the cytochrome p-450 dependent aromatase system which catalyses the aromnatizationof androgens to oestrogens. Artificial inhibition of the cytochrome p-450 dependent aromatasesystem using SH 489 (1-methyl-1,4-androstadiene-3,17-dione) as a steroidal aromatase inhibitorand flavone as a nonsteroidal aromatase inhibitor induces development of imposex in both snails.The same mechanism may apply to TPT. (Bettin et al., Helgolaender Meeresuchungen, 50, 293-317 (1996)).
b) TPT induced Ca release in ruthenium red-sensitive and insensitive ways with EC values++50
of 75 and 270 µM, respectively. The Ca -ATPase activity and Ca uptake of sarcoplasmic++ ++
reticulum were also inhibited by TPT. The study suggests that the internal Ca store of skeletal++
muscle could be depleted by TPT through the inhibition of the Ca uptake and the induction of++
Ca release by acting on the Ca -ATPase and Ca release channel. Development of muscle++ ++ ++
weakness in organotin intoxication could partly explained by this peripheral myopathy relatedfindings (Kang et al., J. Biochem., 122 173-177, 1997).
c) Oral administration of a single dose of TPTCl (60 mg/kg bw) induced diabetes withdecreased insulin secretion in hamsters after 2-3 days without morphological changes in pancreaticislets.
Administration of TPTCl strongly inhibited rise in [Ca ] induced by 27.8 mM glucose, 100 µM++
Acetylcholine in the presence of 5.5 mM glucose, and by 100 nM gastric inhibitory polypeptide inthe presence of 5.5 mM glucose (GZP).
TPTCl administration impaired the insulin secretion in islet cells induced by 27.8 mM glucose, 100nM GIP in the presence of 5.5 mM glucose, and 100 µM Ach in the presence of 5.5 mM glucose.Pathology of TPT induced diabetes in hamsters involves a defect in cellular Ca response due to a++
reduced Ca influx through voltage-gated Ca channels (Miura et al., Endocrinology 138(7),++ ++
2769-2775, 1997).
5. Replace Section 11.2, paragraphs 6 and 7:
A no-observed effect concentration in water has not been established for TPT and imposexin molluscs. Experimentally, by injection, TPT has a similar potency to TBT in the genus Thais. TPTis less potent than TBT in Nucella, however, TPT shows greater bioaccumulation than TBT. Fromthis it can be assumed that the NOEC for TPT will be in the range of 1 - 10 mg/litre. The observedprevalence of imposex in Thais in the wild with ambient concentrations in this range supports thisassumption. Since residues of TPT and TBT occur together in the environment, their relativecontribution to observed imposex cannot be assessed for Thais species. Use of either TPT or TBTin antifoulant paint would lead to population declines of marine invertebrates on this basis.
