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IPCS

International Programme on Chemical Safety

REPORT OF THE IPCS TENTH FINAL REVIEW BOARDMEETING ON CONCISE INTERNATIONAL CHEMICAL

ASSESSMENT DOCUMENTS (CICADs)

Monks Wood, United Kingdom: 16 - 19 September 2002

Programme international sur la Sécurite des Substances Chimiques

Internal Technical ReportRapport Technique Interne

United Nations Environment ProgrammeProgramme des Nations Unies pour

l'Environnement

International Labour OrganizationBureau International du Travail

World Health OrganizationOrganisation mondiale de la Santé

3

UNITED NATIONS ENVIRONMENT PROGRAMMEIPCS/CICAD/02.01/Rev 1INTERNATIONAL LABOUR ORGANIZATION English onlyWORLD HEALTH ORGANIZATION

REPORT OF THE IPCS TENTH FINAL REVIEW BOARDMEETING ON CONCISE INTERNATIONAL CHEMICAL

ASSESSMENT DOCUMENTS (CICADs)


The issue of this document does not constitute formal publication. It should not bereviewed, abstracted, or quoted without the written permission of the Coordinator,Programme for the Promotion of Chemical Safety, WHO, Geneva, Switzerland.

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CONTENTS

Introduction............................................................................................................ 7

Background ............................................................................................................ 7

Document evaluation.............................................................................................. 7

General issues for consideration by the Steering Group ........................................ 8

Other business........................................................................................................ 8

Participants of the FRB Meeting............................................................................ 9

Agenda ................................................................................................................. 13

Terms of reference for a Final Review Board ...................................................... 14

Final Review Board comments on draft CICADs................................................ 15

Arsine. Human health aspects ...................................................................... 15

Ethylene oxide .............................................................................................. 19

1,1-Dichloroethene ....................................................................................... 21

Hydrogen cyanide and cyanides................................................................... 25

Hydrogen sulfide. Human health aspects ..................................................... 29

Thiourea........................................................................................................ 33

1,2,3-Trichloropropane ................................................................................. 35

Acknowledgements .............................................................................................. 38

IntroductionDr D. Osborn on behalf of the Centre for Ecology and Hydrology, 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. Dr Aitio expressed thanks for the supportof UK Department of Health and UK Department for Environment, Food and Rural Affairs inmaking available the facilities for the meeting.

The meeting opened with the election of officers: Dr S. Dobson was elected as Chairand Dr J. Sekizawa as Vice-Chair and Dr R. Liteplo and Dr J. Stauber as Rapporteurs.Following a brief introduction of each participant (List of participants, Appendix I), theagenda was adopted as proposed (Appendix II).

None of the members of the 10th Final Review Board (FRB) declared any conflict ofinterests.

BackgroundDr 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 clarifiedthe roles of Members and Observers, namely that Members are responsible for taking theformal decisions on the CICADs, whereas Observers are restricted to commenting on thefactual content of the documents. Members were reminded that they are selected to serve onthe FRB for their individual scientific expertise and not, in any way, as representatives oftheir governments.

Document evaluationThe FRB systematically reviewed responses of the authors to each comment submitted

during the peer-review phase. Areas where additional changes were recommended are notedin Appendix IV. All other comments were considered to have been adequately addressed bythe authors. The tables of peer-review comments are to be held by the Secretariat and madeavailable, upon request.

Arsine. Human health aspectsThe CICAD on arsine was approved by the Final Review Board as an international

assessment and recommended for publication subject to the requested changes being made asnoted in Appendix 4, as approved by the Chair.

1,1-DichloroetheneThe CICAD on 1,1-dichloroethene was approved by the Final Review Board as an

international assessment and recommended for publication subject to the requested changesbeing made as noted in Appendix IV, as approved by the Chair.

Ethylene oxideThe CICAD on ethylene oxide was approved by the Final Review Board as an


Hydrogen cyanide and cyanidesThe CICAD on Hydrogen cyanide and cyanides to be limited to human health effects

(with appropriate condensation of the sections 3,4,5, and 6, and deletion of sections 9 and11.2), complemented by inclusion of toxicological and kinetic information on acetonecyanohydrin; information in the ECETOC draft document (to be provided by the ECETOCobserver) to be considered, a new systematic literature update to be performed, the section onhazard and risk characterization to be expanded to fulfil the needs of the WHO drinking water

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guideline programme, and the further processing of the document to be discussed in thesteering group, with an aim to consider the new version of the document in the 11th FRB.

Hydrogen sulfide and sulfides. Human health aspectsThe CICAD on Hydrogen sulfide and sulfides was approved by the Final Review

Board as an international assessment and recommended for publication subject to therequested changes being made as noted in Appendix IV, as approved by the Chair.

ThioureaThe CICAD on Thiourea was approved by the Final Review Board as an international

assessment and recommended for publication subject to the requested changes being made asnoted in Appendix IV, as approved by the Chair.

1,2,3-TrichloropropaneThe CICAD on 1,2,3-Trichloropropane was approved by the Final Review Board as an


General issues for consideration by the Steering Group§ Inconsistencies between CICADs were noted, for example different approaches for risk

assessment, reflecting the CICAD process of using national reports. This is a concernwhere the differences are significant or there is insufficient information for a CICAD to beused to support WHO normative functions, such as the establishment of guidelines fordrinking water quality; this may result in duplication of effort.

§ Consider whether source documents are to be referenced only in the foreword or whetherthey should be included again in the summary for greater emphasis.

§ Standardise the description of the peer review process of national source documents forCICADs where possible.

§ Guidance on chemical purity and chemical specification: state up front in document andonly mention again if it differs in particular critical studies. For new studies insist onpurity data in future.

§ Need to give guidance to authors on use of specific terminology e.g. NTP levels ofevidence, for future CICADs.

§ Need to give guidance to authors/reviewers on whether metabolites or related compoundsshould be included. This will be CICAD specific, depending on source document,chemical etc. but in future related chemicals may need to be addressed together.

§ Need to encourage more industry input into CICADs (especially use and production data).§ Consider changing title of Section 3 in all CICADs to “Sampling and Analytical

Methods”§ Need to ensure ICSCards are attached to the draft CICADs. Cards to be updated prior to

publication of CICAD where possible.§ Ensure glossaries are included for each CICAD (unique terms to be provided by author).§ Consider having a section justifying why a particular chemical was chosen for the

development of a CICAD§ Guidance required for changing EHC documents to CICADs

Other business

11th Final Review Board meetingThe 11th FRB is planned to take place in June 2003. The closing date for the receipt of

first draft of CICADs is December 30, 2002.

APPENDIX I

9

Participants of the FRB Meeting

MembersDr R. Benson, US Environmental Protection Agency, Region VIII, 999 18th Street

suite 500, Denver, Colorado 80202-2466, USA, tel: 1-303-312-7070, fax: 1-303-312 6131, e-mail: [email protected]

Mr R. Cary, Health and Safety Executive, Industrial Chemicals Unit HD D3, Room202, Magdalen House, Trinity Road, Bootle, Merseyside, L20 3QZ, UK tel: 44 151 951 4820fax: 44 151 951 3308; e-mail: [email protected]

Dr R. Chhabra, National Institute of Environmental Health Sciences, PO Box 12233,Research Triangle Park, North Carolina 27709, USA tel: 1 919 541 3386 fax: 1 919 541 4704e-mail: [email protected]

Dr S. Chou, Agency for Toxic Substances and Disease Registry (ATSDR), 1600Clifton Road, N.E., E-29, Atlanta, GA 30333, USA. tel:1 404 498 0705 fax: 1 404 498 0092email: [email protected]

Dr S. Czerczak, Nofer Institute of Occupational Medicine, 8 Sw. Teresy Street, POBox 199, 90-950 Lodz, Poland. tel: 484 2631 4701 fax: 484 2631 4702 email:[email protected]

Dr C. De Rosa (invited but unable to attend), Agency for Toxic Substances andDisease Registry (ATSDR) Centers for Disease Control, 1600 Clifton road, N.E. Atlanta,Georgia 30333, USA, tel: 1 404 498 0160 / 0744, fax: 1 404 498 0094, e-mail: [email protected]

Dr S. Dobson, Centre for Ecology and Hydrology, Monks Wood, Abbots Ripton,Huntingdon, Cambridgeshire, PE28 2LS, UK, tel: 44-1487-772 494 (direct) 44-1487-772 400(Switchboard), fax: 44-1487-773 467, e-mail: [email protected]

Dr G. Dura, National Institute of Environmental Health of Jozsef Fodor Public HealthCentre, Gyáli út 2.6, Budapest 1097, Hungary tel: 361 218 3158, fax: 361 215 0148, email:[email protected]

Dr L. Fishbein, 4320 Ashford Lane, Fairfax, Virginia 22032, USA, tel: 1 703 7645232, fax: 1 703 764 7281, e-mail: [email protected]

Dr H. Gibb1, National Center for Environmental Assessment, US EnvironmentalProtection Agency (8601D), Ariel Rios Building, 1200 Pennsylvania Avenue, NW,Washington, DC 20460, USA, tel: 1-202-564 3334, fax: 1-202 565 0059, e-mail:[email protected]

Dr Y. Hayashi, Division of Chem-Bio Informatics, National Institute of HealthSciences, Minsitry of Health, Labour and Welfare, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo158-8501, Japan tel: 81 3 3700 1141, fax: 81 3 3707 6950, e-mail: [email protected]

Dr R. F. Hertel, Federal Institute for Health Protection of Consumers and VeterinaryMedicine, FG-82, BGVV, Thielallee 88-92, 14195 Berlin, Germany, tel: 49 30 8412 3931,fax: 49 30-8412 3003, e-mail: [email protected]

Dr A. Hirose, Division of Risk Assessment, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501 Japan, tel: 81 3-3700-1429, fax: 81-3-3707-6950, e-mail [email protected]

Mr P. Howe , Centre for Ecology and Hydrology, Monks Wood, Abbots Ripton,Huntingdon, Cambridgeshire, PE28 2LS, UK, tel: 44 1487 772 499, fax: 44 1487 773 467, e-mail: [email protected]

Prof J. Jeyaratnam, 31/1 Castle Street, Colombo 5, Sri Lanka, tel: 941 692 773,email: [email protected]

1 Present when Agenda items 1-7 were discussed

APPENDIX I

10

Dr J. Kielhorn, Fraunhofer Institute for Toxicology and Aerosol Research, Nikolai-Fuchs-Strasse 1, D-30625 Hannover, Germany, tel: 49 511 5350 329, fax: 49 511 5350 335email: [email protected]

Dr R. Liteplo, Existing Substances Division, Environmental Contaminants Bureau,Health Canada, Tunney’s Pasture, Ottawa, Ontario K1A OL2, Canada, tel: 1 613 957 1880,fax: 1 613 954 2486, email: [email protected]

Prof Y.-X. Liang, School of Public Health, Fudan University, Shanghai MedicalCollege, 138 Yi Xue Yuan Road, Shanghai 2000 32, People’s Republic of China, tel: 86 216404 3069 Ext 2196, fax: 86 21 6404 3069, email: [email protected]

Ms M.E. Meek2, Existing Substances Division, Safe Environments Programme,Health Canada, AL 0801C2, Tunney's Pasture, Ottawa, Ontario K1A OL2, Canada tel: 1 613957 3129, fax: 1 613 954 2486, e-mail: [email protected]

Mr F.K. Muchiri, Directorate of Occupational Health and Safety Services, PO Box34120, Nairobi, Kenya, tel: 254 2 550825, fax: 254 2 544428/558814, e-mail:[email protected]

Dr O. Sabzevari, Department of Toxicology & Pharmacology, Faculty of Pharmacy,Tehran University of Medical Sciences, Tehran, 14155/6451, IR IRAN tel: 98 911248 6166,fax: 98 21 646 1178, e-mail: [email protected]

Dr J. Sekizawa, Division of Chem-Bio Informatics, National Institute of HealthSciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8591, Japan, tel: 813 3700 9548, fax:813 5717 7180, e-mail: [email protected]

Dr F. Petrova Simeonova, Bul. Zarigradsko shosse 4a block 2a, Sofia 1113, Bulgaria,tel: 359 2 72 6587, email: [email protected]

Dr J. Stauber, CSIRO Energy Technology, Centre for Advanced AnalyticalChemistry, Private Mail Bag 7, Bangor, NSW 2234, Australia, tel: 61 2 9710 6808, fax: 6129710 6837, email: [email protected]

Dr M. H. Sweeney, Document Development Branch, Education and InformationDivision, NIOSH Mailstop C32, 4676 Columbia Parkway, Cincinnati, OH 45226, USA, tel:1-513-533-8339, fax: 1-513-533-8230, e-mail: [email protected]

Dr K. Ziegler-Skylakakis, European Commission, DG Employment & Social Affairs,Rue Alcide de Gasperi, 2920 Luxembourg, tel: 352 4301 34424, fax: 352 4301 43259, email:[email protected]

Resource PersonsDr C. Cowles, Health and Safety Executive, Industrial Chemicals Unit HD (D3),

Magdalen House, Trinity Road, Bootle, Merseyside, L20 3QZ, United Kingdom, tel: 44 151951 3358 fax: 44 151 951 3308, e-mail: [email protected]

Dr C. Elliott-Minty, Health and Safety Executive, Industrial Chemicals Unit HD(D3), Magdalen House, Trinity Road, Bootle, Merseyside, L20 3QZ, United Kingdom, tel: 44151 951 4217 fax: 44 151 951 3308, e-mail: [email protected]

Dr K. Fuller, Health and Safety Executive, Industrial Chemicals Unit HD (D3),Magdalen House, Trinity Road, Bootle, Merseyside, L20 3QZ, United Kingdom, tel: 44 151951 3168, fax: 44 151 951 3308, e-mail: [email protected]

2 Present when Agenda items 1-7 were discussed

APPENDIX I

11

ObserversA. G. Berends, Solvay S.A, DCRT/Health, Safety and Environment, Rue de Ransbeek

310, B-1120 Brussels, Belgium tel: 322 264 3398 fax: 322 264 2990, email:[email protected]; CEFIC / ECETOC observer for trichloropropane, environmentalaspects.

Mr W. Gulledge, American Chemistry Council, 1300 Wilson Avenue, Arlington, VA22209, USA tel: 1 703 741 5613, fax: 1 703 741 6091, email:[email protected]; American Chemistry Council observer forethylene oxide.

Mr. C. Newsome , Product Stewardship/Regulatory Management, Dow ChemicalCompany Limited, 2 Heathrow Boulevard, 284 Bath Road, West Drayton, Middlesex, UnitedKingdom, tel: 44 8707 104 574, fax: 448707 104 574, email: [email protected]; CEFIC /ECETOC observer for ethylene oxide.

Mr. M. A. Pemberton, 84 Hazelwood Road, Wilmslow, GB-Cheshire SK9 2QA,United Kingdom, tel: 44 1625 518 059, fax: 44 1625 548 076, email:[email protected]; CEFIC / ECETOC observer for hydrogen cyanide andcyanides.

Mr. W. Stott, 1803 Bldg., Dow Chemical Company, Midland, MI, USA tel: 1 989 6368203, fax: 1 989 638 9863, email: [email protected]; CEFIC / ECETOC observer for 1,1-dichloroethene.

Mr J. M. Waechter, Jr., Research Leader, Toxicology Consulting, The DowChemical Company, Toxicology and Environmental Research & Consulting, Building 1803,Midland, Michigan 48674, USA tel: 1989 636 1859, fax: 1 989 638 9863, email:[email protected]; CEFIC / ECETOC observer for trichloropropane, human healthaspects.

SecretariatDr A. Aitio, International Programme on Chemical Safety, World Health

Organization, 20 Avenue Appia, 1211 Geneva 22, Switzerland, tel: 41 22 791 3592, fax: 4122 791 4848, e-mail: [email protected]

Mr T. Ehara, International Programme on Chemical Safety, World HealthOrganization, 20 Avenue Appia, 1211 Geneva 22, Switzerland, tel: 41 22 791 4334, fax: 4122 791 4848, e-mail: [email protected]

Mr H. Malcolm, Centre for Ecology and Hydrology, Monks Wood, Abbots Ripton,Huntingdon, Cambridgeshire, PE28 2LS, United Kingdom, tel: 44 1487 772 494, fax: 441487 772 467, email: [email protected]

Ms. C. Vickers , International Programme on Chemical Safety, World HealthOrganization, 20 Avenue Appia, 1211 Geneva 22, Switzerland, tel: 41 22 791 1286, fax: 4122 791 4848, e-mail: [email protected]

APPENDIX I

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APPENDIX II

13

Agenda

TENTH FINAL REVIEW BOARD ON CONCISE INTERNATIONALCHEMICAL ASSESSMENT DOCUMENTS


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. Draft CICAD on Ethylene oxide

4. Draft CICAD on Arsine. Human health aspects

5. Draft CICAD on Trichloropropane

6. Draft CICAD on Hydrogen sulphide and sulphides. Human health aspects

7. Draft CICAD on 1,1-Dichloroethene

8. Draft CICAD on Hydrogen cyanide and cyanides

9. Draft CICAD on Thiourea

10. Future CICADs

12. Any other business

13. Closure of the meeting

= = =

APPENDIX III

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Terms of reference for a final review board

The Final Review Board is responsible for the following functions:

ensuring that each CICAD has been subjected to an appropriate and thoroughpeer review;

verifying that peer reviewers’ comments have been addressed appropriately;

providing guidance to authors on how to resolve any remaining issues if, in theopinion of the Board, all comments of the reviewers have not been adequatelyaddressed;

approving CICADs as international assessments.

The Final Review Board conducts most of its business at meetings, but also bycorrespondence between meetings. It is guided in its work by the IPCS Programme AdvisoryCommittee, and functions in collaboration with the newly-formed IPCS Steering Group onRisk Assessment.

APPENDIX IV

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Final review board comments on draft CICADsFor all CICAD drafts, the changes in the text to be reflected in the Executive summary.

Arsine. Human health aspects

IntroductionDr. S. Czerczak (first author) opened the discussion by a brief presentation of the

information presented in the CICAD.Dr. R. Chhabra (discussion leader) opened the discussion of the comments &

responses, indicating that this document was first brought to the 8th FRB as an EHC, and theeffort to convert this into a CICAD was considered successful at this juncture. Dr. Chhabrapointed out that the authors have done an outstanding job in addressing the reviewerscomments. Dr. Chhabra highlighted the critical outstanding issue, concerning whether theeffect level in the critical study should be considered a NOAEL or LOAEL, and derivation ofthe guidance value. Following consultation with experts at the USEPA and NIEHS, Dr.Chhabra reported that this value could be considered the NOAEL (the effect - decrease inhematocrit value around 5%, though statistically significant, was not likely clinicallysignificant, and the increased splenic weight was not reproduced). Also, based upon arecommendation made to the IPCS Secretariat by the CICAD Steering Group, it was alsorecommended that this critical value be considered the NOAEL, based upon the approachtaken in the US EPA source documentation, and that the values selected for the uncertaintyfactor also be consistent with that taken in the US EPA source documentation.

Specific CommentsThe following text to be inserted into sections 1 &10; “The information presented in

this CICAD on arsine focuses on effects associated with the short-term exposure to thissubstance. Within the body, arsine is oxidised to other arsenic species and effects (i.e., cancer)associated with long-term exposure to arsenic and arsenic compounds have been recentlyreviewed (IPCS, 2001). Arsenic and arsenic compounds are carcinogenic to humans (IPCS,2001). Similarly, though information on the genotoxicity of arsine has not been identified,the genotoxicity of arsenic and arsenic compounds have also been reviewed (IPCS, 2001),and have been shown to be genotoxic in humans and animal cells (IPCS, 2001).”

Section 1

Add additional paragraph describing acute toxicity in humans.

Section 1, para 18

Delete para

Section 1, para 15

Delete the added text.

Section 2

Replace current text re arsine ignition with: Arsine vapour is heavier than air andaccumulating close to the surface which makes distant ignition possible in the presence of aflame or spark”.

Include explosive limits.

APPENDIX IV

16

Section 3

Include information on newly developed method of quantitation and whether capableof measuring to levels in range of guidance value developed in this CICAD. Also include insummary statement in Section 1.

Section 6

Delete reference to Muller et al (2000) study in paragraph 5b.Delete quantitative information on exposure in description of Sheehy & Jones

reference and only indicate that exposure was to particulate and vapour phase arsine.

Section 7, para 21

Provide more detail on the sampling procedure employed by Clay 1977.

Section 9, para 15

Indicate that urinary arsenic was measured and method used to extrapolate to arsineexposure level was not specified in published account.

Section 9, para 18

Reword to clarify meaning; Delete “spontaneous” in last sentence.

Section 9, para 28

Sentence in line 2-5; reword to clarify, specify type of sensory and nerve tests anddelete “voltage of ”.

Section 9.4

Delete paragraphs 33 and 34.

Section 10. 1

Include text indicating large database identified on effects observed in humansfollowing acute exposure (e.g., poisonings).

Section 10.1.2

Include a description on the use of the guidance value developed (i.e., under whatsettings and what exposure conditions (i.e., duration and patterns).

Section 10.1.2 and summary

Note that guidance value is only for short-term to medium term exposure and related tonon-cancer effects and does not cover effects associated with long-term exposure (i.e.Cancer).

Section 10.1.2

Line 18; delete rats, mice and SG hamsters and retain original wording (i.e., severalspecies).

Line 21; delete “carcinogenicity and mutagenicity”.

Section 10.1.3

Accepted by FRB that there should be no risk characterization due to inadequatehuman exposure data.

APPENDIX IV

17

Section 10.1.4

Uncertainties should include a discussion of the uncertainties surrounding selection ofthe critical (NOAEL) effect level. This should include a discussion of this interpretation as theNOAEL or LOAEL, the clinical significance of the changes, the lack of reproducibility of theobserved effect in other studies, a discussion on how use of a NOAEL/LOAEL for this effectdoes not provide an adequate job of capturing the subtleties of the dose-response in thisexperimental investigation. An alternative approach to the dose-response analysis should beone which takes into account all of the dose-response information available.

Also include uncertainties with respect to guidance value that is only based upon non-cancer endpoints, and there is no information in humans or experimental animals onmutagenicity and carcinogenicity for direct arsine exposure. Arsine is oxidised in the body toarsenic species, which are carcinogenic in humans and have induced genotoxic effects inanimals and humans.

Section 10.1.4 Para 7b

Delete

APPENDIX IV

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Ethylene oxideDiscussion of the draft CICAD on Ethylene oxide was led by Dr H. Gibb.

IntroductionThe author Robert Liteplo provided a brief introduction on the use of the Canadian

national document as the basis for this CICAD. The authors justified the use of animal data toquantify the cancer risk on the basis that the human epidemiological data were of limited usedue to the short duration of exposure and latency. The estimated cancer risk based on animaldata was however compared to the human data.

Herman Gibb summarised the main points of the reviewers that he felt had not beensufficiently addressed by the authors. The main point of discussion was that four reviewersfelt that greater emphasis should have been placed on the human data to quantify cancer risk.Risk estimates from modeling the human data suggested that the risk would be lower than therisk calculated from the animal data. This was resolved as described below.

General commentsDefine list of acronyms and abbreviations from Table 4 in glossary.

Detailed comments

Section 7, para 2

Delete lines 38 and 39. Insert “ In animals and humans, ethylene oxide is a direct-acting alkylating agent and is metabolised by both hydrolysis and glutathione conjugation.There are no available data on metabolism in humans to determine quantitative relationshipsin these pathways.

Section 8, para 16

Change text to “In one carcinogenicity study…" Add one sentence to describe theother study (Secretariat to provide one sentence and German reference).

Section 8

Delete immune system from the title of the subsection 8.6

Section 9, para 23

Use IARC words" There was no evidence of confounding exposure to otheroccupational carcinogens”

Section 9, para 12, line 7ff

Description of Schulte study is adequate – leave as is.

Section 9, para 17

Insert after Teta (1993) “They evaluated exposure using latency and duration ofemployment in ethylene oxide-related departments but did not quantify EO exposure levels”.

Section 9, para 22, line 35

Authors to verify whether there was a significant difference between males andfemales. If not, check the concordance analysis and adjust accordingly.

APPENDIX IV

20

Section 10.1

Check whether aquatic toxicity test references use nominal or measuredconcentrations. Change text/table accordingly, describe approach taken and include anyuncertainties in uncertainty section.

Section 11, para 1, line 1

• Delete “kidney”

Section 11, para 4

Line 19: Delete “and the only investigation”.Delete last sentence “Difficult…cohort”.

Section 11, para 25 and Table 6

Clarify approach, check figures, review text and check final value in Table 6 (LA datarisk estimate).

Section 11.1.4

It was agreed that the quantitation of cancer risk in this CICAD would be based on theanimal data. However it should be noted in a footnote that the FRB is aware that the NIOSHstudy using human data is currently being updated and this may lead to a need forreassessment of the use of the human data for quantitation of cancer risk in future.

The Teta (1999) study should be referenced as a second footnote. Include body textoutlining that risk estimates from modelling the human data suggest that the risk would belower than the risk calculated from the animal data.

Section 11.2.3

Include discussion of uncertainties in the use of air exposure data for theenvironmental risk characterisation.

APPENDIX IV

21

1,1-Dichloroethene

IntroductionDr. B. Benson (author) opened the discussion by indicating that the IRIS source

document was now available on the USEPA web site, and provided a synopsis of commentsand author’s responses.

Dr. J Kielhorn (discussion leader) indicated the reviewers commented that thedocument was well written and that since the source document was now available publicly,the current text could be condensed in a format more consistent with CICADs. It was alsonoted that there were a few key areas for discussion by the FRB (condensation of effectssections, role of individual variation in metabolism of DCE, developmental toxicity and issuesrelating to the sample risk assessment).

Specific commentsThe title of the CICAD shall be changed to “1,1 Dichloroethene (Vinylidene

chloride)”.

Section 1, para 2

include more information on use patterns.

Section 1, para 3

delete last sentence and indicate the principal sources of environmental exposure areambient air and contaminated water

Section 1

Add new paragraph after current para 3, with information on biotransformation ofDCE to vinyl chloride and potential concerns at hazardous waste sites.

Section 1, para 5

Ensure that new relevant data on mode of action is also included here.

Section 2

IPCS Secretariat to include structure of DCE.

Section 3

Dr. M. Sweeney to assist author in identification of NIOSH method of analysis.Method to be included if considered appropriate.

Section 4

New information on production and use patterns of DCE was provided to the FRB byan observer (industrial stakeholder). This information will be provided in hard copy to theIPCS Secretariat. Detection limits related to measurements of DCE in products would need tobe provided by the observer. The author will review the new information and incorporate intothe CICAD if appropriate, with citation as a personal communication to IPCS. The author willalso review new use pattern information provided during contact point review by GlobalChlorinated Organics and Cal/Mag and incorporate into the CICAD if considered appropriateand cited as personal communication to IPCS.

APPENDIX IV

22

Section 5

The IPCS Secretariat will renumber and name the headings as follows:5.1 Transformation & Distribution5.1.1 Air5.1.2 Water5.1.3 Soils & Sediment5.2 Biotransformation5.3 Bioaccumulation

Section 6

Highlight which data on exposure are used in sample risk characterization.Include new data on levels on food wrap if appropriate.

Section 6.1.2

Author to check (in ATSDR tox profile) if useful information on levels on DCE ingroundwater at hazardous waste sites are available and will include range of concentrations ifdata easily derived.

Section 7

Address questions posed by reviewer #9 re paragraph 2 and 4 in section 7 (re: enzymeactivities changes and toxicological effects) Information should be consistent with text inSection 8.8 (Mode of Action). Also, fill in appropriate response in Comment/Response Table.

Section 8

The author will review whether effect levels should be described as N(L)OELs orN(L)OAELs and define use of the acronyms in the Table of Abbreviations.

Section 8.1

This section is to be revised and reordered as follows (based upon current paragraphnumbering in FRB CICAD draft):

Section starts with para 4Followed by Para 2 & 3 to be condensedTable 1 (delete LD50 study values using adrenalectomized rats; and check publicationdate of Anderson et al 1979 study. Include footnote of description/definition of LT50).Para 5.Delete paras 6 to 10.Para 11.Delete paras 12-15Para 16.Delete paras 17 & 18.Include statement as appropriate that clinical signs generally not addressed in thesestudies

Section 8.2.2

Delete para 22.

APPENDIX IV

23

Section 8.4.1

Section to be revised and reordered as follows:Section starts with same text presented in para 8 in section 11.1.1Delete paras 28-29Para 30.Delete para 31-33.

Section 8.4.2

Section to be revised and reordered as follows:Section starts with same text presented in para 9 of section 11.1.1Delete paras 34-38Para 39 (delete text material in this paragraph that refers to lack of tumours in this

study).Delete paras 40-42.Para 43 (delete text material related to non-neoplastic changes in kidneys; clarify inlast line of this paragraph that the researchers mentioned are Maltoni et al.). Addcomment that because of the study design, it is difficult to assess tumour developmentin relation to histopathological changes due to appearance of typical age relatedchanges in kidney

Section 8, para 44

Delete para

Section 8.5

Reverse order of paras contained therein.

Section 8, para 50

Delete para

Section 8, para 54

Revise reference to “Section 3”, noted 2/3 way through para.

Section 8, paras 58 & 59

Delete the last sentence

Section 9

Condense – provide brief overview of results and limitations of study.

Section 10.1

Provide introduction to Table 10.1 and summarise study limitations.Add information on carcinogenicity study conducted with trout.

Table 10.2

Provide information of growth rate or cell count/biomass measured in relevant studiescited in table.

Section 10.2

Change “grown” shoots to “growth” shoots.

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Section 11, para 1

Replace current wording with “Existing epidemiological data are inadequate to assesscancer and non-cancer effects of 1,2-dichloroethene”. Also include this sentence in theExecutive Summary.

Section 11, para 9

Delete reference to text on equivalency to group C carcinogen under USEPA guidance.

Section 11.1.1, Paras 12 & 13

Delete

Section 11, paras 18-21

Delete (ensure information located therein is found elsewhere in CICAD).

Section 11, para 22

For sample risk characterization use ambient air data range of (0.004 to 4 ug/m3)[replaces current values of 0.001-0.008 mg/m3] and range of 2-3 ug/litre [replaces currentvalues of 0.001-0.002 mg/litre] for drinking water levels from California.

Section 11.1.4

Include uncertainties related to observed cardiac effects as noted in last part of para 6in section 11.1.1 (i.e., There is also no evidence that teratogenicity is a critical effect. There issome evidence of developmental variations in the heart following direct infusion of 1,1-DCEinto the uterus of pregnant rats or fertilised chicken eggs and by ingestion of 1,1-DCE bypregnant rats from drinking water (Dawson et al., 1993), but it is not clear if these effects aredirectly caused by exposure to 1,1-DCE. The biological significance of these cardiacstructural variations is unclear. There is no indication that the structural variations havefunctional consequences in the animals. However, animals known to have the structuralvariations have not been tested under conditions of stress.)

Section 11, para 26

Include new text prepared by P. Howe and J. Stauber and reviewed by FRB.

Section 11.2.3

Include new text prepared by P. Howe and J. Stauber and reviewed by FRB.

Section 12

Add new paragraph “WHO established a drinking water quality guideline for 1,1-dichloroethene of 30 µg/litre in 1996. WHO has advised that this guideline is under review.”Also add statement that new information relevant to the revised guideline should becomeavailable on relevant WHO web site (site address to be added). This format of reference toWHO guidelines was generally recommended for future CICADs where relevant.

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25

Hydrogen cyanide and cyanides

IntroductionThe IPCS CICAD Secretariat opened the discussion noting that this review was

initially prepared as an EHC by Prof. Simeonova and that Dr. Fishbein was involved inchanging the format to a CICAD. Also, based upon reviewer's comments referring to thelimitations on the environmental aspects, it was decided that this CICAD would only focus onhuman health aspects. Therefore work should be done on the document to delete those partsrelated primarily to environmental aspects. A number of issues related to the process forcompleting responses to all comments (from both authors) were noted and that some editorialcomments will be dealt with subsequently. It was also noted that the WHO intends to use thisCICAD as a basis for derivation of a drinking water guidance value, and that the assessmentsection also needs to include a review and discussion of the available database upon whichsuch a guidance value (short- and long-term) could be based. WHO noted the existence of 15-day drinking water toxicological study (Sousa et al., 2002), and requested the CICADcritically review this study. WHO also suggested that spills of cyanide are not altogetherinfrequent and there exists therefore the potential for drinking water contamination.

Dr. Simeonova (author) presented a brief overview of the information presented in theCICAD based upon the material presented therein. Dr. Fishbein (author) indicated that exceptfor some circumstances (e.g., the consumption of foodstuffs containing cyanogen glycosides),the general population was not at risk from exposure to cyanides.

R. Cary (discussion leader) opened the discussion of the comments and responses bycomplimenting the authors in preparing this CICAD based upon the large available dataset.Based upon available information concerning the future preparation of a CICAD on theenvironmental aspects of cyanides, it was decided to continue with the preparation of aCICAD focused only on human health aspects.

It was important that the CICAD clearly delineate what effects were associated withexposure to what particular cyanide compounds, and throughout the document it is importantto indicate which substances were used in each of the studies cited. Information on howdiffering effects might be related to phys/chem properties could also be included.

A representative from ECETOC noted future release of a draft report on selectedcyanides and effects on human health and environment that will be made available to theauthors. Relevant information on human exposure and health-related effects may be identifiedtherein, and therefore the inclusion of substantial new texts will require additional review.This will also result in modification of the literature cut-off date.

Send reviewers’ comments on environmental section of cyanide CICAD to NICNASin Australia for inclusion in their national document

Specific comments

Section 1, para 19

Delete last line and replace with “Dermal toxicity has been observed”. Also providedermal LD50 values.

Section 2

Add table of phys/chem properties for range of chemicals covered in CICAD (dataavailable in MAK document; use CICAD on chlorinated naphthalenes as model for suchpresentation.).

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26

Section 3

The IPCS Secretariat will reorder the material in this section (according to method)and include information on detection limits for currently used methods of analysis.

Section 6, para 20

Information on occupational exposures from MAK and ACGIH documents to beincluded once documentation obtained by authors. Drs Ziegler-Skylakakis and Sweeney toassist authors in obtaining these MAK and ACGIH documents, respectively.

Section 6.2.2

Include new data on occupational exposure in relation to processing of CN-containingfoods.

Section 7

R. Cary to assist authors in revising texts in this section to improve clarification.

Section 7, Figure 3

Revise for first step illustrated to correct stoichiometry. R. Cary to assist as needed.

Section 8.3

3-month Monsanto inhalation study of ACH will be provided by ECETOC andreviewed. And data on this substance to be included in the CICAD.

Section 8, para 7

Review Sousa et al. 2002 study (in context with other new information) and add moredetail on methods and results if considered critical for derivation of drinking water guidancevalue.

Section 8.5

ECETOC will provide additional information on genotoxicity of selected cyanides tothe authors, which will be reviewed and considered, for inclusion in the CICAD.

Section 8, para 20

Provide additional detail on methods and findings related to exposure levels andwhether effects observed associated (or not) with maternal toxicity.

Section 8.6

Additional developmental studies (provided by ECETOC) will be reviewed andincluded in CICAD as appropriate along with limitations.

Section 8, para 29

Include more data on analyses and effects, and limitations of the Jackson 1988 study.

Section 8, para 32

Provide some additional experimental detail (exposure and levels with respect tonoise) for this study. Delete the last sentence.

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27

Section 9, para 1

Change value of 0.056 to 0.56. Review US EPA document and verify range andreliability of how average fatal dose in humans was developed.

Section 9.2

Move relevant text on Banerjee et al 1997 study from Section 7.4(para 20) to section9.2

Section 10.1

Include description of critical studies used in derivation of guidance values and thecritical effect and level upon which guidance values are based.

Section 10.2

Delete paragraph 5. Provide original citation for critical toxicological study selectedand indicate citation for guidance value developed as the ATSDR source document. CheckUS EPA 1987 document to see if acute guidance value developed therein.

Section 10.3

Provide sample risk characterization for acute-, short-term and long-term exposuresvia inhalation, water and the consumption of foodstuffs. Involves comparison of appropriateestimated exposure scenario with guidance value. Comparison will provide basis forstatement of little or no risk to human health. (Exposure estimates for humans reported inJackson 1988 could be used if considered appropriate in the context of other exposure datapresented in the CICAD).

Section 10.2

Indicate existence of other toxicological study (i.e., Jackson, 1988) that couldpotentially be used for derivation of guidance value, based upon changes in thyroid functionin mini-pigs (also note changes in neurobehaviour). Outline limitations of this latter study re:small number of animals, bolus injections, castration of males, and housing conditions andlimitations of studies on neurobehavioural effects examined (which are also referred to in thelast paragraph of the paper). Also, indicate that a guidance value developed on the basis ofthis study would be similar to the value currently developed in section 10.2. Also includediscussion of uncertainties associated with interpretation of results from dietary and gavagestudies.

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Hydrogen sulfide. Human health aspects

IntroductionDr. Chou (author) presented brief an overview of the information on hydrogen sulfide

from the executive summary and indicated that the CICAD was based upon an ATSDR(1999) source document.

Dr. Hertel (discussion leader) presented an overview of the comments and indicatedthat the reviewers noted that the CICAD had been well prepared and that the changes made bythe authors had improved the document. Dr. Hertel noted that for one of the medium termguidance values derived from an animal study, a new study had been selected (Breunemann etal., 2000). There was important discussion concerning the human study selected as the basisfor derivation of the acute guidance value. The decision was made to retain the Jappinenstudy for this purpose.

General commentsIn Executive Summary, Glossary and evaluation sections define “medium-term

guidance value”. Author to also provide glossary

Specific Comments

Section 1, para 7

Replace "oral in halation" by "ingestion".

Section 1, para 10

Remove the risk management advice from the last sentence; indicate simply that due tomarked acute toxicity, all exposure should be avoided.

Section 2

Describe the basis and distinguish between reference to two odour thresholds.

Section 3

Indicate the relationship between detection limits and sampling time.

Section 6, para 7

Delete text related to the Barik et al. 1987 publication.

Section 6, para 9

Include additional information on presumed reactions leading to formation of HS.

Section 7

Reorder and condense text to improve readability.

Section 8, para 17

Move information on developmental effects to section 8.6.2

Section 8.3, para 19

Revise and reorder text with distinct descriptions of CIIT 1983, a, b and c studies toclarify presentations. Delete sentence regarding “crusty eye results”.

Section 8, para 19

Delete reference to reduction in absolute brain weight.

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30

Specify what neurological functions were assessed in results reported in line 19

Section 8, para 20

Delete sentence in lines 35-36 (i.e., The nasal olfactory…)

Section 8, para 21

Reword text to improve clarity.

Section 8, para 24

Change “adequate” to “inadequate” in line 13. Indicate that identified data ongenotoxicity are limited and highlight limitations of the single salmonella mutagenicity test.

Section 8, para 26

Include data on parturition time of controls and indicate that no additional data onmaternal toxicity identified.

Section 8, para 28-33

Cross-reference data on maternal toxicity to toxicity data presented in previousSections.

Section 9

Emphasise that in confined spaces human acute poisonings continue to occur.Condense descriptions of human ecological studies (paras 5 and 8). In Section 9.2, combineparas 15-17 into para 18).

Section 9, para 9

Line 22: delete “occurrence”

Section 9, para 13

If appropriate, indicate that these workers were employed at the time of study.

Section 9, para 20

Provide data on duration of exposures. In line 19, change 50-2000 to 500-2000.

Section 9, para 22

Delete text related to Kilburn 1997 study.

Section 9, para 23

Provide information on how data on headache incidence was obtained. Cross-referenceelsewhere Jappinen study that data collected by self-reporting.

Section 9, para 28

Provide detail on study population (e.g., number of subjects, age, and sex).

Section 10.2

Include description (definition) of what is meant by “acute” and “medium” termguidance values.

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31

Section 10.4

Include a discussion of the choice of the study (Jappinen vs. Bhambhani) upon whichthe acute guidance value was derived including the populations studied, information on thelimitations of methods, tests conducted and interpretations, and uncertainties associated witheach. This should also include discussion about the ethical nature of exposing severelyasthmatic individuals to higher concentrations of this substance. Also indicate that guidancevalues derived from either study would not differ markedly.

Section 11

The Secretariat will verify the value of 150 µg/m3 for the ambient air guideline,include the date it was set, and clarify the nature of the guideline.

International Chemical Safety Card

The ICSC programme was requested to reconsider the expression of hazards due toinhalation exposure to hydrogen sulfide, notably the possibility of acute poisoning in confinedspaces

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33

ThioureaDiscussion of CICAD draft on Thiourea was led by Dr Sekizawa.

IntroductionThe authors Dr Kielhorn and Dr Ziegler-Skylakakis introduced the CICAD based on

source documents from BUA (1995) and MAK (1988, 1997). The literature review cut offdate was November 2001.

The discussion leader Dr Sekizawa summarised the main outstanding comments of thereviewers, but noted that most were of a minor nature. The comments below relate to answersthe authors have yet to provide in the table of reviewers’ comments, rather than changesrequired for the actual CICAD text.

Specific Comments

Section 1, page 1, para 5 and Section 6.2.1, para 4c

No additional data to verify the Russian OEL for thiourea was found on the NIOSHwebsite

Section 1, para 13

The lamb study was useful so is included. EU classifications are not to be used in theCICAD.

Section 3, para 5

Difficult to add analytical detection limits for HPLC methods for thiourea in biologicalmaterials

Section 4.2, para 3

Delete lines 19-21, as reviewer did not supply reference for countries producingthiourea.

Section 4.3

Authors to insert additional text on thiourea uses described in air toxics list(California)

Section 4.3, para 5

NTP (2000) reference found by authors so additional data on thiourea use in flame-retardant resins now included.

Section 4.4, para 11

EPA’s Risk Screening Environmental Indicators Model too complicated so notincluded

Section 6, para 2

Author to add data provided by Dr Sekizawa.

Section 6

Information on thiourea in textiles as a potential dermal source of exposure waslacking and could therefore not be included.

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34

Section, para 10 and 11

Cross-reference study described here and in Section 8.7.1.

Section 8, para 13

Authors to include an additional paragraph justifying the inclusion of the Hatzellstudy. This was a chronic study so was not included in Table 3.

Section 8, para 25

Authors to alter discussion on genotoxic studies that showed inconsistent results. Manyof the studies were negative, however, those that were positive were often carried out at highconcentrations/doses of thiourea and cytotoxicity could not be ruled out. Present cytotoxicityvalues and explain inconsistencies where possible. Emphasise that thiourea is not consideredto be a genotoxic carcinogen, however the authors should check the original studies. Section11 may also need changing to reflect this.

Section 8, para 40

Lamb study to be moved to the developmental toxicity section 8.7.2.Definition of hogget to be added as a footnote


These two papers from IARC now included but cited as the original papers.Data on the oxygenated metabolites exists but how much thiourea is metabolised to

these compounds is unknown therefore no additional data were added.

Section 10, Table 4

Clarify if algal cell multiplication inhibition was cell yield or growth rate.


Text already added on thiourea as a skin sensitiser and adverse effects upon whichNOAELs are based. EU classification schemes not to be used in CICADs.

Section 11.1.4

Add a sentence on oral scenario uncertainties after rechecking original study

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35

1,2,3-TrichloropropaneDiscussion on CICAD draft on 1,2,3-Trichloropropane was led by M.E. Meek.

IntroductionThe author Janet Kielhorn provided a brief introduction on the use of the German

national documents (BUA, 1993) as the basis for this CICAD. Betty Meek (discussion leader)reiterated that most of the proposed changes outlined below were relatively minor.

General commentsPurity of compound included for critical studies only. Mention purity at beginning of

document and then only again if different and known for particular studies.Don’t reference NTP levels of evidence or other classifications but do paraphrase the

definitions to describe conclusions in particular studies.Mode of action to be delineated more clearly for metabolites re.

carcinogenicity/mutagenicity if information is available.If practical, include brief discussion of relative toxicity of related compounds (other

chlorinated propanes) e.g. does toxicity increase with increasing substitution?Cut off date for the cited literature extended to September 2002 to accommodate new

critical ecotox study from Solvay.

Specific Comments

Section 1

Expand section on peer review of the national BUA document

Section 1, Para 3

Delete last sentence

Section 1, Para 4

Delete last sentence

Section 1, para 11

Change text to read: “1,2,3-TCP is an irritant to skin and mucous membrane" Nofurther changes to this para as paper not received describing slight sensitisation.

Section 4

Industry data on production and uses to add. Globally there are less than 20production sites in France, Germany, Netherlands, Poland, Czech Republic, Russia, USA,Japan and Taiwan. Total production globally is less than 100,000 tpa. TCP is produced as aby-product in a closed system: some is incinerated on site with the remainder used forproduction of other products. No consumer use, only industrial. (However note that somecountries may not follow best practice). Janet to include above data and cite as IPCS (pers.comm). Need a letter from Solvay to Secretariat giving above production and usage data.

Section 4, para 3

Correct date – should be March/April 2002

Section 5

Add new para on Yamamoto study (from CEH/Paul Howe’s comments)

APPENDIX IV

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Section 6.2

Use intake not uptake when referring to intake from food and water.

Section 7.1

Clarify text with regards to toxic/active metabolites, particularly metabolic pathwaysin various species and their role in toxicity.

Section 7, para 10

Improve text " Pretreatment of rats…”

Section 8

Strengthen argument for choice of critical study versus others (i.e. drinking waterstudy)

Section 8, para 6

Comment on the fact that one test suggested TCP was a mild irritant while a similarstudy found TCP caused severe irritation

Section 8, para 12

Characterise the irritant effects of these doses but don’t call the 1.5 ppm a NOAEL.

Section 8, Tables 2a, 2b, 2c, 2d

Add a statement that the experiment at highest dose level was terminated at x weeksdue to tumours affecting survival, not due to toxicity of TCP.

Section 8, para 45

Author to check detail of the Swenberg studies comparing gavage and drinking waterdoses – what was done and how, biological relevance, how were the doses compared?Implications of the comparisons are to be included in the uncertainty section if appropriate.

Section 10

Mr Berends (Solvay) discussed the results from a new ecotoxicological study withDaphnia and Selenastrum, using closed systems to prevent volatilisation of TCP. Losses wereless than 10% over the test duration. It was proposed that the 48-h LC50 for Daphnia (20mg/L) should be used as the PNEC to derive the Hazard Quotient for the environmental riskcharacterisation.

A footnote describing the study and process should be added to the table. Add drafted(Kielhorn, Howe & Stauber) text for Section 10 and Section 11.2.1. Need to carefully definenominal, measured initial and effective concentrations in table footnote. (Note that this hasbeen done and text given to authors).

Section 11, para 9a

Additional text provided by Ms Meek to be added, including emphasising tumourpotency and rapid tumour development, mode of action, irritant properties, evidence forcarcinogenesis. This text to be circulated to FRB. State that no guidance value for riskquantification is given in source document. Antero to add sentence that there is no safe valuefor genotoxic carcinogens but guideline values are sometimes still derived to show risk at aparticular dose (depends on source document).

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Minor Changes

Other minor changes outlined in “Other observations” to be added at author’sdiscretion – not discussed by FRB.

The FRB noted that 1,2,3-TCP has been measured in drinking water and that the lackof quantitation of the dose-response relationship was potentially an issue should WHO wishto consider the establishment of a drinking water quality guideline. This is a general issue forCICADs that is dependent on the scope of the source document.

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Acknowledgements

The International Programme on Chemical Safety (IPCS) wishes to express itsgratitude to the Japanese Ministry of Health and Welfare and the United States EnvironmentalProtection Agency, and European Commission for their generosity in providing financialsupport for the CICADs Project, which enabled the IPCS to convene this 10th Final ReviewBoard. Thanks are also due to the Centre for Ecology and Hydrology for providing themeeting facilities and the practical arrangements of the meeting. Finally, appreciation isextended to those FRB members who agreed to fulfil the roles of Chairman, Vice-Chairmanand Rapporteurs, i.e., Drs Dobson, Sekizawa, Liteplo and Stauber, respectively, as well as tothose participants who acted as discussion leaders. They gave generously of their time andtheir expertise. The commitment of all the aforementioned has contributed to the furtherdevelopment of the IPCS CICADs Project.

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