Formaldehyde: Concise International Chemical Assessment Document 40

This report contains the collective views of an international group of experts and does not
necessarily represent the decisions or the stated policy of the United Nations Environment
Programme, the International Labour Organization, or the World Health Organization.
Concise International Chemical Assessment Document 40
FORMALDEHYDE
Please note that the layout and pagination of this pdf file are not necessarily identical to
those of the printed CICAD
First draft prepared by

R.G. Liteplo, R. Beauchamp, M.E. Meek, Health Canada, Ottawa, Canada, and
R. Chnier, Environment Canada, Ottawa, Canada
Published under the joint sponsorship of the United Nations Environment Programme, the
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framework of the Inter-Organization Programme for the Sound Management of Chemicals.
World Health Organization

Geneva, 2002
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purpose of the IOMC is to promote coordination of the policies and activities pursued by the Participating
Organizations, jointly or separately, to achieve the sound management of chemicals in relation to human
health and the environment.
WHO Library Cataloguing-in-Publication Data
Formaldehyde.
(Concise international chemical assessment document ; 40)
1.Formaldehyde - adverse effects 2.Risk assessment 3.Environmental

exposure I.International Programme on Chemical Safety II.Series
ISBN 92 4 153040 5 (NLM Classification: QV 225)

ISSN 1020-6167
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TABLE OF CONTENTS
FOREWORD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1. EXECUTIVE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
2. IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
3. ANALYTICAL METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
4. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
4.1 Natural sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

4.2 Anthropogenic sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
4.3 Secondary formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
4.4 Production and use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
5. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION . . . . . . . . . . . . . . . . . . . . . 10
5.1 Air . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
5.2 Water . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
5.3 Sediment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
5.4 Soil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
5.5 Biota . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
5.6 Environmental partitioning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
6. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
6.1 Environmental levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

6.1.1 Ambient air . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
6.1.2 Indoor air . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
6.1.3 Water . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
6.1.3.1 Drinking-water . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
6.1.3.2 Surface water . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
6.1.3.3 Effluent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
6.1.3.4 Groundwater . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
6.1.3.5 Atmospheric water . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
6.1.4 Sediment and soil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
6.1.5 Biota . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
6.1.6 Food . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
6.1.7 Consumer products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
6.1.7.1 Clothing and fabrics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
6.1.7.2 Building materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
6.2 Human exposure: environmental . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
6.3 Human exposure: occupational . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
7. COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS AND

HUMANS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
8. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS . . . . . . . . . . . . . . . . . . . . . . . . . . 20
8.1 Single exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

8.2 Short- and medium-term exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
iii
8.2.1 Inhalation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
8.2.2 Oral exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
8.3 Long-term exposure and carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
8.3.1 Long-term exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
8.3.2 Carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
8.3.2.1 Inhalation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
8.3.2.2 Oral exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
8.4 Genotoxicity and related end-points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
8.5 Reproductive toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
8.6 Immunological effects and sensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
8.7 Mode of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
9. EFFECTS ON HUMANS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
9.1 Case reports and clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

9.2 Epidemiological studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
9.2.1 Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
9.2.2 Genotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
9.2.3 Respiratory irritancy and function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
9.2.4 Immunological effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
9.2.5 Other effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
10. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
10.1 Aquatic environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

10.2 Terrestrial environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
11. EFFECTS EVALUATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
11.1 Evaluation of health effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

11.1.1 Hazard identification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
11.1.1.1 Genotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
11.1.1.2 Carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
11.1.1.3 Non-neoplastic effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
11.1.2 Exposureresponse analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
11.1.2.1 Inhalation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
11.1.2.2 Oral exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
11.1.3 Sample human health risk characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
11.1.4 Uncertainties in the evaluation of health effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
11.2 Evaluation of environmental effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
11.2.1 Assessment end-points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
11.2.1.1 Aquatic end-points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
11.2.1.2 Terrestrial end-points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
11.2.2 Sample environmental risk characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
11.2.2.1 Aquatic organisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
11.2.2.2 Terrestrial organisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
11.2.2.3 Discussion of uncertainty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
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Formaldehyde
APPENDIX 1 SOURCE DOCUMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
APPENDIX 2 CICAD PEER REVIEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
APPENDIX 3 CICAD FINAL REVIEW BOARD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
APPENDIX 4 BIOLOGICALLY MOTIVATED CASE-SPECIFIC MODEL FOR CANCER . . . . . . . . . . . . . . 64
APPENDIX 5 ESTIMATION OF TUMORIGENIC CONCENTRATION05 (TC05) . . . . . . . . . . . . . . . . . . . . . 67
APPENDIX 6 ADDITIONAL INFORMATION ON ENVIRONMENTAL RISK CHARACTERIZATION . 67
INTERNATIONAL CHEMICAL SAFETY CARD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
RSUM DORIENTATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
RESUMEN DE ORIENTACIN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
v
Formaldehyde
FOREWORD provided as guidance only. The reader is referred to EHC

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has been developed to encourage consistency in form.
The primary objective of CICADs is characteri- The first draft undergoes primary review by IPCS and
zation of hazard and doseresponse from exposure to a one or more experienced authors of criteria documents to
chemical. CICADs are not a summary of all available data ensure that it meets the specified criteria for CICADs.
on a particular chemical; rather, they include only that
information considered critical for characterization of the The draft is then sent to an international peer
risk posed by the chemical. The critical studies are, review by scientists known for their particular expertise
however, presented in sufficient detail to support the and by scientists selected from an international roster
conclusions drawn. For additional information, the compiled by IPCS through recommendations from IPCS
reader should consult the identified source documents national Contact Points and from IPCS Participating
upon which the CICAD has been based. Institutions. Adequate time is allowed for the selected
experts to undertake a thorough review. Authors are
Risks to human health and the environment will required to take reviewers comments into account and
vary considerably depending upon the type and extent revise their draft, if necessary. The resulting second draft
of exposure. Responsible authorities are strongly
encouraged to characterize risk on the basis of locally
measured or predicted exposure scenarios. To assist the 1
International Programme on Chemical Safety (1994)
reader, examples of exposure estimation and risk Assessing human health risks of chemicals: derivation
characterization are provided in CICADs, whenever of guidance values for health-based exposure limits.
possible. These examples cannot be considered as Geneva, World Health Organization (Environmental
representing all possible exposure situations, but are Health Criteria 170).
1
CICAD PREPARATION FLOW CHART
SELECTION OF PRIORITY CHEMICAL
SELECTION OF HIGH QUALITY

NATIONAL/REGIONAL
ASSESSMENT DOCUMENT(S)
FIRST DRAFT
PREPARED
PRIMARY REVIEW BY IPCS

( REVISIONS AS NECESSARY)
REVIEW BY IPCS CONTACT POINTS/

SPECIALIZED EXPERTS
R E V I E W O F C O M M E N T S ( PRODUCER/RESPONSIBLE OFFICER),
PREPARATION
OF SECOND DRAFT 1
FINAL REVIEW BOARD 2
FINAL DRAFT 3
EDITING
APPROVAL BY DIRECTOR, IPCS
PUBLICATION
1 Taking into account the comments from reviewers.

2 The second draft of documents is submitted to the Final Review Board together with the reviewers comments.
3 Includes any revisions requested by the Final Review Board.
2
Formaldehyde
is submitted to a Final Review Board together with the

reviewers comments.
A consultative group may be necessary to advise
on specific issues in the risk assessment document.
The CICAD Final Review Board has several

important functions:
to ensure that each CICAD has been subjected to

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

representatives of any organization, government, or
industry. They are selected because of their expertise in
human and environmental toxicology or because of their
experience in the regulation of chemicals. Boards are
chosen according to the range of expertise required for a
meeting and the need for balanced geographic
representation.
Board members, authors, reviewers, consultants,

and advisers who participate in the preparation of a
CICAD are required to declare any real or potential
conflict of interest in relation to the subjects under
discussion at any stage of the process. Representatives
of nongovernmental organizations may be invited to
observe the proceedings of the Final Review Board.
Observers may participate in Board discussions only at
the invitation of the Chairperson, and they may not
participate in the final decision-making process.
3
1. EXECUTIVE SUMMARY
Formaldehyde (CAS No. 50-0-0) is a colourless,
highly flammable gas that is sold commercially as 30
This CICAD on formaldehyde was prepared jointly 50% (by weight) aqueous solutions. Formaldehyde
by the Environmental Health Directorate of Health enters the environment from natural sources (including
Canada and the Commercial Chemicals Evaluation forest fires) and from direct human sources, such as
Branch of Environment Canada based on documentation automotive and other fuel combustion and industrial on-
prepared as part of the Priority Substances Program site uses. Secondary formation also occurs, by the
under the Canadian Environmental Protection Act oxidation of natural and anthropogenic organic
(CEPA). The objective of assessments on Priority compounds present in air. The highest concentrations
Substances under CEPA is to assess potential effects of measured in the environment occur near anthropogenic
indirect exposure in the general environment on human sources; these are of prime concern for the exposure of
health as well as environmental effects. This CICAD humans and other biota. Motor vehicles are the largest
additionally includes information on occupational direct human source of formaldehyde in the environment
exposure. Data identified as of the end of December 1999 of the source country (Canada). Releases from industrial
(environmental effects) and January 1999 (human health processes are considerably less. Industrial uses of
effects) were considered in this review.1 Other reviews formaldehyde include the production of resins and
that were also consulted include IARC (1981, 1995), IPCS fertilizers.
(1989), RIVM (1992), BIBRA Toxicology International
(1994), and ATSDR (1999). Information on the nature of When formaldehyde is released to or formed in air,
the peer review and availability of the source document most of it degrades, and a very small amount moves into
(Environment Canada & Health Canada, 2001) and its water. When formaldehyde is released into water, it does
supporting documentation is presented in Appendix 1. It not move into other media but is broken down. Formal-
should be noted, as indicated therein, that the dehyde does not persist in the environment, but its con-
biologically motivated case-specific model for tinuous release and formation result in long-term expo-
exposureresponse analyses for cancer included in this sure near sources of release and formation.
CICAD was the product of a joint effort involving the US
Environmental Protection Agency (EPA), Health Canada, The focus of the human health assessment is air-
the Chemical Industry Institute of Toxicology (CIIT), and borne exposure, due primarily to the lack of representa-
others. The product of this collaborative effort tive data on concentrations in media other than air and
superceded the content of a draft CICAD on limited data on effects following ingestion.
formaldehyde prepared previously by the Office of
Pollution Prevention and Toxics of the US EPA, on the Extensive recent data are available for concentra-
basis of health-related toxicological information pub- tions of formaldehyde in air at industrial, urban, sub-
lished prior to1992. Information on the peer review of urban, rural, and remote locations in the source country
this CICAD is presented in Appendix 2. This CICAD was (Canada). There are fewer but still considerable data on
approved as an international assessment at a meeting of concentrations in indoor air, which are higher. Data on
the Final Review Board, held in Geneva, Switzerland, on concentrations in water are more limited. Although
812 January 2001. Participants at the Final Review formaldehyde is a natural component of a variety of
Board meeting are listed in Appendix 3. The International foodstuffs, monitoring has generally been sporadic and
Chemical Safety Card for formaldehyde (ICSC 0275), source directed. Based on available data, the highest
produced by the International Programme on Chemical concentrations of formaldehyde occurring naturally in
Safety (IPCS, 2000), has also been reproduced in this foods are in some fruits and marine fish. Formaldehyde
document. may also be present in food due to its use as a bacterio-
static agent in production and its addition to animal feed
to improve handling characteristics. Formaldehyde and
formaldehyde derivatives are also present in a wide
1
New information flagged by reviewers and obtained in
variety of consumer products to protect the products
a literature search conducted prior to the Final Review
from spoilage by microbial contamination. The general
Board meeting has been scoped to indicate its likely
impact on the essential conclusions of this assessment, population is also exposed during release from combus-
primarily to establish priority for its consideration in an tion (e.g., from cigarettes and cooking) and emission
update. More recent information not critical to the hazard from some building materials, such as pressed wood
characterization or exposureresponse analysis, products.
considered by reviewers to add to informational content,
has been included.
4
Formaldehyde
Since formaldehyde (also a product of intermediary cancer, although the possibility of increased risk of
metabolism) is water soluble, highly reactive with respiratory cancers, particularly those of the upper
biological macromolecules, and rapidly metabolized, respiratory tract, cannot be excluded on the basis of
adverse effects resulting from exposure are observed available data. Therefore, based primarily upon data
primarily in those tissues or organs with which formal- derived from laboratory studies, the inhalation of
dehyde first comes into contact (i.e., the respiratory and formaldehyde under conditions that induce cytotoxicity
aerodigestive tract, including oral and gastrointestinal and sustained regenerative proliferation is considered to
mucosa, following inhalation or ingestion, respectively). present a carcinogenic hazard to humans.
Sensory irritation of the eyes and respiratory tract The majority of the general population is exposed
by formaldehyde has been observed consistently in to airborne concentrations of formaldehyde less than
clinical studies and epidemiological surveys in occupa- those associated with sensory irritation (i.e., 0.083 ppm
tional and residential environments. At concentrations [0.1 mg/m3]). However, in some indoor locations,
higher than those generally associated with sensory concentrations may approach those associated with eye
irritation, formaldehyde may also contribute to the and respiratory tract sensory irritation in humans. Risks
induction of generally small, reversible effects on lung of cancer estimated on the basis of a biologically
function. motivated case-specific model for calculated exposure of
the general population to formaldehyde in air based on
For the general population, dermal exposure to the sample exposure scenario for the source country
concentrations of formaldehyde, in solution, in the (Canada) are exceedingly low. This model incorporates
vicinity of 12% (10 00020 000 mg/litre) is likely to two-stage clonal growth modelling and is supported by
cause skin irritation; however, in hypersensitive dosimetry calculations from computational fluid
individuals, contact dermatitis can occur following dynamics modelling of formaldehyde flux in various
exposure to formaldehyde at concentrations as low as regions of the nose and single-path modelling for the
0.003% (30 mg/litre). In North America, less than 10% of lower respiratory tract.
patients presenting with contact dermatitis may be
immunologically hypersensitive to formaldehyde. Environmental toxicity data are available for a wide
Although it has been suggested in case reports for some range of terrestrial and aquatic organisms. Based on the
individuals that formaldehyde-induced asthma was maximum concentrations measured in air, surface water,
attributable to immunological mechanisms, no clear effluents, and groundwater in the sample exposure
evidence has been identified. However, in studies with scenario from the source country and on the estimated
laboratory animals, formaldehyde has enhanced their no-effects values derived from experimental data for
sensitization to inhaled allergens. terrestrial and aquatic biota, formaldehyde is not likely to
cause adverse effects on terrestrial or aquatic organisms.
Following inhalation in laboratory animals, formal-
dehyde causes degenerative non-neoplastic effects in
mice and monkeys and nasal tumours in rats. In vitro,
formaldehyde induced DNAprotein crosslinks, DNA 2. IDENTITY AND PHYSICAL/CHEMICAL
single-strand breaks, chromosomal aberrations, sister PROPERTIES
chromatid exchange, and gene mutations in human and
rodent cells. Formaldehyde administered by inhalation or
gavage to rats in vivo induced chromosomal anomalies Formaldehyde (CH2O) is also known as methanal,
in lung cells and micronuclei in the gastrointestinal methylene oxide, oxymethylene, methylaldehyde, oxo-
mucosa. The results of epidemiological studies in methane, and formic aldehyde. Its Chemical Abstracts
occupationally exposed populations are consistent with Service (CAS) registry number is 50-00-0.
a pattern of weak positive responses for genotoxicity,
with good evidence of an effect at site of contact (e.g., At room temperature, formaldehyde is a colourless
micronucleated buccal or nasal mucosal cells). Evidence gas with a pungent, irritating odour. It is highly reactive,
for distal (i.e., systemic) effects is equivocal. Overall, readily undergoes polymerization, is highly flammable,
based on studies in both animals and humans, and can form explosive mixtures in air. It decomposes
formaldehyde is weakly genotoxic, with good evidence at temperatures above 150 C. Formaldehyde is readily
of an effect at site of contact, but less convincing soluble in water, alcohols, and other polar solvents. In
evidence at distal sites. Epidemiological studies taken as aqueous solutions, formaldehyde hydrates and polymer-
a whole do not provide strong evidence for a causal izes and can exist as methylene glycol, polyoxymethyl-
association between formaldehyde exposure and human ene, and hemiformals. Solutions with high
5
concentrations (>30%) of formaldehyde become turbid Pure formaldehyde is not available commercially
as the polymer precipitates (IPCS, 1989). As a reactive but is sold as 3050% (by weight) aqueous solutions.
aldehyde, formaldehyde can undergo a number of self- Formalin (37% CH2O) is the most common solution.
association reactions, and it can associate with water to Methanol or other substances are usually added to the
form a variety of chemical species with properties solution as stabilizers to reduce the intrinsic polymeri-
different from those of the pure monomolecular zation of formaldehyde (IPCS, 1989; Environment
substance. These associations tend to be most prevalent Canada, 1995). In solid form, formaldehyde is marketed
at high concentrations of formaldehyde; hence, data on as trioxane [(CH2O)3] and its polymer paraformaldehyde,
properties at high concentrations are not relevant to with 8100 units of formaldehyde (IPCS, 1989).
dilute conditions.
Values reported for the physical and chemical

properties of formaldehyde are given in Table 1. Addi- 3. ANALYTICAL METHODS
tional physical/chemical properties are presented in the
International Chemical Safety Card reproduced in this
document. Selected methods for the determination of formal-
dehyde in air, food, and wood are presented in Table 2
(IARC, 1995). The most widely used methods for the
Table 1: Physical and chemical properties of formaldehyde detection of formaldehyde are based on spectrophotom-
reported in literature.a
etry, but other methods, such as colorimetry, fluorimetry,
Range of reported high-performance liquid chromatography, polarography,
Property values b
gas chromatography, infrared detection, and gas
Relative molecular mass 30.03 detector tubes, are also used. Organic and inorganic
Melting point (C) !118 to !92 chemicals, such as sulfur dioxide and other aldehydes
and amines, can interfere with these methods of
Boiling point (C, at 101.3 kPa) !21 to !19
detection. The most sensitive of these methods is flow
Vapour pressure (calculated) (Pa, at 516 000
injection (Fan & Dasgupta, 1994), which has a detection
25 C)
limit of 9 ppt (0.011 g/m3). Another commonly used
Water solubility (mg/litre, at 25 C)c 400 000 to 550 000 method is high-performance liquid chromatography,
Henrys law constant (Pa@m /mol, at
3 2.2 10 2 to 3.4 10 2 which offers a detection limit of 0.0017 ppm (0.002 mg/m3)
25 C) (IARC, 1995). Gas detector tubes and infrared analysers
Log octanol/water partition !0.75 to 0.35 are often used for monitoring workplace atmospheres
coefficient (log K ow) and have a sensitivity of about 0.330.42 ppm (0.40.5
Log organic carbon/water partition 0.70 to 1.57 mg/m3) (IARC, 1995).
coefficient (log K oc)
Conversion factor 1 ppm = 1.2 mg/m 3
a Because of polymerization and other reactions, care should 4. SOURCES OF HUMAN AND
be taken in interpreting or using reported values. See also
text. ENVIRONMENTAL EXPOSURE
b Includes experimental and calculated values from Hansch &
Leo (1979, 1981); Karickhoff et al. (1979); Kenaga & Goring
(1980); Weast (19821983); Verschueren (1983); Perry &
Data on sources and emissions primarily from the
Green (1984); Dean (1985); US EPA (1985); Betterton &
Hoffmann (1988); Deneer et al. (1988); Howard (1989); source country of the national assessment on which the
Sangster (1989); Zhou & Mopper (1990); Mackay et al. (1995); CICAD is based (i.e., Canada) are presented here as an
Staudinger & Roberts (1996). example. Sources and patterns of emissions in other
c Water solubility of a chemical is defined as the maximum
countries are expected to be similar, although quantita-
amount of the chemical that will dissolve in water at a
specified temperature, pressure, and pH. Results such as tive values may vary.
1 220 000 mg/litre (Dean, 1985) and 1.0 10 8 mg/litre
(DMER & AEL, 1996) have been quoted. These values are Formaldehyde is formed primarily by the combus-
pseudo-solubilities, since solutions become turbid as the tion of organic materials and by a variety of natural and
polymer precipitates at concentrations of approximately 55%
and greater. anthropogenic activities. Secondary formation of formal-
dehyde occurs in the atmosphere through the oxidation
of natural and anthropogenic volatile organic
compounds (VOCs) in the air. While there are no reliable
6
Formaldehyde
Table 2: Methods for the analysis of formaldehyde in air and food.a,b
Sample matrix/preparation Assay procedure Limit of detection Reference
Air
Draw air through an impinger containing aqueous S 0.0083 ppm Georghiou et al., 1993
pararosaniline and sodium sulfite. (0.01 mg/m 3)
Draw air through PTFE filter and impingers, each S 0.025 ppm Eller, 1989a
treated with sodium bisulfite solution; develop colour (0.03 mg/m 3)
with chromotropic acid and sulfuric acid; read
absorbance at 580 nm.
Draw air through solid sorbent tube treated with 10% 2- GC/FID 0.25 ppm Eller, 1989b
(hydroxymethyl) piperidine on XAD-2; desorb with (0.3 mg/m 3)
toluene.
GC/NSD 0.017 ppm US OSHA, 1990
(0.02 mg/m 3)
Draw air through tube that contains a smaller concentric Fluorescence 9 ppt Fan & Dasgupta, 1994
tube made of Nafion (semipermeable) through which (FIA) (0.011 g/m 3)
water flows in the opposite direction and serves to trap
formaldehyde; add 1,3-cyclohexanedione in acidified
ammonium acetate to form dihydropyridine derivative
in flow injection analysis system.
Draw air through impinger containing hydrochloric acid/ HPLC/UV 0.0017 ppm US EPA, 1988a
2,4-dinitrophenylhydrazine reagent and isooctane; (0.002 mg/m 3)
extract with hexane/dichloromethane.
Draw air through silica gel coated with acidified 2,4- HPLC/UV 0.0017 ppm US EPA, 1988b
dinitrophenylhydrazine reagent. (0.002 mg/m 3)
Expose passive monitor (Du Pont Pro-Tek Chromotropic acid 0.083 ppm Kennedy & Hull, 1986;
Formaldehyde Badge) for at least 2 ppm-h. Analyse test (0.1 mg/m 3) Stewart et al., 1987
according to manufacturers specifications.
Food
Distil sample; add 1,8-dihydroxynaphthalene-3,6- Chromotropic acid NR Helrich, 1990

disulfonic acid in sulfuric acid; purple colour indicates test
presence of formaldehyde.
Distil sample; add to cold sulfuric acid; add aldehyde- Hehner-Fulton test NR Helrich, 1990
free milk; add bromine hydrate solution; purplish-pink
colour indicates presence of formaldehyde.
Wood
Large-scale chamber tests. 0.083 ppm European Commission, 1989;

(0.1 mg/m 3) ASTM, 1990; Groah et al.,
1991; Jann, 1991
Formaldehyde, absorbed in distilled water, reacts 2-h desiccator test NR National Particleboard
specifically with a chromotropic acidsulfuric acid Association, 1983; Groah et
solution. al., 1991
Small samples are boiled in toluene, and the formalde- Perforator method NR British Standards Institution,
hyde-laden toluene is distilled through 1989
distilled/deionized water, which absorbs the
formaldehyde; a sample of the water is then analysed
photometrically by the acetylacetone or pararosaniline
method.
Formaldehyde in water is determined by adding sulfuric Iodometric method NR British Standards Institution,
acid solution and an excess of iodine; the iodine 1989
oxidizes the formaldehyde, and the excess is back-
titrated with sodium thiosulfate.
a From IARC (1995).

b Abbreviations used: GC/FID = gas chromatography/flame ionization detection; GC/NSD = gas chromatography/nitrogen selective
detection; FIA = fluorescence immunoassay; HPLC/UV = high-performance liquid chromatography/ultraviolet detection; NR = not
reported; PTFE = polytetrafluoroethylene; S = spectrometry.
7
estimates for releases from natural sources and for formaldehyde from automotive sources have changed
secondary formation, these may be expected to be much and will continue to change; many current and planned
larger than direct emissions from anthropogenic modifications to automotive emission control
activities. However, highest concentrations have been technology and gasoline quality would lead to decreases
measured near key anthropogenic sources, such as in the releases of formaldehyde and other VOCs
automotive and industrial emissions (see section 6.1.1). (Environment Canada, 1999b).
4.1 Natural sources Other anthropogenic combustion sources

(covering a range of fuels from wood to plastics) include
Formaldehyde occurs naturally in the environment wood-burning stoves, fireplaces, furnaces, power plants,
and is the product of many natural processes. It is agricultural burns, waste incinerators, cigarette smoking,
released during biomass combustion, such as forest and and the cooking of food (Jermini et al., 1976; Kitchens et
brush fires (Howard, 1989; Reinhardt, 1991). In water, it al., 1976; Klus & Kuhn, 1982; Ramdahl et al., 1982;
is also formed by the irradiation of humic substances by Schriever et al., 1983; Lipari et al., 1984; IPCS, 1989;
sunlight (Kieber et al., 1990). Walker & Cooper, 1992; Baker, 1994; Guski & Raczynski,
1994). Cigarette smoking in Canada is estimated to
As a metabolic intermediate, formaldehyde is produce less than 84 tonnes per year, based on
present at low levels in most living organisms (IPCS, estimated emission rates (IPCS, 1989) and a consumption
1989; IARC, 1995). It is emitted by bacteria, algae, rate of approximately 50 billion cigarettes per year
plankton, and vegetation (Hellebust, 1974; Zimmermann (Health Canada, 1997). Canadian coal-based electricity
et al., 1978; Eberhardt & Sieburth, 1985; Yamada & generating plants are estimated to emit 0.723 tonnes per
Matsui, 1992; Nuccio et al., 1995). year, based on US emission factors (Lipari et al., 1984;
Sverdrup et al., 1994), the high heating value of fuel, and
4.2 Anthropogenic sources Canadian coal consumption in 1995 (D. Rose, personal
communication, 1998). A gross estimate of formaldehyde
Anthropogenic sources of formaldehyde include emissions from municipal, hazardous, and biomedical
direct sources such as fuel combustion, industrial on- waste in Canada is 10.6 tonnes per year, based on
site uses, and off-gassing from building materials and measured emission rates from one municipal incinerator
consumer products. in Ontario (Novamann International, 1997; Environment
Canada, 1999a).
Although formaldehyde is not present in gasoline,
it is a product of incomplete combustion and is released, Industrial releases of formaldehyde can occur at
as a result, from internal combustion engines. The any stage during the production, use, storage, transport,
amount generated depends primarily on the composition or disposal of products with residual formaldehyde.
of the fuel, the type of engine, the emission control Formaldehyde has been detected in emissions from
applied, the operating temperature, and the age and state chemical manufacturing plants (Environment Canada,
of repair of the vehicle. Therefore, emission rates are 1997b,c, 1999a), pulp and paper mills, forestry product
variable (Environment Canada, 1999a). plants (US EPA, 1990; Fisher et al., 1991; Environment
Canada, 1997b, 1999a; OConnor & Voss, 1997), tire and
Based on data for 1997 reported to the National rubber plants (Environment Canada, 1997a), petroleum
Pollutant Release Inventory, on-road motor vehicles are refining and coal processing plants (IARC, 1981; US
the largest direct source of formaldehyde released into EPA, 1993), textile mills, automotive manufacturing
the Canadian environment. Data on releases from on- plants, and the metal products industry (Environment
road vehicles were estimated by modelling (Mobile 5C Canada, 1999a).
model), based on assumptions outlined in Environment
Canada (1996). The amount estimated by modelling to Total environmental releases in Canada from
have been released in 1997 from on-road motor vehicles 101 facilities were 1423.9 tonnes in 1997, with reported
was 11 284 tonnes (Environment Canada, 1999b). While releases to different media as follows: 1339.3 tonnes to
Environment Canada (1999b) did not distinguish air, 60.5 tonnes to deep-well injection, 19.4 tonnes to
between gasoline-powered and diesel-powered vehicles, surface water, and 0 tonnes to soil. From 1979 to 1989,
it has been estimated, based on emissions data from about 77 tonnes were spilled in Canada as a result of
these vehicles, that they account for about 40% and 60% 35 reported incidents. Releases of formaldehyde to
of on-road automotive releases, respectively. Aircraft groundwater from embalming fluids in bodies buried in
emitted an estimated 1730 tonnes, and the marine sector cemeteries are expected to be very small based on
released about 1175 tonnes (Environment Canada, groundwater samples and the estimated loading rates of
1999b). It can be expected that the rates of release of six cemeteries in Ontario (Chan et al., 1992). In the USA
8
Formaldehyde
in 1992, total releases of formaldehyde to environmental oxide catalyst (ATSDR, 1999). Similar methods of pro-
media from certain types of US industries were approx- duction are used in many countries worldwide. Table 3
imately 8960 tonnes, of which approximately 58%, 39%, shows the production of formaldehyde by selected
2%, and 1% were released to the atmosphere, to under- countries, with the highest amounts originating from the
ground injection sites, to surface water, and to land, USA and Japan.
respectively (TRI, 1994).
In 1996, the domestic production of formaldehyde
Formaldehyde has been detected in the off- in Canada was approximately 222 000 tonnes (Environ-
gassing of formaldehyde products such as wood panels, ment Canada, 1997bc); in 1994, domestic production in
latex paints, new carpets, textile products, and resins. the USA was 3.6 million tonnes (Kirschner, 1995). The
While emission rates have been estimated for some of production of formaldehyde worldwide in 1992 was
these sources, there are insufficient data for estimating estimated at approximately 12 million tonnes (IARC,
total releases (Little et al., 1994; NCASI, 1994; 1995).
Environment Canada, 1995). In some countries, there
have been regulatory and voluntary initiatives to control Total Canadian domestic consumption of formalde-
emissions from building materials and furnishings, since hyde was reported at about 191 000 tonnes for 1996
these are recognized as the major sources of elevated (Environment Canada, 1997b). Formaldehyde is used
concentrations of formaldehyde in indoor air. predominantly in the synthesis of resins, with urea-
formaldehyde (UF) resins, phenolic-formaldehyde resins,
4.3 Secondary formation pentaerythritol, and other resins accounting for about
92% of Canadian consumption. About 6% of uses were
Formaldehyde is formed in the troposphere by the
photochemical oxidation of many types of organic Table 3: Production of formaldehyde in selected countries.a
compounds, including naturally occurring compounds,
Production (kilotonnes)b
such as methane (IPCS, 1989; US EPA, 1993) and
isoprene (Tanner et al., 1994), and pollutants from mobile Country or region 1982 1986 1990
and stationary sources, such as alkanes, alkenes (e.g., Brazil 152 226 N/A
ethene, propene), aldehydes (e.g., acetaldehyde, Canada 70 117 106
acrolein), and alcohols (e.g., allyl alcohol, methanol,
China 286 426 467
ethanol) (US EPA, 1985; Atkinson et al., 1989, 1993;
Grosjean, 1990a,b, 1991a,b,c; Skov et al., 1992; Grosjean Former Czechoslovakia 254 274 N/A
et al., 1993a,b, 1996a,b; Bierbach et al., 1994; Kao, 1994). Denmark N/A 3 0.3
Finland N/A 5 48
Given the diversity and abundance of formalde-
hyde precursors in urban air, secondary atmospheric France 79 80 100
formation frequently exceeds direct emissions from Germany 630 714 680
combustion sources, especially during photochemical air Hungary 13 11 N/A
pollution episodes, and it may contribute up to 7090%
Italy 125 135 114
of the total atmospheric formaldehyde (Grosjean, 1982;
Grosjean et al., 1983; Lowe & Schmidt, 1983). In Japan N/A 1188 1460
California, USA, Harley & Cass (1994) estimated that Mexico 83 93 N/A
photochemical formation was more important than direct
Poland 219 154 N/A
emissions in Los Angeles during the summertime days
studied; in winter or at night and in the early morning, Portugal N/A 70 N/A
direct emissions can be more important. This was also Republic of Korea N/A 122 N/A
observed in Japan, where the concentrations of formal- Spain N/A 91 136
dehyde in the central mountainous region were not
Sweden N/A 223 244
associated directly with motor exhaust but rather were
associated with the photochemical oxidation of anthro- Taiwan N/A 204 215
pogenic pollutants occurring there through long-range Turkey N/A 21 N/A
transport (Satsumabayashi et al., 1995).
United Kingdom 107 103 80
4.4 Production and use USAc 2185 2517 3048
Former Yugoslavia 108 99 88

Formaldehyde is produced commercially from
a From IARC (1995).
methanol. The primary methanol oxidation processes use b N/A = not available.
metal catalyst (silver now, previously copper) or metal c 37% by weight.
9
related to fertilizer production, while 2% of the formalde- 5. ENVIRONMENTAL TRANSPORT,

hyde was used for various other purposes, such as DISTRIBUTION, AND TRANSFORMATION
preservatives and disinfectants (Environment Canada,
1997b). Formaldehyde can be used in a variety of indus-
tries, including the medical, detergent, cosmetic, food, The sections below summarize the available infor-
rubber, fertilizer, metal, wood, leather, petroleum, and mation on the distribution and fate of formaldehyde
agricultural industries (IPCS, 1989), and as a hydrogen released into the environment. More detailed fate infor-
sulfide scavenger in oil operations (Tiemstra, 1989). mation is provided in Environment Canada (1999a).
Formaldehyde is often added to cosmetics, in 5.1 Air

which it acts as a preservative and an antimicrobial
agent. Its use in cosmetics is regulated or voluntarily Formaldehyde emitted to air primarily reacts with
restricted. In Canada, for example, formaldehyde is photochemically generated hydroxyl radicals in the
acceptable for use in non-aerosol cosmetics, provided troposphere or undergoes direct photolysis (Howard et
the concentration does not exceed 0.2% (R. Green, al., 1991; US EPA, 1993). Minor processes include
personal communication, 1994). It is also included in the reactions with nitrate radicals, hydroperoxyl radicals,
Cosmetic Notification Hot List, with the recommendation hydrogen peroxide, ozone, and chlorine (US EPA, 1993).
to limit its concentration in cosmetics to less than 0.3%, Small amounts of formaldehyde may also transfer into
except for fingernail hardeners, for which a maximum rain, fog, and clouds or be removed by dry deposition
concentration of 5% applies (A. Richardson, personal (Warneck et al., 1978; Zafiriou et al., 1980; Howard, 1989;
communication, 1999). Atkinson et al., 1990; US EPA, 1993).
In the agriculture industry, formaldehyde has been Reaction with the hydroxyl radical is considered to
used as a fumigant, as a preventative for mildew and be the most important photooxidation process, based on
spelt in wheat, and for rot in oats. It has also been used the rate constants and the concentrations of the
as a germicide and fungicide for plants and vegetables reactants (Howard et al., 1991; US EPA, 1993). Factors
and as an insecticide for destroying flies and other influencing the atmospheric lifetime of formaldehyde,
insects. In Canada, formaldehyde is registered as a such as time of day, intensity of sunlight, temperature,
pesticide under the Pest Control Products Act; about etc., are mainly those affecting the availability of
131 tonnes are applied annually for pest control. hydroxyl and nitrate radicals (US EPA, 1993). The
Approximately 80% of the slow-release fertilizer market is atmospheric half-life of formaldehyde, based on hydroxyl
based on UF-containing products (ATSDR, 1999; HSDB, radical reaction rate constants, is calculated to be
1999). In Canada, there are currently 59 pest control between 7.1 and 71.3 h (Atkinson, 1985; Atkinson et al.,
products containing formaldehyde registered with the 1990). Products that can be formed from hydroxyl radical
Pest Management Regulatory Agency. Formaldehyde is reaction include water, formic acid, carbon monoxide,
present as a formulant in 56 of these products, at and the hydroperoxyl/formaldehyde adduct (Atkinson et
concentrations ranging from 0.02% to 1% by weight. al., 1990).
Formaldehyde is an active ingredient in the remaining
three products, at concentrations ranging from 2.3% to Photolysis can take two pathways. The dominant
37% in the commercially available products (G. Moore, pathway produces stable molecular hydrogen and
personal communication, 2000). carbon monoxide. The other pathway produces the
formyl radical and a hydrogen atom (Lowe et al., 1980),
Formaldehyde is also used as an antibacterial which react quickly with oxygen to form the
agent in processing of foodstuffs. For example, the Food hydroperoxyl radical and carbon monoxide. Under many
and Drugs Act allows up to 2 ppm (i.e., 2 mg/kg) conditions, the radicals from photolysis of formaldehyde
formaldehyde in maple syrup resulting from the use of are the most important net source of smog generation
paraformaldehyde to deter bacterial growth in the tap (US EPA, 1993). When the rates of these reactions are
holes of maple trees in Canada (M. Feeley, personal combined with estimates of actinic radiance, the
communication, 1996). Formaldehyde is also registered estimated half-life of formaldehyde due to photolysis is
as a feed under the Feed Act in Canada. 1.6 h in the lower troposphere at a solar zenith angle of
40 (Calvert et al., 1972). A half-life of 6 h was measured
based on simulated sunlight (Lowe et al., 1980).
The nighttime destruction of formaldehyde is

expected to occur by the gas-phase reaction with nitrate
radicals (US NRC, 1981); this tends to be more signifi-
cant in urban areas, where the concentration of the
10
Formaldehyde
nitrate radical is higher than in rural areas (Altshuller & 5.2 Water
Cohen, 1964; Gay & Bufalini, 1971; Maldotti et al., 1980).
A half-life of 160 days was calculated using an average In water, formaldehyde is rapidly hydrated to
atmospheric nitrate radical concentration typical of a form a glycol. Equilibrium favours the glycol (Dong &
mildly polluted urban centre (Atkinson et al., 1990), while Dasgupta, 1986); less than 0.04% by weight of unhy-
a half-life of 77 days was estimated based on measured drated formaldehyde is found in highly concentrated
rate constants (Atkinson et al., 1993). Nitric acid and solutions (Kroschwitz, 1991). In surface water or
formyl radical have been identified as products of this groundwater, formaldehyde can be biodegraded (US
reaction. They react rapidly with atmospheric oxygen to EPA, 1985; Howard, 1989). Incorporated into atmospheric
produce carbon monoxide and hydroperoxyl radicals, water, formaldehyde or its hydrate can be oxidized.
which can react with formaldehyde to form formic acid.
However, because of this rapid back-reaction, the Formaldehyde is degraded by various mixed micro-
reaction of nitrate radicals with formaldehyde is not bial cultures obtained from sludges and sewage
expected to be a major loss process under tropospheric (Kitchens et al., 1976; Verschueren, 1983; US EPA, 1985).
conditions. Formaldehyde in lake water decomposed in
approximately 30 h under aerobic conditions at 20 C and
Overall half-lives for formaldehyde in air can vary in approximately 48 h under anaerobic conditions
considerably under different conditions. Estimations for (Kamata, 1966). Howard et al. (1991) estimated half-lives
atmospheric residence time in several US cities ranged of 24168 h in surface water and 48336 h in
from 0.3 h under conditions typical of a rainy winter groundwater based on scientific judgement and
night to 250 h under conditions typical of a clear summer estimated aqueous aerobic biodegradation half-lives.
night (assuming no reaction with hydroperoxyl radicals)
(US EPA, 1993). During the daytime, under clear sky When incorporated from air into cloud water, fog
conditions, the residence time of formaldehyde is water, or rain, formaldehyde can react with aqueous
determined primarily by its reaction with the hydroxyl hydroxyl radicals in the presence of oxygen to produce
radical. Photolysis accounted for only 25% of the formic acid, water, and hydroperoxide (aqueous). The
removal. formaldehyde glycol can also react with ozone (Atkinson
et al., 1990).
Given the generally short daytime residence times
for formaldehyde, there is limited potential for long-range 5.3 Sediment
transport of this compound. However, in cases where
organic precursors are transported long distances, Because of its low organic carbon/water partition
secondary formation of formaldehyde may occur far from coefficient (Koc) and high water solubility, formaldehyde
the actual anthropogenic sources of the precursors is not expected to significantly sorb to suspended solids
(Tanner et al., 1994). and sediments from water. Biotic and abiotic degradation
are expected to be significant processes affecting the
Because of its high solubility in water, formalde- fate of formaldehdye in sediment (US EPA, 1985;
hyde will transfer into clouds and precipitation. A Howard, 1989).
washout ratio (concentration in rain/concentration in air)
of 73 000 at 25 C is estimated by Atkinson (1990). Gas- 5.4 Soil
phase organic compounds that have a washout ratio of
greater than 105 are generally estimated to be efficiently Formaldehyde is not expected to adsorb to soil
rained out (California Air Resources Board, 1993). particles to a great degree and would be considered
Based on the washout ratio, the wet deposition (removal mobile in the soil, based on its estimated Koc. According
of gases and particles by precipitation) of formaldehyde to Kenaga (1980), compounds with a Koc of <100 are
could be significant as a tropospheric loss process considered to be moderately mobile. Formaldehyde can
(Atkinson, 1989). However, Zafiriou et al. (1980) esti- be transported to surface water through runoff and to
mated that rainout was responsible for removing only groundwater as a result of leaching. Parameters other
1% of formaldehyde produced in the atmosphere by the than Koc affecting its leaching to groundwater include
oxidation of methane. Warneck et al. (1978) showed that the soil type, the amount and frequency of rainfall, the
washout is important only in polluted regions. Neverthe- depth of the groundwater, and the extent of degradation
less, it is expected that wet deposition can lead to a of formaldehyde. Formaldehyde is susceptible to
somewhat shorter tropospheric lifetime of formaldehyde degradation by various soil microorganisms (US EPA,
than that calculated from gas-phase processes alone. 1985). Howard et al. (1991) estimated a soil half-life of 24
168 h, based on estimated aqueous aerobic biodegrada-
tion half-lives.
11
5.5 Biota g/m3]) to maxima of 22.9 ppb (27.5 g/m3) for eight
urban sites, 10.03 ppb (12.03 g/m3) for two suburban
In view of the very low bioconcentration factor of sites, 7.59 ppb (9.11 g/m3) for two rural sites considered
0.19, based on a log octanol/water partition coefficient to be affected by urban and/or industrial influences, and
(Kow) of 0.65 (Veith et al., 1980; Hansch & Leo, 1981), 8.23 ppb (9.88 g/m3) for four rural sites considered to be
formaldehyde is not expected to bioaccumulate. When regionally representative. Long-term (1 month to 1 year)
examined, bioconcentration was not observed in fish or mean concentrations for these sites ranged from 0.65 to
shrimp (Stills & Allen, 1979; Hose & Lightner, 1980). 7.30 ppb (0.78 to 8.76 g/m3). The single highest 24-h
concentration measured was 22.9 ppb (27.5 g/m3),
5.6 Environmental partitioning obtained for an urban sample collected from Toronto,
Ontario, on 8 August 1995. Available data indicate that
Fugacity modelling was carried out to provide an levels are highest between June and August, and there
overview of key reaction, intercompartment, and advec- is no evidence that concentrations of formaldehyde were
tion (movement out of a system) pathways for formalde- systematically increasing or decreasing at these sites
hyde and its overall distribution in the environment. A over this 9-year period (Health Canada, 2000).
steady-state, non-equilibrium model (Level III fugacity
model) was run using the methods developed by Atmospheric measurements made in 1992 during
Mackay (1991) and Mackay & Paterson (1991). the dark winter and sunlit spring of an extremely remote
Assumptions, input parameters, and results are site at Alert, Nunavut, ranged from 0.033 to 0.70 ppb
presented in Mackay et al. (1995) and Environment (0.04 to 0.84 g/m3) on a 5-min basis (detection limit 0.033
Canada (1999a). ppb [0.04 g/m3]), with a mean of 0.40 ppb (0.48 g/m3)
(De Serves, 1994).
Based on formaldehydes physical/chemical prop-
erties, Level III fugacity modelling indicates that when In air near a forest products plant in Canada, the
formaldehyde is continuously discharged into one maximum 24-h average concentrations for three 3-month
medium, most of it can be expected to be present in that periods between March 1995 and March 1996 ranged
medium (Mackay et al., 1995; DMER & AEL, 1996). from 1.43 to 3.67 ppb (1.71 to 4.40 g/m3) (detection limit
However, given the uncertainties relating to use of not specified) (Environment Canada, 1997b).
pseudo-solubility, hydration in water, and the complex
atmospheric formation and degradation processes for 6.1.2 Indoor air
formaldehyde, quantitative estimates of mass
distribution are not considered reliable. Data concerning concentrations of formaldehyde
in residential indoor air from seven studies conducted in
Canada between 1989 and 1995 were examined (Health
Canada, 2000). Despite differences in sampling mode and
6. ENVIRONMENTAL LEVELS AND duration (i.e., active sampling for 24 h or passive
HUMAN EXPOSURE sampling for 7 days), the distributions of concentrations
were similar in five of the studies. The median, arithmetic
mean, 95th percentile, and 99th percentile concentrations
Data on concentrations in the environment primar- of the pooled data (n = 151 samples) from these five
ily from the source country of the national assessment studies were 25, 30, 71, and 97 ppb (30, 36, 85, and 116
on which the CICAD is based (i.e., Canada) are g/m3), respectively (Health Canada, 2000). In view of
presented here as a basis for the sample risk the potential for less dilution from indoor sources in
characterization. Patterns of exposure in other countries Canadian residential structures owing to lower average
are expected to be similar, although quantitative values air exchange rates due to energy conservation, levels of
may vary. formaldehyde in indoor air in residences located in
warmer climates might be expected to be less. Identified
6.1 Environmental levels values measured in non-workplace indoor air in other
countries are, however, similar to those reported here.
6.1.1 Ambient air
Concurrent 24-h measurements in outdoor air and
Formaldehyde was detected (detection limit indoor air of Canadian residences were available from
0.042 ppb [0.05 g/m3]) in 3810 of 3842 24-h samples from some of these studies. Average concentrations of
rural, suburban, and urban areas, collected at 16 sites in formaldehyde were an order of magnitude higher in
six provinces surveyed from August 1989 to August indoor air than in outdoor air, indicating the presence of
1998 (Environment Canada, 1999a). Concentrations indoor sources of formaldehyde and confirming similar
ranged from below the detection limit (0.042 ppb [0.05 findings in other countries (IPCS, 1989; ATSDR, 1999).
12
Formaldehyde
Information concerning the presence of environmental October 1989 averaged 1.2 g/litre, with a peak value of
tobacco smoke (ETS) in the homes sampled was 9.0 g/litre. These concentrations were influenced by
available from some of these studies; however, there was climatological events such as spring runoff, major rainfall
no clear indication that concentrations of formaldehyde events, and the onset of winter, as evidenced by con-
were greater in homes where ETS was present. centration increases during spring runoff and major rain-
Acetaldehyde, rather than formaldehyde, is the most fall and concentration decreases (<0.2 g/litre) following
abundant carbonyl compound in mainstream and river freeze-up (Huck et al., 1990).
sidestream cigarette smoke. Based on data from the USA
and elsewhere, ETS does not increase concentrations of Anderson et al. (1995) measured formaldehyde
formaldehyde in indoor air, except in areas with high concentrations in the raw water of three drinking-water
rates of smoking and minimal rates of ventilation treatment pilot plants in Ontario, Canada. The study
(Godish, 1989; Guerin et al., 1992). included three distinct types of surface waters, covering
a range of characteristics and regional influences: a
Data from several studies indicate that various moderately hard waterway with agricultural impacts
cooking activities may contribute to the elevated levels (Grand River at Brantford), a soft, coloured river (Ottawa
of formaldehyde sometimes present in indoor air (Health River at Ottawa), and a river with moderate values for
Canada, 2000). In recent work from the USA, the most parameters, typical of the Great Lakes waterways
emission rate of formaldehyde from meat charbroiling (Detroit River at Windsor). Concentrations were less
over a natural gas-fired grill in a commercial facility was than the detection limit (1.0 g/litre) and 8.4 g/litre in
higher (i.e., 1.38 g/kg of meat cooked) than emission raw water samples collected on 2 December 1993 and 15
rates of all other VOCs measured except for ethylene February 1994, respectively, from the Detroit River. In
(Schauer et al., 1999). the Ottawa River, concentrations were below the
detection limit (1.0 g/litre) in three profiles taken
6.1.3 Water between 12 April and 7 June 1994. In the Grand River, a
mean concentration of 1.1 g/litre was obtained for
6.1.3.1 Drinking-water seven sampling dates between 11 May and 21 June 1994.
Representative data concerning concentrations in 6.1.3.3 Effluent

drinking-water in Canada were not available. The con-
centration of formaldehyde in drinking-water is likely The highest reported concentration from one of
dependent upon the quality of the raw source water and the four plants reporting releases for 1997 (Environment
purification steps (Krasner et al., 1989). Ozonation may Canada, 1999b) was a 1-day mean of 325 g/litre, with a
slightly increase the levels of formaldehyde in drinking- 4-day mean of 240 g/litre (Environment Canada, 1999a).
water, but subsequent purification steps may attenuate
these elevated concentrations (Huck et al., 1990). Ele- 6.1.3.4 Groundwater
vated concentrations have been measured in US houses
equipped with polyacetal plumbing elbows and tees. Extensive monitoring of groundwater from a
Normally, an interior protective coating prevents water Canadian site of production and use of formaldehyde
from contacting the polyacetal resin (Owen et al., 1990). included 10 samples in which formaldehyde concentra-
However, if routine stress on the supply lines results in a tions were below the detection limit (50 g/litre) and
break or fracture of the coating, water may contact the 43 samples with concentrations ranging from 65 to
resin directly. The resultant concentrations of formalde- 690 000 g/litre (mean of two duplicates) from November
hyde in the water are largely determined by the residence 1991 to February 1992 (Environment Canada, 1997b).
time of the water in the pipes. Owen et al. (1990) esti- Data had been collected as part of a monitoring
mated that at normal water usage rates in occupied programme to delineate the boundaries of groundwater
dwellings, the resulting concentration of formaldehyde contamination at the facility and were used to design a
in water would be about 20 g/litre. In general, groundwater containment and recovery system. Formal-
concentrations of formaldehyde in drinking-water are dehyde was not detected in samples taken from outside
expected to be less than 100 g/litre (IPCS, 1989; IARC, the contaminated zone.
1995).
Quarterly analyses of five monitoring wells on the
6.1.3.2 Surface water property of a Canadian plant that produces UF resins
were carried out during 19961997. Concentrations
Concentrations of formaldehyde in raw water from ranged from below the detection limit (50 g/litre) to
the North Saskatchewan River were measured at the 8200 g/litre, with an overall median of 100 g/litre.
Rossdale drinking-water treatment plant in Edmonton, Concentrations for different wells indicated little disper-
Alberta, Canada. Concentrations between March and
13
sion from wells close to the source of contamination concentrations of formaldehyde naturally occurring in
(Environment Canada, 1997b). foods (i.e., up to 60 mg/kg) are in some fruits (Mhler &
Denbsky, 1970; Tsuchiya et al., 1975) and marine fish
Groundwater samples collected from wells down- (Rehbein, 1986; Tsuda et al., 1988).
stream from six cemeteries in Ontario, Canada, contained
concentrations of formaldehyde of 130 g/litre Formaldehyde develops postmortem in marine fish
(detection limit not specified), although a blank sample and crustaceans, from the enzymatic reduction of tri-
contained 7.3 g/litre in these analyses (Chan et al., methylamine oxide to formaldehyde and dimethylamine
1992). (Sotelo et al., 1995). While formaldehyde may be formed
during the ageing and deterioration of fish flesh, high
6.1.3.5 Atmospheric water levels do not accumulate in the fish tissues, due to
subsequent conversion of the formaldehyde formed to
Concentrations of formaldehyde in rain ranged other chemical compounds (Tsuda et al., 1988). However,
from 0.44 g/litre (near Mexico City) to 3003 g/litre formaldehyde accumulates during the frozen storage of
(during the vegetation burning season in Venezuela; some fish species, including cod, pollack, and haddock
anthropogenic sources). Mean concentrations ranged (Sotelo et al., 1995). Formaldehyde formed in fish reacts
from 77 g/litre (in Germany) to 321 g/litre (during the with protein and subsequently causes muscle toughness
non-burning season in Venezuela). In snow, concentra- (Yasuhara & Shibamoto, 1995), which suggests that fish
tions of formaldehyde ranged from 18 to 901 g/litre containing the highest levels of formaldehyde (e.g.,
in California, USA. A mean snow concentration of 1020 mg/kg) may not be considered palatable as a
4.9 g/litre is reported for Germany. In fog water, con- human food source.
centrations of 48017 027 g/litre have been measured in
the Po valley, Italy, with a mean of 3904 g/litre Higher concentrations of formaldehyde (i.e., up to
(Environment Canada, 1999a). 800 mg/kg) have been reported in fruit and vegetable
juices in Bulgaria (Tashkov, 1996); however, it is not
6.1.4 Sediment and soil clear if these elevated levels arise during processing.
Formaldehyde is used in the sugar industry to inhibit
No data were identified on concentrations of form- bacterial growth during juice production (ATSDR, 1999).
aldehyde in sediments in the source country (Canada). In a study conducted by Agriculture Canada,
concentrations of formaldehyde were higher in sap from
Concentrations in soil were measured at manufac- maple trees that had been implanted with paraformalde-
turing plants that use phenol/formaldehyde resins. At a hyde to deter bacterial growth in tap holes (Baraniak et
plywood plant, six soil samples collected in 1991 con- al., 1988). The resulting maple syrup contained concen-
tained formaldehyde concentrations of 7380 mg/kg, trations up to 14 mg/kg, compared with less than 1 mg/kg
with a mean of 76 mg/kg (detection limit not specified) in syrup from untreated trees.
(G. Dinwoodie, personal communication, 1996). At a
fibreglass insulation plant, formaldehyde was not In other processed foods, the highest concentra-
detected (detection limit 0.1 mg/kg) in soil samples tions (i.e., 267 mg/kg) have been reported in the outer
collected in 1996 from six depths at four industrial areas layer of smoked ham (Brunn & Klostermeyer, 1984) and
on-site. Formaldehyde was also not detected in samples in some varieties of Italian cheese, where formaldehyde
taken from a non-industrial site 120 km away from the is permitted for use under regulation as a bacteriostatic
plant. agent (Restani et al., 1992). Hexamethylenetetramine, a
complex of formaldehyde and ammonia that decomposes
6.1.5 Biota slowly to its constituents under acid conditions, has
been used as a food additive in fish products such as
No data were identified on concentrations of herring and caviar in the Scandinavian countries
formaldehyde in biota in the source country (Canada). (Scheuplein, 1985).
6.1.6 Food Concentrations of formaldehyde in a variety of

alcoholic beverages ranged from 0.04 to 1.7 mg/litre in
There have been no systematic investigations of Japan (Tsuchiya et al., 1994) and from 0.02 to 3.8 mg/litre
levels of formaldehyde in a range of foodstuffs as a in Brazil (de Andrade et al., 1996). In earlier work
basis for estimation of population exposure (Health conducted in Canada, Lawrence & Iyengar (1983) com-
Canada, 2000). Although formaldehyde is a natural pared levels of formaldehyde in bottled and canned cola
component of a variety of foodstuffs (IPCS, 1989; IARC, soft drinks (7.48.7 mg/kg) and beer (0.11.5 mg/kg) and
1995), monitoring has generally been sporadic and concluded that there was no significant increase in the
source directed. Available data suggest that the highest formaldehyde content of canned beverages due to the
14
Formaldehyde
plastic inner coating of the metal containers. Concentra- antimicrobial agent in hair preparations, lotions (e.g.,
tions of 3.4 and 4.5 mg/kg in brewed coffee and 10 and 16 suntan lotion and dry skin lotion), makeup, and mouth-
mg/kg in instant coffee were reported in the USA washes and is also present in hand cream, bath
(Hayashi et al., 1986). These concentrations reflect the products, mascara and eye makeup, cuticle softeners,
levels in the beverages as consumed. nail creams, vaginal deodorants, and shaving cream
(IPCS, 1989; ATSDR, 1999).
Formaldehyde is used in the animal feed industry,
where it is added to ruminant feeds to improve handling Some preservatives are formaldehyde releasers.
characteristics. The food mixture contains less than 1% The release of formaldehyde upon their decomposition is
formaldehyde, and animals may ingest as much as 0.25% dependent mainly on temperature and pH. Information
formaldehyde in their diet (Scheuplein, 1985). Formalin on product categories and typical concentrations for
has been added as a preservative to skim milk fed to pigs chemical products containing formaldehyde and formal-
in the United Kingdom (Florence & Milner, 1981) and to dehyde releasers was obtained from the Danish Product
liquid whey (from the manufacture of cheddar and cot- Register Data Base (PROBAS) by Flyvholm & Andersen
tage cheeses) fed to calves and cows in Canada. Maxi- (1993). Industrial and household cleaning agents, soaps,
mum concentrations in the milk of cows fed whey with shampoos, paints/lacquers, and cutting fluids comprised
the maximum level of formalin tested (i.e., 0.15%) were up the most frequent product categories for formaldehyde
to 10-fold greater (i.e., 0.22 mg/kg) than levels in milk releasers. The three most frequently registered formalde-
from control cows fed whey without added formalin hyde releasers were bromonitropropanediol, bromonitro-
(Buckley et al., 1986, 1988). In a more recent study, the dioxane, and chloroallylhexaminium chloride (Flyvholm
concentrations of formaldehyde in commercial 2% milk & Andersen, 1993).
and in fresh milk from cows fed on a typical North
American dairy total mixed diet were determined. Con- Formaldehyde is present in the smoke resulting
centrations in the fresh milk (i.e., from Holstein cows, from the combustion of tobacco products. Estimates of
morning milking) ranged from 0.013 to 0.057 mg/kg, with emission factors for formaldehyde (e.g., g/cigarette)
a mean concentration (n = 18) of 0.027 mg/kg, while from mainstream and sidestream smoke and from ETS
concentrations in processed milk (i.e., 2% milk fat, partly have been determined by a number of different protocols
skimmed, pasteurized) ranged from 0.075 to 0.255 mg/kg, for cigarettes in several countries.
with a mean concentration (n = 12) of 0.164 mg/kg. The
somewhat higher concentrations in the commercial 2% A range of mainstream smoke emission factors
milk were attributed to processing technique, packaging, from 73.8 to 283.8 g/cigarette was reported for 26 US
and storage, but these factors were not assessed further brands, which included non-filter, filter, and menthol
(Kaminski et al., 1993). cigarettes of various lengths (Miyake & Shibamoto,
1995). Differences in concentrations reflect differences in
The degree to which formaldehyde in various tobacco type and brand. More recent information is
foods is bioavailable following ingestion is not known. available from the British Columbia Ministry of Health
from tests conducted on 11 brands of Canadian ciga-
6.1.7 Consumer products rettes. Mainstream smoke emission factors ranged from
8 to 50 g/cigarette when tested under standard
Formaldehyde and formaldehyde derivatives are conditions.1
present in a wide variety of consumer products (Preuss
et al., 1985) to protect the products from spoilage by Levels of formaldehyde are higher in sidestream
microbial contamination. Formaldehyde is used as a smoke than in mainstream smoke. Guerin et al. (1992)
preservative in household cleaning agents, dishwashing reported that popular commercial US cigarettes deliver
liquids, fabric softeners, shoe care agents, car shampoos approximately 10002000 g formaldehyde/cigarette
and waxes, carpet cleaning agents, etc. (IPCS, 1989). in their sidestream smoke. Schlitt & Knppel (1989)
Levels of formaldehyde in hand dishwashing liquids and reported a mean (n = 5) formaldehyde content of
liquid personal cleansing products available in Canada 2360 g/cigarette in the sidestream smoke from a single
are less than 0.1% (w/w) (A. McDonald, personal brand in Italy. Information from the British Columbia
communication, 1996). Ministry of Health from tests conducted on 11 brands of
Formaldehyde has been used in the cosmetics

industry in three principal areas: preservation of cos- 1
Data from British Columbia Ministry of Health web site
metic products and raw materials against microbial (www.cctc.ca/bcreorts/results.htm) regarding emission
contamination, certain cosmetic treatments such as factors of toxic chemicals from mainstream and
hardening of fingernails, and plant and equipment sidestream smoke from 11 brands of Canadian cigarettes.
sanitation (Jass, 1985). Formaldehyde is also used as an Victoria, British Columbia, 1998.
15
Canadian cigarettes indicates that emission factors from frequently measured in indoor air. Historically, the most
sidestream smoke ranged from 368 to 448 g/cigarette.1 important indoor source among the many materials used
in building and construction has been urea-
Emission factors for toxic chemicals from ETS, formaldehyde foam insulation (UFFI), which is produced
rather than from mainstream or sidestream smoke, have by the aeration of a mixture of UF resin and an aqueous
also been determined. This is in part due to concerns surfactant solution containing a curing catalyst (Meek et
that emission factors for sidestream smoke may be too al., 1985). UFFI was banned from use in Canada in 1980
low for reactive chemicals such as formaldehyde, due to and in the USA in 1982, although the US ban was
losses in the various apparati used to determine side- subsequently overturned.
stream smoke emission factors. Daisey et al. (1994)
indicated that ETS emission factors for formaldehyde Pressed wood products (i.e., particleboard,
from six US commercial cigarettes ranged from 958 to medium-density fibreboard, and hardwood plywood) are
1880 g/cigarette, with a mean of 1310 349 g/cigarette. now considered the major sources of residential formal-
Data concerning emission factors for formaldehyde from dehyde contamination (Godish, 1988; Etkin, 1996).
ETS produced by Canadian cigarettes were not Pressed wood products are bonded with UF resin; it is
identified. this adhesive portion that is responsible for the emission
of formaldehyde into indoor air. The emission rate of
6.1.7.1 Clothing and fabrics formaldehyde is strongly influenced by the nature of the
material. Generally, release of formaldehyde is highest
Formaldehyde-releasing agents provide crease from newly made wood products. Emissions then
resistance, dimensional stability, and flame retardance decrease over time, to very low rates, after a period of
for textiles and serve as binders in textile printing (Priha, years (Godish, 1988).
1995). Durable-press resins or permanent-press resins
containing formaldehyde have been used on cotton and Concentrations of formaldehyde in indoor air are
cotton/polyester blend fabrics since the mid-1920s to primarily determined by such factors as source strength
impart wrinkle resistance during wear and laundering. (i.e., mass of substance released per unit time or per unit
Hatch & Maibach (1995) identified nine major resins area), loading factors (i.e., the ratio of the surface area of
used. These differ in formaldehyde-releasing potential a source [e.g., a particleboard panel] to the volume of an
during wear and use. enclosed area [e.g., a room] where the source is present),
and the presence of source combinations (Godish, 1988).
Priha (1995) indicated that formaldehyde-based Emission rates for formaldehyde from pressed wood
resins, such as UF resin, were once more commonly used products determined by emission chamber testing in
for crease resistance treatment; more recently, however, Canada (Figley & Makohon, 1993; Piersol, 1995), the
better finishing agents with lower formaldehyde release United Kingdom (Crump et al., 1996), and the USA (Kelly
have been developed. Totally formaldehyde-free cross- et al., 1999) are now typically less than 0.3 mg/m2 per
linking agents are now available, and some countries hour (Health Canada, 2000).
have legally limited the formaldehyde content of textile
products. In 1990, the percentage of durable-press fabric Formaldehyde release from pressed wood materials
manufactured in the USA finished with resins rated as is greater in mobile homes than in conventional housing,
having high formaldehyde release was 27%, about one- as mobile homes typically have higher loading ratios
half the percentage in 1980, according to Hatch & Mai- (e.g., exceeding 1 m2/m3) of these materials. In addition,
bach (1995). It has been reported that the average level mobile homes can have minimal ventilation, are minimally
contained by textiles made in the USA is approximately insulated, and are often situated in exposed sites subject
100200 g free formaldehyde/g (Scheman et al., 1998). to temperature extremes (Meyer & Hermanns, 1985).
Piletta-Zanin et al. (1996) studied the presence of The use of scavengers (e.g., urea) to chemically
formaldehyde in moist baby toilet tissues and tested 10 remove unreacted formaldehyde while the curing
of the most frequently sold products in Switzerland. One process is taking place has been investigated as a
product contained more than 100 g/g, five products control measure. Other reactants could be used to
contained between 30 and 100 g/g, and the remaining chemically modify the formaldehyde to a non-toxic
four products contained less than 30 g formaldehyde/g. derivative or convert it to a non-volatile reaction
product. There has also been work to effectively seal the
6.1.7.2 Building materials resin and prevent the residual formaldehyde from
escaping (Tabor, 1988). Surface coatings and treatments
The emission of formaldehyde from building (e.g., paper and vinyl decorative laminates) can
materials has long been recognized as a significant significantly affect the potential for off-gassing and in
source of the elevated concentrations of formaldehyde some cases can result in an order of magnitude reduction
16
Formaldehyde
in the emission rates for formaldehyde from pressed Pooled data (n = 151) from five studies in which
wood products (Figley & Makohon, 1993; Kelly et al., concentrations of formaldehyde were measured in the
1999). On the other hand, high emissions of indoor air of residences in Canada between 1989 and
formaldehyde during the curing of some commercially 1995 were the basis for the range and distribution of
available conversion varnishes (also known as acid- concentrations to which the general population of
catalyst varnishes) have been reported. An initial Canada is currently assumed to be exposed via
emission rate of 29 mg formaldehyde/m2 per hour was inhalation of residential indoor air (Health Canada, 2000)
determined for one product (McCrillis et al., 1999). (Table 4).
Emission rates for formaldehyde from carpets and The distribution of the time spent outdoors is
carpet backings, vinyl floorings, and wall coverings in arbitrarily assumed to be normal in shape with an
the source country (Canada) are now generally less than arithmetic standard deviation of 2 h. In the probabilistic
0.1 mg/m2 per hour (Health Canada, 2000). simulation, this distribution is truncated at 0 h and 9 h.
The time spent indoors is calculated as 24 h minus the
6.2 Human exposure: environmental time spent outdoors. Individuals residing in warmer
climates may spend a greater amount of time outdoors.
This sample exposure estimation is based primarily
on data on concentrations in the environment from the Estimates of the distribution of time-weighted 24-h
source country of the national assessment on which the concentrations of formaldehyde to which the general
CICAD is based (i.e., Canada) as a basis for the sample population is exposed were developed using simple
risk characterization. Owing to the ubiquitous sources of random sampling (Monte Carlo analysis) with Crystal
formaldehyde, which are likely similar in most countries, Ball Version 4.0 (Decisioneering, Inc., 1996) and
the overall magnitude of relative contributions from simulations of 10 000 trials.
various sources of exposure presented here are expected
to be reasonably representative of those in other parts of Two simulations were run. The parameters for the
the world. simulations and estimates of the median, arithmetic
mean, and upper percentiles of the distributions of 24-h
Estimates of the total daily intake of formaldehyde time-weighted average concentrations of formaldehyde
by six age groups of the general population of Canada determined from these probabilistic simulations are
were developed primarily to determine the relative con- summarized in Table 5. Based on the assumptions under-
tributions from various media. These estimates indicate lying these probabilistic simulations, the estimates sum-
that the daily intake of formaldehyde via inhalation is marized in Table 5 indicate that one of every two persons
consistently less than that estimated for the ingestion of would be exposed to 24-h average concentrations
foodstuffs. However, it should be noted that critical of formaldehyde in air of 2024 ppb (2429 g/m3) or
effects associated with exposure to formaldehyde occur greater (i.e., median concentrations). Similarly, 1 in
primarily at the site of first contact (i.e., the respiratory 20 persons (i.e., 95th percentile) would be exposed to 24-
tract following inhalation and the aerodigestive tract, h average concentrations of formaldehyde in air of 67
including oral and gastrointestinal mucosa, following 78 ppb (8094 g/m3) or greater.
ingestion) and are related to the concentration of
formaldehyde in media to which humans are exposed, Based on limited data from the USA, concentra-
rather than to the total intake of this substance. For this tions in drinking-water may range up to approximately 10
reason, effects of exposure by inhalation and ingestion g/litre, in the absence of specific contributions from the
are addressed separately. formation of formaldehyde by ozonation during water
treatment or from leaching of formaldehyde from
Due primarily to limitations of available data as a polyacetal plumbing fixtures. One-half this concentration
basis for characterization of exposure via ingestion, the (i.e., 5 g/litre) was judged to be a reasonable estimate of
principal focus of the assessment is airborne exposure. the average concentration of formaldehyde in Canadian
The less representative assessment for ingestion drinking-water, in the absence of other data. Concen-
involves comparison of the concentration of trations approaching 100 g/litre were observed in a US
formaldehyde in a limited number of food products with study assessing the leaching of formaldehyde from
a tolerable concentration (ingestion). domestic polyacetal plumbing fixtures, and this concen-
tration is assumed to be representative of a reasonable
A subset of data from the National Air Pollution worst case.
Surveillance programme was selected to represent the
range and distribution of concentrations to which the Similarly, very few data are available with which to
general population of Canada is currently assumed to be estimate the range and distribution of concentrations of
exposed via inhalation of outdoor air (Table 4). formaldehyde in foods to which the general population
17
in Canada is exposed. According to the limited available 6.3 Human exposure: occupational
data, concentrations of formaldehyde in food are highly
variable. In the few studies of the formaldehyde content Since the principal focus of the source document
of foods in Canada, the concentrations of formaldehyde was on exposure in the general environment, the follow-
were within the range <0.0314 mg/kg (Health Canada, ing provides only a brief overview of occupational
2000). However, the proportion of formaldehyde in foods exposure to formaldehyde. Occupational exposure to
that is bioavailable is unknown. Formaldehyde is a formaldehyde occurs in all workplaces, as the sources
metabolite of methanol (IPCS, 1997). (e.g., combustion) are ubiquitous. Although it is not
possible to accurately estimate the number of people
Table 4: Concentrations of formaldehyde in outdoor air and residential indoor air in Canada.
Mid-points of Upper percentiles of distributions of

distributions (g/m3) concentrations (g/m3)
Number of
Medium of exposure samples Median Meana 75th 90th 95th 97.5th
b
Outdoor air NAPS data 2819 2.8 3.3 4.1 6.0 7.3 9.1
Outdoor air reasonable worst-case 371 2.9 4.0 4.8 7.3 10.4 17.3
sitec
Indoor air five studiesd 151 29.8 35.9 46.2 64.8 84.6 104.8
e
Indoor air lognormal distribution 28.7 46.1 70.7 91.2 113.8
a These are the arithmetic mean concentrations. Since formaldehyde was detected in more than 99% of the samples, censoring of
the data for limit of detection was not required.
b Data are for selected suburban (n = 4) and urban (n = 4) sites of the National Air Pollution Surveillance (NAPS) programme (T.
Dann, unpublished data, 1997, 1999) for the period 19901998. Concentrations are slightly lower for the subset of suburban sites
and slightly higher for the subset of urban sites. Distributions are positively skewed.
c One of the four urban sites (i.e., NAPS site 060418 in Toronto) was selected for the reasonable worst-case purpose.
d Data were pooled from five studies of concentrations of formaldehyde in residential indoor air. These studies were conducted at
various locations in Canada between 1989 and 1995.
e The geometric mean and standard deviation of the pooled data (n = 151) from the five Canadian studies were calculated. A
lognormal distribution with the same geometric mean and standard deviation was generated, and the upper percentiles of this
distribution were estimated.
Table 5: Probabilistic estimates of 24-h time-weighted average concentrations of formaldehyde in air.
Mid-points of Upper percentiles of distributions of concentrations (g/m3) and relative

distributions (g/m3) standard deviations (%)
Median Meana 75th 90th 95th 97.5th

b
Simulation 1 29 36 46 ( 0.5%) 62 ( 1.3%) 80 ( 1.9%) 97 ( 0.7%)
Simulation 2 c 24 33 45 ( 1.2%) 75 ( 1.2%) 94 ( 1.6%) 109 ( 1.3%)
a This is the arithmetic mean concentration.

b In simulation 1, the distribution of concentrations of formaldehyde is represented by a frequency histogram of the pooled data from
the five selected studies (n = 151 samples).
c For simulation 2, a lognormal distribution of concentrations, truncated at 150 g/m 3, is assumed. This lognormal distribution has the
same geometric mean (28.7 g/m 3) and standard deviation (2.92) as the distribution of concentrations for the pooled data from the
five selected studies.
occupationally exposed to formaldehyde worldwide, it is clerical, transport equipment, and furniture and fixtures
likely to be several millions in industrialized countries (IARC, 1995).
alone (IARC, 1995). Industries with greatest potential
exposure include health services, business services, Formaldehyde occurs in occupational environ-
printing and publishing, manufacture of chemicals and ments mainly as a gas. Formaldehyde-containing par-
allied products, apparel and allied products, paper and ticles can also be inhaled when paraformaldehyde or
allied products, personal services, machinery except powdered resins are being used in the workplace (IARC,
1995). These resins can also be attached to carriers, such
18
Formaldehyde
as wood dust. Exposure may also occur dermally when activities can result in heavy exposures, with high peak
formalin solutions or liquid resins come into contact with exposure occurring many times per day.
skin.
Formaldehyde is used as a tissue preservative and
Exposure concentrations are highly variable disinfectant in embalming fluids. The concentration of
between workplaces. The reported mean concentrations formaldehyde in the air during embalming is variable, but
in the air of factories producing formaldehyde-based the mean level is about 1 ppm (1.2 mg/m3) (IARC, 1995).
resins vary from <1 to >10 ppm (<1.2 to >12 mg/m3) The mean concentrations of formaldehyde measured in
(IARC, 1995). Formaldehyde-based glues have been hospitals range from 0.083 to 0.83 ppm (0.1 to 1.0 mg/m3),
used in the assembly of plywood and particleboard for but the measurements were made during disinfection,
over 30 years, and concentrations in these factories were which usually takes a relatively short time. Formalin
usually >1 ppm (>1.2 mg/m3) before the mid-1970s but solution is commonly used to preserve tissue samples in
have been below that level more recently (IARC, 1995). histopathology laboratories. The concentrations are
The development of glues with lower formaldehyde sometimes high, but the mean level during exposure is
content and better ventilation has reduced about 0.5 ppm (0.6 mg/m3) (IARC, 1995).
concentrations to about 1 ppm (1.2 mg/m3) or below
(Kauppinen & Niemel, 1985). Furniture varnishes may Occupational exposure to formaldehyde may also
contain UF resins dissolved in organic solvents. As a occur in the construction industry, agriculture, forestry,
result, workers are continuously exposed to an average and the service sector. Specialized workers can be
level of about 1 ppm (1.2 mg/m3), but the levels have exposed to very high concentrations. For example,
decreased slightly since 1975 (Priha et al., 1986). Coating workers who varnish wood floors are exposed to mean
agents and other chemicals used in paper mills may levels of 25 ppm (2.46.0 mg/m3) during each coat. Each
contain formaldehyde as a bactericide. The average worker may complete 510 coats of varnish per day
levels related to lamination and impregnation of paper in (IARC, 1995). Formaldehyde is used in agriculture as a
mills in the USA, Sweden, and Finland were usually preservative for fodder and as a disinfectant for
below 1 ppm (1.2 mg/m3), but variation can occur brooding houses. Although exposure is high at the time
depending on the type of resin used and the product of application (78 ppm [8.49.6 mg/m3]), the annual
manufactured (IARC, 1995). exposure from this source remains very low (Heikkil
et al., 1991). Lumberjacks can also be exposed to
Formaldehyde has been used in the textile industry formaldehyde from the exhaust of their chainsaws;
to produce crease-resistant and flame-retardant fabrics. however, the average exposure in Sweden and Finland
These fabrics release formaldehyde into the air of the was <0.1 ppm (<0.12 mg/m3) (IARC, 1995).
plants, leading to average concentrations of 0.22 ppm
(0.242.4 mg/m3) in the late 1970s and 1980s. Measure-
ments from the 1980s indicate that levels are dropping
owing to the lower content of formaldehydes in fabrics 7. COMPARATIVE KINETICS AND
(IARC, 1995). METABOLISM IN LABORATORY ANIMALS
AND HUMANS
Formaldehyde-based resins are commonly used as
core binders in foundries. The mean levels of formalde-
hyde in core-making and post-core-making operations in Formaldehyde is formed endogenously during the
the 1980s in Sweden and Finland were usually below metabolism of amino acids and xenobiotics. In vivo, most
1 ppm (1.2 mg/m3). Formaldehyde-based plastics are formaldehyde is probably bound (reversibly) to
used in the production of electrical parts, dishware, and macromolecules.
various other products. The concentrations measured in
such industries have usually been below 1 ppm Owing to its reactivity with biological macromole-
(1.2 mg/m3), but much higher concentrations may occur, cules, most of the formaldehyde that is inhaled is depos-
especially in factories creating moulded plastic products ited and absorbed in regions of the upper respiratory
(IARC, 1995). The heating of bake-drying paints and tract with which the substance comes into first contact
soldering as well as the coating and development of (Heck et al., 1983; Swenberg et al., 1983; Patterson et al.,
photographic films can lead to the release of small 1986). In rodents, which are obligate nose breathers,
amounts of formaldehyde in the workplace, but levels are deposition and local absorption occur primarily in the
usually well below 1 ppm (1.2 mg/m3) (IARC, 1995). nasal passages; in oronasal breathers (such as monkeys
Formaldehyde can also be released or formed during the and humans), they likely occur primarily in the nasal
preservation of fur, leather, barley, and sugar beets and passages and oral mucosa, but also in the trachea and
during many other industrial operations. Some of these bronchus. Species-specific differences in the actual sites
19
of uptake of formaldehyde and associated lesions of the for 30 min) (IPCS, 1989). For rats and guinea-pigs, oral
upper respiratory tract are determined by complex inter- LD 50s of 800 and 260 mg/kg body weight have been
actions among nasal anatomy, ventilation, and breathing reported (IPCS, 1989). Acute exposure of animals to
patterns (e.g., nasal versus oronasal) (Monticello et al., elevated concentrations of inhaled formaldehyde (e.g.,
1991). >100 ppm [>120 mg/m3]) produces dyspnoea, vomiting,
hypersalivation, muscle spasms, and death (IPCS, 1989).
Formaldehyde produces intra- and intermolecular Alterations in mucociliary clearance and histopatholog-
crosslinks within proteins and nucleic acids upon ical changes within the nasal cavity have been observed
absorption at the site of contact (Swenberg et al., 1983). in rats exposed acutely to formaldehyde at concentra-
It is also rapidly metabolized to formate by a number of tions of $2.2 ppm ($2.6 mg/m3) (Monteiro-Riviere &
widely distributed cellular enzymes, the most important Popp, 1986; Morgan et al., 1986a; Bhalla et al., 1991).
of which is NAD+ -dependent formaldehyde dehydroge-
nase. Metabolism by formaldehyde dehydrogenase 8.2 Short- and medium-term exposure
occurs subsequent to formation of a formaldehyde
glutathione conjugate. Formaldehyde dehydrogenase 8.2.1 Inhalation
has been detected in human liver and red blood cells and
in a number of tissues (e.g., respiratory and olfactory Histopathological effects and an increase in cell
epithelium, kidney, and brain) in the rat. proliferation have been observed in the nasal and
respiratory tracts of laboratory animals repeatedly
Due to its deposition principally within the respira- exposed by inhalation to formaldehyde for up to 13
tory tract and rapid metabolism, exposure to concentra- weeks. Most short- and medium-term inhalation toxicity
tions of formaldehyde of 1.9 ppm (2.3 mg/m3), 14.4 ppm studies have been conducted in rats, with
(17.3 mg/m3), or 6 ppm (7.2 mg/m3) has not been shown histopathological effects (e.g., hyperplasia, squamous
to result in an increase in concentrations of metaplasia, inflammation, erosion, ulceration,
formaldehyde in blood in humans, rats, and monkeys, disarrangements) and sustained proliferative response in
respectively (Heck et al., 1985; Casanova et al., 1988). the nasal cavity at concentrations of 3.1 ppm (3.7 mg/m3)
and above. Effects were generally not observed at 1 or 2
In animal species, the half-life of formaldehyde ppm (1.2 or 2.4 mg/m3), although there have been
(administered intravenously) in the circulation ranges occasional reports of small, transient increases in
from approximately 1 to 1.5 min (Rietbrock, 1969; epithelial cell proliferation at lower concentrations
McMartin et al., 1979). Formaldehyde and formate are (Swenberg et al., 1983; Zwart et al., 1988). Owing to the
incorporated into the one-carbon pathways involved in reactivity of this substance as well as to differences in
the biosynthesis of proteins and nucleic acids. Owing to breathing patterns between rodents and primates,
the rapid metabolism of formaldehyde, much of this adverse effects following short-term inhalation exposure
material is eliminated in the expired air (as carbon of formaldehyde in rodents are generally restricted to the
dioxide) shortly after exposure. Excretion of formate in nasal cavity, while effects in primates may be observed
the urine is the other major route of elimination of deeper within the respiratory tract. The development of
formaldehyde (Johansson & Tjlve, 1978; Heck et al., histopathological changes and/or increases in epithelial
1983; Billings et al., 1984; Keefer et al., 1987; Upreti et al., cell proliferation within the nasal cavity of rats appear to
1987; Bhatt et al., 1988). be more closely related to the concentration of formalde-
hyde to which the animals are exposed than to the total
dose (i.e., cumulative exposure) (Swenberg et al., 1983,
1986; Wilmer et al., 1987, 1989).
8. EFFECTS ON LABORATORY
MAMMALS AND IN VITRO TEST SYSTEMS 8.2.2 Oral exposure
Data on toxicological effects arising from short-

term oral exposure are limited to one study in which
Information on non-neoplastic effects associated
histopathological effects in the forestomach were not
with the repeated inhalation or oral exposure of labora-
observed in Wistar rats receiving 25 mg/kg body weight
tory animals to formaldehyde is summarized in Tables 6
and 7, respectively. per day in drinking-water over a period of 4 weeks (Til et
al., 1988). Information on toxicological effects of the
Single exposure medium-term oral exposure of laboratory animals to
8.1
formaldehyde is limited to single studies in rats and
Reported LC50s in rodents for the inhalation of dogs, in which the target intakes may not have been
achieved (Johannsen et al., 1986). Reduction of weight
formaldehyde range from 414 ppm (497 mg/m3) (in mice
gain in both species was observed at 100 mg/kg body
exposed for 4 h) to 820 ppm (984 mg/m3) (in rats exposed
20
Table 6: Summary of non-neoplastic effect levels (inhalation) for formaldehyde in animals.
Effect levels (mg/m3)

Critical effect
Protocol NO(A)EL LO(A)EL [comments] Reference
Short-term toxicity
F344 rats and B6C3F1 mice exposed to 0, 0.5, 2, 6, or 15 ppm (0, 0.6, 2.4 (rats) 7.2 (rats) Increased cell proliferation in nasal cavity. In rats, a small Swenberg et al.,
2.4, 7.2, or 18 mg/m 3) formaldehyde for 6 h/day for 3 days. 7.2 (mice) 18 (mice) transient increase in cell proliferation was observed following 1983, 1986
exposure to 0.6 mg/m3 (and to a lesser extent to 2.4 mg/m3) after
1 day of exposure only. [number and sex of animals not specified]
Groups of six male F344 rats exposed to 0, 0.5, 2, 5.9, or 14.4 ppm (0, 2.4 7.1 Histopathological effects in nasal cavity. Inhibition of mucociliary Morgan et al., 1986b
0.6, 2.4, 7.1, or 17.3 mg/m 3) formaldehyde for 6 h/day, 5 days/week, clearance.
for 1, 2, 4, 9, or 14 days.
Groups of 10 male Wistar rats exposed to 0, 5, or 10 ppm (0, 6, or 12 6 Histopathological effects and increased cell proliferation in nasal Wilmer et al., 1987
mg/m 3) formaldehyde for 8 h/day (continuous exposure) or to 10 or 20 cavity. In animals with the same daily cumulative exposure to
ppm (12 or 24 mg/m 3) formaldehyde for eight 30-min exposure periods formaldehyde, the effects were greater in animals exposed
separated by 30-min intervals (intermittent exposure), 5 days/week for intermittently to the higher concentration.
4 weeks.
Groups of three male rhesus monkeys exposed to 0 or 6 ppm (0 or 7.2 7.2 Histopathological effects and increased cell proliferation in nasal Monticello et al.,
mg/m 3) formaldehyde for 6 h/day, 5 days/week, for either 1 or 6 weeks. cavity and upper portions of respiratory tract. [exposure to 1989
formaldehyde had no histopathological effect on the lungs or
other internal organs]
Groups of 10 male Wistar rats exposed to 0, 0.3, 1.1, or 3.1 ppm (0, 1.3 3.7 Histopathological effects and increased cell proliferation in nasal Reuzel et al., 1990
0.36, 1.3, or 3.7 mg/m 3) formaldehyde for 22 h/day for 3 consecutive cavity.
days.
Groups of 36 male F344 rats exposed to 0, 0.7, 2, 6.2, 9.9, or 14.8 2.4 7.4 Histopathological effects and increased cell proliferation in nasal Monticello et al.,
ppm (0, 0.84, 2.4, 7.4, 11.9, or 17.8 mg/m 3) formaldehyde for 6 h/day, cavity. [exposure to formaldehyde had no histopathological effect 1991
5 days/week, for 1, 4, or 9 days or 6 weeks. on the lungs, trachea, or carina]
Groups of 56 Wistar rats exposed to 0, 1, 3.2, or 6.4 ppm (0, 1.2, 3.8 1.2 3.8 Histopathological effects and increased cell proliferation in nasal Cassee et al., 1996
or 7.7 mg/m 3) formaldehyde, 6 h/day for 3 consecutive days. cavity.
Subchronic toxicity
Groups of 10 male and female Wistar rats exposed to 0, 1, 9.7, or 19.8 1.2 11.6 Histopathological effects in nasal cavity. [exposure of males to Woutersen et al., 1987
ppm (0, 1.2, 11.6, or 23.8 mg/m 3) formaldehyde for 6 h/day, 5 23.8 mg/m 3 produced non-significant increase in incidence of
days/week, for 13 weeks. histopathological effects in the larynx. The authors noted
minimal focal squamous metaplasia within the respiratory
epithelium in a small number (2/10 males, 1/10 females) of
animals exposed to 1.2 mg/m 3]
Groups of 10 male Wistar rats exposed to 0, 0.1, 1.0, or 9.4 ppm (0, 1.2 11.3 Histopathological effects in nasal cavity. [exposure to Appelman et al., 1988
0.12, 1.2, or 11.3 mg/m 3) formaldehyde for 6 h/day, 5 days/week, for formaldehyde had no effect upon hepatic protein or glutathione
13 weeks. levels]
Groups of 50 male and female Wistar rats exposed to 0, 0.3, 1, or 3 1.2 3.6 Histopathological effects and increased cell proliferation in nasal Zwart et al., 1988
ppm (0, 0.36, 1.2, or 3.6 mg/m 3) formaldehyde for 6 h/day, 5 cavity. [mostly qualitative description of histopathological
days/week, for 13 weeks. changes in the nasal cavity. Evidence presented of some
transiently increased cell proliferation at lower concentrations]
Groups of 25 male Wistar rats exposed to 0, 1, or 2 ppm (0, 1.2, or 2.4 2.4 4.8 Histopathological effects in nasal cavity. In animals with the same Wilmer et al., 1989
mg/m 3) formaldehyde for 8 h/day (continuous exposure) or to 2 or cumulative exposure to formaldehyde (i.e., 19.2 mg/m 3-h per
4 ppm (2.4 or 4.8 mg/m 3) formaldehyde in eight 30-min exposure day), the incidence of substance-related histopathological
periods separated by 30-min intervals (intermittent exposure), changes in the respiratory epithelium was increased in animals
5 days/week for 13 weeks. exposed intermittently to the higher concentration. [these
concentrations of formaldehyde had no significant effect upon
cell proliferation in the nasal cavity]
Table 6 (contd).
Effect levels (mg/m3)
Critical effect
Protocol NO(A)EL LO(A)EL [comments] Reference
Groups of 10 male F344 rats exposed to 0, 0.7, 2.0, 5.9, 10.5, or 14.5 2.4 7.1 Histopathological effects and increased cell proliferation in nasal Casanova et al., 1994
ppm (0, 0.84, 2.4, 7.1, 12.6, or 17.4 mg/m 3) formaldehyde for 6 h/day, cavity.
5 days/week, for 11 weeks and 4 days.
Chronic toxicity
Groups of cynomolgus monkeys (6 male), rats (20 male and female), 1.2 3.6 Monkeys and rats (histopathological effects in nasal cavity). Rusch et al., 1983
and hamsters (10 male and female) exposed to 0, 0.2, 1, or 3 ppm (0, Comparable effects observed in both species.
0.24, 1.2, or 3.6 mg/m 3) formaldehyde for 22 h/day, 7 days/week, for
26 weeks.
Groups of approximately 120 male and female F344 rats and B6C3F1 2.4 (mice) 2.4 (rats) Rats and mice (histopathological effects in nasal cavity). Swenberg et al.,
mice exposed to 0, 2.0, 5.6, or 14.3 ppm (0, 2.4, 6.7, or 17.2 mg/m 3) 1980; Kerns et al.,
formaldehyde for 6 h/day, 5 days/week, for up to 24 months, followed 1983
by an observation period of 6 months.
Groups of 10 male Wistar rats exposed to 0, 0.1, 1.0, or 9.4 ppm (0, 1.2 11.3 Histopathological effects in nasal cavity. Appelman et al., 1988
0.12, 1.2, or 11.3 mg/m 3) formaldehyde for 6 h/day, 5 days/week, for
52 weeks.
Groups of 30 male Wistar rats exposed to 0, 0.1, 1, or 9.8 ppm (0, 0.12, 1.2 11.8 Histopathological effects in nasal cavity. Woutersen et al., 1989
1.2, or 11.8 mg/m 3) formaldehyde for 6 h/day, 5 days/week, for 28
months.
Groups of 30 Wistar rats exposed to 0, 0.1, 1, or 9.2 ppm (0, 0.12, 1.2, 1.2 11.0 Histopathological effects in nasal cavity. [relatively short period of Woutersen et al., 1989
or 11.0 mg/m 3) formaldehyde for 6 h/day, 5 days/week, for 3 months exposure to formaldehyde]
and then observed for a further 25-month period.
Groups of approximately 90150 male F344 rats exposed to 0, 0.7, 2, 2.4 7.2 Histopathological effects and increased cell proliferation in nasal Monticello et al.,
6, 10, or 15 ppm (0, 0.84, 2.4, 7.2, 12, or 18 mg/m 3) formaldehyde for cavity. 1996
6 h/day, 5 days/week, for up to 24 months.
Groups of 32 male F344 rats exposed to 0, 0.3, 2.17, or 14.85 ppm (0, 0.36 2.6 Histopathological effects in nasal cavity. [incidence summed for Kamata et al., 1997
0.36, 2.6, or 17.8 mg/m 3) formaldehyde for 6 h/day, 5 days/week, for all animals examined during interim and terminal sacrifices]
up to 28 months.
Table 7: Summary of non-neoplastic effect levels (oral exposure) for formaldehyde in animals.
Effect levels (mg/kg body

weight per day)
Critical effect
Protocol NOEL LO(A)EL [comments] Reference
Short-term toxicity
Groups of 10 male and female Wistar rats administered drinking-water 25 125 Histopathological effects in the forestomach and increase in relative Til et al., 1988
containing amounts of formaldehyde estimated sufficient to provide target kidney weight. [exposure to formaldehyde had no effect upon the
intakes of 0, 5, 25, or 125 mg/kg body weight per day for 4 weeks. morphology of the liver or kidneys]
Subchronic toxicity
Groups of 15 male and female Sprague-Dawley rats administered drinking- 50 100 Reduction in weight gain. [exposure to formaldehyde had no effect Johannsen et al.,
water containing amounts of formaldehyde estimated sufficient to achieve on the blood or urine and produced no histopathological changes 1986
target doses of 0, 50, 100, or 150 mg/kg body weight per day for 13 weeks. in internal organs (including the gastrointestinal mucosa); limited
number of end-points examined; target intakes may not have been
achieved]
Groups of four male and female beagle dogs administered diets containing 75 100 Reduction in weight gain. [exposure to formaldehyde had no effect Johannsen et al.,
solutions of formaldehyde in amounts estimated sufficient to achieve target upon haematological or clinical parameters or organ 1986
doses of 0, 50, 75, or 100 mg/kg body weight per day for 90 days. histopathology (including the gastrointestinal mucosa); limited
number of end-points examined; target intakes may not have been
achieved]
Chronic toxicity
Groups of 70 male and female Wistar rats administered drinking-water 15 82 Histopathological effects in the forestomach and glandular Til et al., 1989
containing formaldehyde adjusted to achieve target intakes ranging from 0 stomach. Reduced weight gain. [exposure to formaldehyde had no
to 125 mg/kg body weight per day for up to 2 years. [The average effect upon haematological parameters]
concentration of formaldehyde in the drinking-water was 0, 20, 260, or 1900
mg/litre in the control, low-, mid-, and high-dose groups, respectively.]
Groups of 20 male and female Wistar rats administered drinking-water 10 300 Reduced weight gain, altered clinical chemistries, and Tobe et al., 1989
containing 0, 0.02%, 0.1%, or 0.5% (0, 200, 1000, or 5000 mg/litre) histopathological effects in the forestomach and glandular stomach.
formaldehyde for 24 months (for approximate intakes of 0, 10, 50, and 300 [small group sizes]
mg/kg body weight per day, respectively).
50
40
% Tumour 30
Response
20
10
0
0 0.4 0.8 2.4 2.6 6.7 7.2 12 14.8 17-18
[Formaldehyde] (mg/cu.m)
Monticello et al. (1996) Tobe et al. (1985) Sellakumar et al. (1985) Kerns et al. (1983) Kamata et al. (1997)
Figure 1: Formaldehyde carcinogenicity.
weight per day; no-observed-effect levels (NOELs) were tigations in which animals were injected with formal-
50 and 75 mg/kg body weight per day, respectively. dehyde (IPCS, 1989) add little additional weight to the
evidence for the carcinogenicity of formaldehyde in
8.3 Long-term exposure and animals.
carcinogenicity
8.3.2.1 Inhalation
8.3.1 Long-term exposure
The results of carcinogenesis bioassays by the
The principal non-neoplastic effects in animals inhalation route in rats in which there were increases in
exposed to formaldehyde by inhalation are histopatho- nasal tumour incidence are presented in Figure 1.
logical changes (e.g., squamous metaplasia, basal Exposureresponse in these investigations was similar
hyperplasia, rhinitis) within the nasal cavity and upper and highly non-linear, with sharp increases in tumour
respiratory tract. Most chronic inhalation toxicity studies incidence in the nasal cavity occurring only at concen-
have been conducted in rats, with the development of trations greater than 6 ppm (7.2 mg/m3) formaldehyde.
histopathological effects in the nasal cavity being The most extensive bioassay conducted to date in which
observed at concentrations of formaldehyde of 2 ppm proliferative responses in the epithelium of various
(2.4 mg/m3) and higher (Swenberg et al., 1980; Kerns et regions of the nasal cavity were investigated is that by
al., 1983; Rusch et al., 1983; Appelman et al., 1988; Monticello et al. (1996).
Woutersen et al., 1989; Monticello et al., 1996). The
principal non-neoplastic effect in animals exposed orally In a study in which groups of male and female F344
to formaldehyde is the development of histopathological rats were exposed to 0, 2.0, 5.6, or 14.3 ppm (0, 2.4, 6.7, or
changes within the forestomach and glandular stomach, 17.2 mg/m3) formaldehyde for 6 h/day, 5 days/week, for
with effects in rats at 82 mg/kg body weight per day and up to 24 months, followed by an observation period of 6
above (Til et al., 1989; Tobe et al., 1989). months, the incidence of squamous cell carcinoma in the
nasal cavity was markedly increased only in the high-
8.3.2 Carcinogenicity concentration groups compared with the unexposed
controls. The incidence of this tumour was 0/118, 0/118,
An increased incidence of tumours in the nasal 1/119 (1%), and 51/117 (44%) in males and 0/118, 0/118,
cavity was observed in five investigations in which rats 1/116 (1%), and 52/119 (44%) in females in the control,
were exposed via inhalation to concentrations of form- low-, mid-, and high-concentration groups, respectively
aldehyde greater than 6.0 ppm (7.2 mg/m3). Currently, (Kerns et al., 1983). Precise histopathological analysis
there is no definitive evidence indicating that formal- revealed that in animals exposed to the highest
dehyde is carcinogenic when administered orally to concentration of formaldehyde, more than half of the
laboratory animals. Chronic dermal toxicity studies nasal squamous tumours were located on the lateral side
(Krivanek et al., 1983; Iversen, 1988) and older inves- of the nasal turbinate and adjacent lateral wall at the
21
front of the nose (Morgan et al., 1986c). Two nasal hyde-induced nasal tumours, when animals with noses
carcinomas (in male and female rats) and two damaged by electrocoagulation were similarly exposed,
undifferentiated carcinomas or sarcomas (in male rats) the incidence of this tumour type was markedly
were also observed in animals from the high- increased in the high-concentration group (i.e., 1/54,
concentration groups. 1/58, 0/56, and 15/58 in animals exposed to 0, 0.1, 1, or 9.8
ppm [0, 0.12, 1.2, or 11.8 mg formaldehyde/m3],
In a follow-up study, Monticello et al. (1996) respectively) (Woutersen et al., 1989).
exposed male F344 rats to 0, 0.7, 2, 6, 10, or 15 ppm (0,
0.84, 2.4, 7.2, 12, or 18 mg/m3) formaldehyde for 6 h/day, 5 In other studies in rats, a small but not statistically
days/week, for up to 24 months. Epithelial cell prolif- significant increase in the incidence of tumours of the
eration at seven sites within the nasal cavity (e.g., anter- nasal cavity was observed in animals exposed daily to
ior lateral meatus, posterior lateral meatus, anterior mid- 20 ppm (24 mg/m3) formaldehyde for 13 weeks and then
septum, posterior mid-septum, anterior dorsal septum, observed until 130 weeks (Feron et al., 1988), but not in
medial maxilloturbinate, and maxillary sinus) was deter- animals exposed to 9.4 ppm (11.3 mg/m3) formaldehyde
mined after 3, 6, 12, and 18 months of exposure. The for 52 weeks (Appelman et al., 1988) or to 12.4 ppm (14.9
overall incidence of nasal squamous cell carcinoma in mg/m3) formaldehyde for 104 weeks (in either the
animals exposed to 0, 0.7, 2, 6, 10, or 15 ppm (0, 0.84, 2.4, presence or absence of wood dust at a concentration of
7.2, 12, or 18 mg/m3) formaldehyde was 0/90, 0/90, 0/90, 25 mg/m3) (Holmstrm et al., 1989a). The lack of observed
1/90 (1%), 20/90 (22%), and 69/147 (47%), respectively. statistically significant increases in tumour incidence in
Tumours were located primarily in the anterior lateral these investigations may be a function of small group
meatus, the posterior lateral meatus, and the mid-septum. sizes and/or short periods of exposure.
In a more limited study in which doseresponse In a study in which groups of male and female
was not examined, Sellakumar et al. (1985) exposed male B6C3F1 mice were exposed to 0, 2.0, 5.6, or 14.3 ppm (0,
Sprague-Dawley rats to 0 or 14.8 ppm (0 or 17.8 mg/m3) 2.4, 6.7, or 17.2 mg/m3) formaldehyde for 6 h/day,
formaldehyde for 6 h/day, 5 days/week, for 5 days/week, for up to 24 months, followed by an obser-
approximately 2 years. These authors reported a marked vation period of 6 months, there were no statistically
increase in the incidence of nasal squamous cell carci- significant increases in the incidence of nasal cavity
noma 0/99 and 38/100 in the control and formalde- tumours, compared with unexposed controls (Kerns et
hyde-exposed animals, respectively. These tumours were al., 1983). After 24 months exposure to formaldehyde,
considered to have arisen primarily from the naso- two male mice in the high-concentration group devel-
maxillary turbinates and nasal septum. An increase in the oped squamous cell carcinoma in the nasal cavity. The
incidence of nasal squamous cell carcinoma was also incidence of lung tumours was not increased in an early
reported in a study by Tobe et al. (1985), in which study in which groups of 4260 C3H mice (sex not speci-
groups of male F344 rats were exposed to formaldehyde fied) were exposed to formaldehyde at concentrations of
at 0, 0.3, 2, or 14 ppm (0, 0.36, 2.4, or 17 mg/m3) for 0, 42, 83, or 167 ppm (0, 50, 100, or 200 mg/m3) for three 1-
6 h/day, 5 days/week, for 28 months. Fourteen of 32 ani- h periods per week for 35 weeks, although, due to high
mals in the high-concentration group (i.e., 44%) devel- mortality, treatment in the high-dose group was
oped nasal squamous cell carcinoma, compared with discontinued in the 4th week, and there was no
none in the unexposed (control), low-, or mid-concen- evaluation of the nasal tissues (Horton et al., 1963).
tration groups. In another study in which male F344 rats Compared with 132 unexposed controls, there was no
were exposed to 0, 0.3, 2.2, or 14.8 ppm (0, 0.36, 2.6, or increase in the incidence of respiratory tract tumours in
17.8 mg/m3) formaldehyde for 6 h/day, 5 days/week, for 88 male Syrian hamsters exposed to 10 ppm (12 mg/m3)
up to 28 months, an increased incidence of nasal squa- formaldehyde for their entire lives (Dalbey, 1982).
mous cell carcinoma was observed in the high-concen-
tration group (Kamata et al., 1997); the overall incidence 8.3.2.2 Oral exposure
of nasal tumours among these formaldehyde-exposed
animals, dead or sacrificed after 12, 18, 24, and 28 months In the most comprehensive study identified in male
on study, was 13/32 (41%), compared with 0/32 and 0/32 and female Wistar rats administered drinking-water con-
in two groups of unexposed controls. taining formaldehyde in amounts estimated to achieve
target intakes ranging up to 125 mg/kg body weight per
Compared with unexposed controls, the incidence day for up to 2 years, there was no significant increase in
of nasal squamous cell carcinoma was not significantly tumour incidence compared with unexposed controls (Til
increased in male Wistar rats exposed to formaldehyde at et al., 1989). Tobe et al. (1989) also reported, although
concentrations of 0.1, 1, or 9.8 ppm (0.12, 1.2, or 11.8 data were not presented, that, compared with unexposed
mg/m3) for 6 h/day, 5 days/week, for 28 months (i.e., 0% controls, tumour incidence was not increased in small
and 4% of the controls and animals exposed to 9.8 ppm groups of male and female Wistar rats administered
[11.8 mg/m3], respectively, had nasal squamous cell car- drinking-water containing up to 5000 mg formaldehyde/
cinomas) (Woutersen et al., 1989). However, consistent litre (i.e., providing intakes up to 300 mg/kg body weight
with the hypothesized role of tissue damage in formalde- per day).
22
Formaldehyde
In contrast, increases in tumours of the haemato- statistically significant (i.e., P < 0.05) increase in the
poietic system were reported by Soffritti et al. (1989), proportion of pulmonary macrophage with chromosomal
based upon the results of a study in which Sprague- aberrations compared with controls (approximately 7%
Dawley rats were administered drinking-water containing and 4%, respectively) (Dallas et al., 1992). However,
formaldehyde at concentrations ranging from 0 to Kitaeva et al. (1990) observed a statistically significant
1500 mg/litre for 104 weeks and the animals observed increase in the proportion of bone marrow cells with
until death (estimated intakes up to approximately chromosomal aberrations (chromatid or chromosome
200 mg/kg body weight per day). The proportion of breaks) from female Wistar rats exposed to low concen-
males and females with leukaemias (all haemolympho- trations of formaldehyde for 4 h/day for 4 months
reticular neoplasias, e.g., lymphoblastic leukaemias and approximately 0.7%, 2.4%, and 4% in animals exposed to
lymphosarcomas, immunoblastic lymphosarcomas, and 0, 0.42, or 1.3 ppm (0, 0.5, or 1.5 mg/m3), respectively. In
other leukaemias) increased from 4% and 3%, respec- older studies, exposure of male and female F344 rats to
tively, in the controls to 22% and 14%, respectively, in approximately 0.5, 5.9, or 14.8 ppm (0.6, 7.1, or 17.8
the animals receiving drinking-water containing 1500 mg mg/m3) formaldehyde for 6 h/day for 5 consecutive days
formaldehyde/litre. Compared with unexposed controls, had no effect upon the frequency of sister chromatid
there was no dose-related increase in the incidence of exchange or chromosomal aberrations and mitotic index
stomach tumours in animals receiving formaldehyde. in blood lymphocytes (Kligerman et al., 1984).
Limitations of this study include the pooling of tumour Statistically significant (P < 0.05) increases in the
types, the lack of statistical analysis, and limited exam- proportion of cells with micronuclei and nuclear anoma-
ination of non-neoplastic end-points. Parenthetically, it lies (e.g., karyorrhexis, pyknosis, vacuolated bodies)
should be noted that the incidence of haematopoietic were observed in the stomach, duodenum, ileum, and
tumours (e.g., myeloid leukaemia, generalized histiocytic colon within 30 h of administration (by gavage) of
sarcoma) was not increased in Wistar rats receiving up 200 mg formaldehyde/kg body weight to male Sprague-
to 109 mg formaldehyde/kg body weight per day in Dawley rats (Migliore et al., 1989). No significant evi-
drinking-water for up to 2 years (Til et al., 1989). dence of genotoxicity (e.g., micronuclei, chromosomal
aberrations) in bone marrow cells, splenic cells, or
8.4 Genotoxicity and related end-points spermatocytes was reported in earlier studies in which
various strains of mice were injected intraperitoneally
A wide variety of end-points have been assessed with formaldehyde (Fontignie-Houbrechts, 1981; Gocke
in in vitro assays of the genotoxicity of formaldehyde et al., 1981; Natarajan et al., 1983).
(see IARC, 1995, for a review). Generally, the results of
these studies have indicated that formaldehyde is The mutational profile for formaldehyde varies
genotoxic in both bacterial and mammalian cells in vitro among cell types and concentration of formaldehyde to
(inducing both point and large-scale mutations) (IARC, which the cells were exposed in vitro and includes both
1995). Formaldehyde induces mutations in Salmonella point and large-scale changes. In human lymphoblasts,
typhimurium and in Escherichia coli, with positive about half of the mutants at the X-linked hprt locus had
results obtained in the presence or absence of metabolic deletions of some or all of the hprt gene bands; the other
activation systems. Formaldehyde increases the fre- half were assumed to have point mutations (Crosby et
quency of chromatid/chromosome aberrations, sister al., 1988). In a subsequent study, six of seven
chromatid exchange, and gene mutations in a variety of formaldehyde-induced mutants with normal restriction
rodent and human cell types. Exposure to formaldehyde fragment patterns had point mutations at AT sites, with
increased DNA damage (strand breaks) in human fibro- four of these six occurring at one specific site (Liber et
blasts and rat tracheal epithelial cells and increased al., 1989). Crosby et al. (1988) also examined the
unscheduled DNA synthesis in rat nasoturbinate and mutational spectra induced by formaldehyde at the gpt
maxilloturbinate cells. gene in E. coli (Crosby et al., 1988). A 1-h exposure to 4
mmol formaldehyde/litre induced a spectrum of mutants
As most formaldehyde is deposited and absorbed that included large insertions (41%), large deletions
in regions with which it first comes into contact, geno- (18%), and point mutations (41%), the majority of which
toxic effects at distal sites following inhalation or inges- were transversions occurring at GC base pairs.
tion might not be expected. Exposure of male Sprague- Increasing the concentration of formaldehyde to 40
Dawley rats to 0.5, 3, or 15 ppm (0.6, 3.6, or 18 mg/m3) mmol/litre resulted in a much more homogeneous
formaldehyde for 6 h/day, 5 days/week, for 1 or 8 weeks spectrum, with 92% of the mutants being produced by a
had no effect upon the proportion of bone marrow cells point mutation, 62% of which were transitions at a single
with cytogenetic anomalies (e.g., chromatid or chromo- AT base pair. In contrast to these findings, when naked
some breaks, centric fusions) compared with unexposed plasmid DNA containing the gpt gene was treated with
controls, although animals in the group exposed to the formaldehyde and shuttled through E. coli, most of the
highest concentration had a modest (1.7- to 1.8-fold), mutations were found to be frameshifts.
23
Results of studies in laboratory animals have indi-

8.5 Reproductive toxicity cated that formaldehyde may enhance their sensitization
to inhaled allergens. In female BALB/c mice sensitized to
Other than a significant (P < 0.01) weight loss in ovalbumin, the serum titre of IgE anti-ovalbumin anti-
the dams and a 21% reduction in the mean weight of the bodies was increased approximately 3-fold in animals
fetuses from dams in the highest concentration group, pre-exposed to 2.0 mg formaldehyde/m3 for 6 h/day on 10
the exposure of pregnant Sprague-Dawley rats to 0, 5.2, consecutive days (Tarkowski & Gorski, 1995). Similarly,
9.9, 20, or 39 ppm (0, 6.2, 11.9, 24.0, or 46.8 mg/m3) formal- exposure of female Dunkin-Hartley guinea-pigs,
dehyde for 6 h/day from days 6 though 20 of gestation sensitized to airborne ovalbumin, to 0.3 mg
had no effect upon the mean number of live fetuses, formaldehyde/m3 produced a significant (P < 0.01) 3-fold
resorptions, and implantation sites or fetal losses per increase in bronchial sensitization, as well as a signi-
litter; although the occurrence of missing sternebra and ficant (P < 0.05) 1.3-fold increase in serum anti-
delayed ossification of the thoracic vertebra were ovalbumin antibodies (Riedel et al., 1996).
increased in fetuses from the highest exposure group,
the increases were neither statistically significant (i.e., P 8.7 Mode of action
> 0.05) nor concentration dependent (Saillenfait et al.,
1989). The mechanisms by which formaldehyde induces
tumours in the respiratory tract of rats are not fully
Similarly, although weight gain was significantly (P understood. Inhibition of mucociliary clearance is
< 0.05) reduced in dams exposed to the highest observed in rats exposed acutely to concentrations of
concentration, exposure of pregnant Sprague-Dawley formaldehyde greater than 2 ppm (2.4 mg/m3) (Morgan et
rats to approximately 2, 5, or 10 ppm (2.4, 6, or 12 mg/m3) al., 1986a). There is also evidence that glutathione-
formaldehyde for 6 h/day on days 6 through 15 of mediated detoxification of formaldehyde within nasal
gestation had no substance-related effect upon the tissues becomes saturated in rats at inhalation exposures
number of fetuses with major malformations or skeletal above 4 ppm (4.8 mg/m3) (Casanova & Heck, 1987). This
anomalies; reduced ossification of the pubic and ischial correlates with the non-linear increase in DNAprotein
bones in fetuses from dams exposed to the two highest crosslink formation at exposures above this level.
concentrations of formaldehyde was attributed to larger
litter sizes and small fetal weights. Indices of embryo- A sustained increase in nasal epithelial cell regen-
toxicity (e.g., number of corpora lutea, implantation sites, erative proliferation resulting from cytotoxicity and
live fetuses, resorptions, etc.) were not affected by mutation, for which DNAprotein crosslinks serve as
exposure to formaldehyde (Martin, 1990). markers of potential, have been identified as likely,
although not sufficient, factors contributing to the
8.6 Immunological effects and induction of nasal tumours in rats induced by formalde-
sensitization hyde. This hypothesis is based primarily on observation
of consistent, non-linear doseresponse relationships
Other than a significant (P < 0.05) 9% increase in for all three end-points (DNAprotein crosslinking, sus-
bacterial pulmonary survival in one study of mice tained increases in proliferation, and tumours) and con-
exposed to 15 ppm (18 mg/m3) (Jakab, 1992), as well as a cordance of incidence of these effects across regions of
statistically significant (P # 0.05 or 0.01) reduction in the nasal passages (Table 8).
serum IgM titres in animals orally administered 40 or
80 mg/kg body weight per day, 5 days/week, for 4 weeks Increased cellular proliferation as a consequence
(Vargov et al., 1993), adverse effects on either cell- or of epithelial cell toxicity is the most significant
humoral-mediated immune responses have generally not determinant of neoplastic progression. The effect of
been observed in rats or mice exposed to formaldehyde formaldehyde exposure on cell proliferation within the
(Dean et al., 1984; Adams et al., 1987; Holmstrm et al., respiratory epithelium of rats has been examined in a
1989b). End-points examined in these studies (Dean et number of short-, medium-, and long-term studies
al., 1984; Adams et al., 1987; Holmstrm et al., 1989b) (Swenberg et al., 1983; Wilmer et al., 1987, 1989; Zwart et
included splenic or thymic weights, bone marrow cellu- al., 1988; Reuzel et al., 1990; Monticello et al., 1991, 1996;
larity, the proportion of splenic B- and T-cells, NK-cell Casanova et al., 1994). A sustained increase in prolifera-
activity, lymphocyte proliferation, the number, function, tion of nasal epithelial cells has not been observed
or maturation of peritoneal macrophages, host resistance following the exposure of rats to concentrations of
to bacterial or tumour challenge, and B-cell function formaldehyde of #2 ppm (#2.4 mg/m3) irrespective of the
through induction of (IgG and IgM) antibodies, with exposure period. In rats exposed to formaldehyde,
exposures ranging from 1 to 15 ppm (1.2 to 18 mg/m3) increased respiratory epithelial cell proliferation in the
formaldehyde. nasal cavity was more closely related to the concentra-
tion to which the animals were exposed than to the total
cumulative dose (Swenberg et al., 1983). The relative
24
Table 8: Comparative effects of formaldehyde exposure upon cell proliferation, DNAprotein crosslinking, and tumour incidence.
DNAprotein crosslink formation

Cell proliferation ([3H]thymidine-labelled (pmol [14C]formaldehyde bound/mg
cells/mm basement membrane)a DNA)b Incidence of nasal carcinomac
Formaldehyde Anterior Posterior
concentration, lateral lateral Anterior high tumour low tumour Anterior Posterior Anterior mid-
mg/m3 (ppm) meatus meatus mid-septum region region All sites lateral meatus lateral meatus septum
0 (0) 10.11 7.69 6.58 0 0 0/90 0/90 0/90 0/90
0.84 (0.7) 10.53 7.82 8.04 5 5 0/90 0/90 0/90 0/90
2.4 (2) 9.83 11.24 12.74 8 8 0/96 0/96 0/96 0/96
7.2 (6) 15.68 9.96 4.15 30 10 1/90 1/90 0/90 0/90
12 (10) 76.79 15.29 30.01 20/90 12/90 2/90 0/90
18 (15) 93.22 59.52 75.71 150 60 69/147 17/147 9/147 8/147
a Cell proliferation measured in three locations of the nasal epithelium in male F344 rats exposed to the indicated concentrations of formaldehyde, 6 h/day, 5 days/week, for 3 months (Monticello et al.,
1996).
b Extent of DNAprotein crosslink formation measured in two regions of the nasal cavity (respiratory mucosa) in male F344 rats exposed to the indicated concentrations of formaldehyde, 6 h/day, 5 days/week,
for about 12 weeks; the complete lateral meatus was designated the high tumour region; the low tumour region comprised the medial aspects of naso- and maxilloturbinates, posterior lateral wall,
posterior dorsal septum excluding olfactory region, and nasopharyngeal meatuses (Casanova et al., 1994). Data were derived from graphical representations in the reference cited.
c Incidence of nasal tumours within the entire nasal cavity or the anterior lateral meatus, posterior lateral meatus, or anterior mid-septum in male F344 rats exposed to the indicated concentrations of
formaldehyde, 6 h/day, 5 days/week, for 24 months (Monticello et al., 1996).
Formaldehyde
magnitude of increase in proliferative response is

dependent upon the specific site within the nasal cavity 9. EFFECTS ON HUMANS
and not always directly related to the length of exposure
(Swenberg et al., 1986; Monticello et al., 1991, 1996;
Monticello & Morgan, 1994). The extent of the carcino- 9.1 Case reports and clinical studies
genic response following exposure to formaldehyde is
also dependent upon the size of the target cell Reports of death following acute inhalation expo-
population within specific regions of the nasal cavity sure to formaldehyde were not identified. Ulceration and
(Monticello et al., 1996). damage along the aerodigestive tract, including oral and
gastrointestinal mucosa, have been observed in cases
It is the interaction with the genome at the site of where formaldehyde had been ingested (Kochhar et al.,
first contact, however, that is of greatest interest with 1986; Nishi et al., 1988; IPCS, 1989). There are frequent
respect to the carcinogenicity of formaldehyde (i.e., in reports on cases of systemic (e.g., anaphylaxis) or more
the induction of nasal tumours in rats). Formaldehyde- often localized (e.g., contact dermatitis) allergic reactions
induced DNAprotein crosslinking has been observed attributed to the formaldehyde (or formaldehyde-
in the nasal epithelium of rats (Casanova & Heck, 1987; containing resins) present in household and personal
Heck & Casanova, 1987; Casanova et al., 1989, 1994), as care (and dental) products, clothing and textiles, bank
well as in epithelia lining the respiratory tract of monkeys note paper, and medical treatments and devices (Maurice
(Casanova et al., 1991) exposed via inhalation. et al., 1986; Feinman, 1988; Ebner & Kraft, 1991; Norton,
DNAprotein crosslinks are considered a marker of 1991; Flyvholm & Menn, 1992; Fowler et al., 1992; Ross
mutagenic potential, since they may initiate DNA repli- et al., 1992; Vincenzi et al., 1992; Bracamonte et al., 1995;
cation errors, resulting in mutation. The exposure El Sayed et al., 1995; Wantke et al., 1995).
response relationship is highly non-linear, with a sharp
increase in DNAprotein crosslinking at concentrations In a number of clinical studies, generally mild to
above 4 ppm (4.8 mg/m3) formaldehyde (see also Table 8) moderate sensory eye, nose, and throat irritation was
without accumulation on repeated exposure (Casanova experienced by volunteers exposed for short periods to
et al., 1994). Formaldehyde has also induced the levels of formaldehyde ranging from 0.25 to 3.0 ppm (0.30
formation of DNAprotein crosslinks in a variety of to 3.6 mg/m3) (Andersen & Mlhave, 1983; Sauder et al.,
human and rat cell types (Saladino et al., 1985; Bermudez 1986, 1987; Schachter et al., 1986; Green et al., 1987, 1989;
& Delehanty, 1986; Snyder & van Houten, 1986; Craft et Witek et al., 1987; Kulle, 1993; Pazdrak et al., 1993).
al., 1987; Heck & Casanova, 1987; Cosma et al., 1988; Mucociliary clearance in the anterior portion of the nasal
Olin et al., 1996). In 5 of 11 squamous cell carcinomas cavity was reduced following exposure of volunteers to
from rats exposed to 15 ppm (18 mg/m3) for up to 2 years, 0.25 ppm (0.30 mg/m3) formaldehyde (Andersen &
there were point mutations at the GC base pairs in the Mlhave, 1983). Based upon the results of experimental
p53 cDNA sequence (Recio et al., 1992). studies, it appears that in healthy individuals as well as
those with asthma, brief exposure (up to 3 h) to
Although direct evidence in humans is lacking, concentrations of formaldehyde up to 3.0 ppm (3.6
increased epithelial cell proliferation (respiratory and mg/m3) had no significant clinically detrimental effect
olfactory epithelia) and DNAprotein crosslink forma- upon lung function (Day et al., 1984; Sauder et al., 1986,
tion (middle turbinates, lateral wall and septum, and 1987; Schachter et al., 1986, 1987; Green et al., 1987;
nasopharynx) within the upper respiratory tract have Witek et al., 1987; Harving et al., 1990).
been observed in monkeys exposed to formaldehyde by
inhalation (Monticello et al., 1989; Casanova et al., 1991). 9.2 Epidemiological studies
At similar levels of exposure, concentrations of
DNAprotein crosslinks were approximately an order of 9.2.1 Cancer
magnitude less in monkeys than in rats. In rats, the
cumulative yield of DNAprotein crosslinks was similar Possible associations between formaldehyde and
after short- and medium-term exposure, suggesting rapid cancers of various organs have been examined exten-
repair (Casanova et al., 1994). Using a model system in sively in epidemiological studies in occupationally
which rat trachea populated with human tracheobron- exposed populations. Indeed, there have been over
chial epithelial cells were xenotransplanted into athymic 30 cohort and casecontrol studies of professionals,
mice, Ura et al. (1989) reported increased human epithe- including pathologists and embalmers, and industrial
lial cell proliferation following in situ exposure to workers. In addition, several authors have conducted
formaldehyde. meta-analyses of the available data.
25
Relevant risk measures from recent casecontrol tionally exposed to formaldehyde, although it should be
and cohort studies are presented in Tables 9 and 10, noted that the total number of cases of this rare cancer in
respectively. all of the studies was small (approximately 15 cases in all
studies in Table 10, with some overlap). Risks were not
In most epidemiological studies, the potential increased in smaller studies of anatomists or mortuary
association between exposure to formaldehyde and workers (Hayes et al., 1990) or in an investigation of
cancer of the respiratory tract has been examined. proportionate incidence in industrial workers (Hansen &
However, in some casecontrol and cohort studies, Olsen, 1995); in the latter study, however, the standard-
increased risks of various non-respiratory tract cancers ized proportionate incidence ratio for cancers of the
(e.g., multiple myeloma, non-Hodgkins lymphoma, nasal cavity was significantly increased (3-fold) in
ocular melanoma, brain, connective tissue, pancreatic, more exposed workers. In a cohort of 11 000 garment
leukaemic, lymphoid and haematopoietic, colon) have workers, the number of deaths due to cancer of the nasal
occasionally been observed. However, such increases cavity was considered too small to evaluate (Stayner et
have been reported only sporadically, with little con- al., 1988). In a cohort of 14 000 workers employed in six
sistent pattern. Moreover, results of toxicokinetic and chemical and plastic factories in the United Kingdom for
metabolic studies in laboratory animals and humans which 35% of the cohort was exposed to >2 ppm
indicate that most inhaled formaldehyde is deposited (>2.4 mg/m3), only one nasal cancer was observed
within the upper respiratory tract. Available evidence for versus 1.7 expected (Gardner et al., 1993). The results of
these tumours at sites other than the respiratory tract the largest industrial cohort mortality study of
does not, therefore, fulfil traditional criteria of causality 26 561 workers first employed before 1966 at 10 plants in
(e.g., consistency, biological plausibility) for associa- the USA (4% of cohort exposed to $2 ppm [$2.4 mg/m3])
tions observed in epidemiological studies, and the indicated an approximately 3-fold excess of deaths due
remainder of this section addresses the tumours for to nasopharyngeal cancer associated with occupational
which the weight of evidence is greatest initially exposure to formaldehyde (Blair et al., 1986). However,
nasal and, subsequently, lung. subsequent analyses revealed that five of the seven
observed deaths were among individuals who had also
In casecontrol studies (see Table 9), while some- been exposed to particulates; four of the seven observed
times no increase was observed overall (Vaughan et al., deaths occurred at one specific industrial plant (Blair et
1986a), significantly increased risks of nasopharyngeal al., 1987; Collins et al., 1988; Marsh et al., 1996). Three of
cancer (up to 5.5-fold) were observed among workers the seven observed deaths due to nasopharyngeal
with 1025 years of exposure or in the highest exposure cancer occurred in individuals with less than 1 year of
category in three out of four investigations (Vaughan et employment (Collins et al., 1988), and the four deaths at
al., 1986a; Roush et al., 1987; West et al., 1993), although one specific plant occurred equally in both short-term
there were limitations associated with most of these and long-term workers (Marsh et al., 1996).
studies, as noted in Table 9. There was no increase in
nasopharyngeal cancers in an additional investigation In most casecontrol studies, there have been no
that is also considered to be limited (Olsen & Asnaes, increases in lung cancer (Bond et al., 1986; Grin et al.,
1986). In three studies in which the association between 1989; Brownson et al., 1993; Andjelkovich et al., 1994). In
formaldehyde and nasal squamous cell carcinomas was the single study where exposureresponse was exam-
examined, there were non-significant increases in two ined, there was no significant increase in adenocarci-
(Olsen & Asnaes, 1986; Hayes et al., 1990) and no noma of the lung for those with longhigh occupa-
increase in another (Luce et al., 1993), although there tional exposure; although the odds ratio was greater
were limitations (as noted in Table 9) associated with all than for lung cancer, the number of cases on which
of these investigations. In the only investigation in this observation was based was small (Grin et al., 1989).
which the association between exposure to There was no association of relative risks (RR) with
formaldehyde and adenocarcinoma of the nasal cavity latency period (Andjelkovich et al., 1994). In the most
was examined, there was a non-significant increase that extensive investigation of exposureresponse, there
was exacerbated in the presence of wood dust (Luce et were no increases in lung cancer in workers subdivided
al., 1993), although possible residual confounding by by latency period, although there was a non-significant
wood dust exposure could not be excluded. increase for those co-exposed to wood dust. There was
no statistically significant increased risk for all respira-
There is little convincing evidence of increased tory cancer by level, duration, cumulative exposure,
risks of nasopharyngeal cancer in cohort studies of pop- duration of repeated exposures to peak levels, or dura
ulations of professionals or industrial workers occupa-
26
Formaldehyde
Table 9: Summary of risk measures from casecontrol studies.
Cancer/ Risk measure

Study population Formaldehyde exposure (95% CI) Reference (comments)
Oropharynx or $10 years occupational exposure OR = 1.3 (0.72.5) Vaughan et al., 1986a
hypopharynx occupational exposure score b of $20 OR = 1.5 (0.73.0) (IARC Working Group noted that different
SEERa population based proportions of interviews conducted with
Washington State next-of-kin cases and controls may have
affected odds ratios)
Nasopharynx exposure score b of $20 OR = 2.1 (0.67.8) Vaughan et al., 1986a

SEER population based (IARC Working Group noted that different
Washington State, USA proportions of interviews conducted with
next-of-kin cases and controls may have
affected odds ratios)
Nasopharynx residential exposure of $10 years OR = 5.5 (1.619.4) Vaughan et al., 1986b
SEER population based residential exposure of <10 years OR = 2.1 (0.76.6) (IARC Working Group considered living in
Washington State, USA a mobile home a poor proxy for exposure)
Nasal squamous cell any occupational exposure; OR = 3.0 (1.36.4)c Hayes et al., 1986
carcinoma assessment A (IARC Working Group noted that a greater
Hospital based any occupational exposure; OR = 1.9 (1.03.6)c proportion of cases than controls were
Netherlands assessment B dead and variable numbers of next-of-kin
were interviewed, 10% of controls but
none of cases, by telephone; noted also
that, although different, results for
exposure assessments A & Bd were both
positive)
Squamous cell carcinoma occupational exposure without OR = 2.0 (0.75.9) Olsen & Asnaes, 1986
of nasal cavity/paranasal exposure to wood dust (IARC Working Group noted possibly
sinus incomplete adjustment for confounding
Danish Cancer Registry for wood dust for adenocarcinoma; felt
that squamous cell carcinoma less likely
to be affected, since no clear association
with wood dust)
(Small number of cases)
Nasopharynx highest potential exposure category OR = 2.3 (0.96.0) Roush et al., 1987
Connecticut Tumour highest potential exposure category OR = 4.0 (1.312)
Registry, USA and dying at 68+ years of age
Oral/oropharynx any occupational exposure OR = 1.6 (0.92.8) Merletti et al., 1991

Population based Turin, probable or definite occupational OR = 1.8 (0.65.5)
Italy exposure
Larynx high occupational exposure OR = 2.0 (0.219.5) Wortley et al., 1992

SEER population based occupational exposure of $10 years OR = 1.3 (0.63.1)
Washington State, USA occupational exposure score b of $20 OR = 1.3 (0.53.3)
Nasal cavity/paranasal males with possible exposure to OR = 0.96 (0.382.42) Luce et al., 1993
sinus (squamous cell formaldehyde (IARC Working Group noted possible
carcinoma) males with duration of exposure: residual confounding by exposure to wood
Population based #20 years OR = 1.09 (0.482.50) dust)
France >20 years OR = 0.76 (0.292.01)
Nasopharynx <15 years of exposure OR = 2.7 (1.16.6) West et al., 1993

Hospital based >25 years since first exposure OR = 2.9 (1.17.6) (IARC Working Group noted no control for
Philippines <25 years of age at first exposure OR = 2.7 (1.16.6) the presence of Epstein-Barr viral
antibodies, for which previous strong
association with nasopharyngeal cancer
was observed)
Lung likely occupational exposure OR = 0.62 (0.291.36) Bond et al., 1986

Nested cohort of
chemical workers Texas,
USA
Lung longhigh occupational exposure Grin et al., 1989

Population based (cancer controls/ OR = 1.5 (0.82.8)/
Montreal, Quebec, population controls) OR = 1.0 (0.42.4)
Canada
27
Table 9 (contd).
Cancer/ Risk measure

Study population Formaldehyde exposure (95% CI) Reference (comments)
Lung (adenocarcinoma) longhigh occupational exposure Grin et al., 1989
Population based (cancer controls/ OR = 2.3 (0.96.0)/
Montreal, Quebec, population controls) OR = 2.2 (0.77.6)
Canada
Respiratory cancer cumulative exposure of $3.6 mg/m 3- OR = 0.69 (0.212.24)c Partanen et al., 1990
Nested cohort of Finnish months, without minimum 10-year (IARC Working Group noted that there
woodworkers induction period were too few cancers at sites other than
cumulative exposure of $3.6 mg/m 3- OR = 0.89 (0.263.0)c the lung for meaningful analysis)
months, with minimum 10-year
induction period
exposure to formaldehyde in wood OR = 1.19 (0.314.56)c
dust
Lung potentially exposed non-smokers OR = 0.9 (0.23.3) Brownson et al., 1993

Population based
Missouri, USA
Lung occupational exposure with latency Andjelkovich et al., 1994

Nested cohort of US period of:
automotive foundry 0 years OR = 1.31 (0.931.85)
workers 10 years OR = 1.04 (0.711.52)
15 years OR = 0.98 (0.651.47)
20 years OR = 0.99 (0.601.62)
Multiple myeloma probably exposed OR = 1.8 (0.65.7) Boffetta et al., 1989

Incident cases in follow-
up of cancer prevention
study in USA
Multiple myeloma males with probable occupational OR = 1.1 (0.71.6) Heineman et al., 1992; Pottern et al.,
Danish Cancer Registry exposure 1992
females with probable occupational OR = 1.6 (0.45.3)
exposure
Non-Hodgkins lymphoma potential lower intensity of exposure OR = 1.2 (0.91.7) Blair et al., 1993
Iowa State Health potential higher intensity of exposure OR = 1.3 (0.53.8)
Registry, USA
Ocular melanoma ever exposed to formaldehyde OR = 2.9 (1.27.0) Holly et al., 1996
Cases diagnosed or
treated at University of
California at San
Francisco Ocular
Oncology Unit, USA
a SEER = Surveillance, Epidemiology and End Results programme of the US National Cancer Institute.
b Weighted sum of number of years spent in each job, with weighting identical to estimated formaldehyde exposure level for each job.
c Data in parentheses represent 90% confidence interval.
d Two independent evaluations of exposure to formaldehyde, designated assessments A and B.
tion of exposure to dust-borne formaldehyde, except in (Stayner et al., 1988). In a cohort of 14 000 workers
one category (Partanen et al., 1990). employed at six chemical and plastic factories in the
United Kingdom for which 35% of the cohort was exposed
In smaller cohort studies of professional and indus- to >2 ppm (>2.4 mg/m3), there was a non-significant excess
trial workers (Table 10), there have been no significant (comparison with local rates) of lung cancers in workers
excesses of cancers of the trachea, bronchus, or lung first employed prior to 1965. Among groups employed at
(Hayes et al., 1990; Andjelkovich et al., 1995), the buccal individual plants, the standardized mortality ratio for lung
mucosa or pharynx (Matanoski, 1989; Hayes et al., 1990; cancer was significantly increased only in the highly
Andjelkovich et al., 1995), the lung (Stroup et al., 1986; exposed subgroup at one plant. However, there was no
Bertazzi et al., 1989; Hansen & Olsen, 1995), or the significant relationship with years of employment or
respiratory system (Matanoski, 1989). In a cohort of 11 000 cumulative exposure (Gardner et al., 1993). There was no
garment workers, there was no increase in cancers of the
trachea, bronchus, lung, buccal mucosa, or pharynx
28
Formaldehyde
Table 10: Summary of risk measures from cohort studies.
Cohort exposed Cancer Risk measurea Reference (comments)
Male anatomists Brain SMR = 270 (130500): 10 Stroup et al., 1986

Leukaemia SMR = 150 (70270): 10 (Likely exposure to other
Other lymphatic tissues SMR = 200 (70440): 6 substances; no
Nasal cavity and sinus SMR = 0 (0720): 0 quantitative data on
Larynx SMR = 30 (0200): 1 exposure)
Lung SMR = 30 (150): 12
Male abrasives production workers Multiple myeloma SIR = 4 (0.514): 2 Edling et al., 1987
Lymphoma SIR = 2 (0.27.2): 2 (Increases based on only
Pancreas SIR = 1.8 (0.26.6): 2 two cases each)
Lung SIR = 0.57 (0.12.1): 2
Garment manufacturing workers Buccal cavity SMR = 343 (118786)b: 4 Stayner et al., 1988
Connective tissue SMR = 364 (123825)b: 4
Trachea, bronchus, and lung SMR = 114 (86149)b: 39
Pharynx SMR = 111 (20359)b: 2
Resin manufacturing workers Alimentary tract SMR = 134 (P > 0.05): 11 Bertazzi et al., 1989
Stomach SMR = 164 (P > 0.05): 5 (Small cohort exposed
Liver SMR = 244 (P > 0.05): 2 primarily to low
Lung SMR = 69: 6 concentrations; few
deaths)
Male pathologists Buccal cavity and pharynx SMR = 52 (2889): 13 Matanoski, 1989
Respiratory system SMR = 56 (4477): 77
Hypopharynx SMR = 470 (971340): 3
Pancreas SMR = 140 (104188): 47
Leukaemia SMR = 168 (114238): 31
Male mortuary workers Buccal cavity and pharynx PMR = 120 (81171): 30 Hayes et al., 1990
Nasopharynx PMR = 216 (59554): 4
Lymphatic and haematopoietic PMR = 139 (115167):
Colon 115
Trachea, bronchus, and lung PMR = 127 (104153):
111
PMR = 94.9: 308
Male chemical workers employed before Lung SMR = 123 (110136): Gardner et al., 1993
1965 Buccal cavity 348 (35% of cohort exposed to
Pharynx SMR = 137 (28141): 3 >2 ppm [>2.4 mg/m 3])
SMR = 147 (59303): 7
Workers exposed to >2 ppm (>2.4 mg/m3) at Lung SMR = 126 (107147): Gardner et al., 1993
one specific plant 165
Male industrial workers Nasal cavity SPIR = 2.3 (1.34.0): 13 Hansen & Olsen, 1995
Nasopharynx SPIR = 1.3 (0.33.2): 4
Lung SPIR = 1.0 (0.91.1): 410
Larynx SPIR = 0.9 (0.61.2): 32
Oral cavity and pharynx SPIR = 1.1 (0.71.7): 23
Male industrial workers exposed above Nasal cavity SPIR = 3.0 (1.45.7): 9 Hansen & Olsen, 1995
baseline levels
Male automotive foundry workers Buccal cavity and pharynx SMR = 131 (48266): 6 Andjelkovich et al., 1995
Trachea, bronchus, and lung SMR = 120 (89158): 51 (25% of cohort exposed to
>1.5 ppm [>1.8 mg/m 3])
White male industrial workers exposed to Nasopharynx SMR = 270 (P < 0.05): 6 Blair et al., 1986
$0.1 ppm formaldehyde (4% of cohort exposed to
$2 ppm [ $2.4 mg/m 3])
White male industrial workers with Nasopharynx Blair et al., 1986
cumulative exposures of: (4% of cohort exposed to
0 ppm-years SMR = 530: 1 $2 ppm [ $2.4 mg/m 3])
#0.5 ppm-years SMR = 271 (P > 0.05): 2
0.515.5 ppm-years SMR = 256 (P > 0.05): 2
>5.5 ppm-years SMR = 433 (P > 0.05): 2
29
Table 10 (contd).
Cohort exposed Cancer Risk measurea Reference (comments)

White male industrial workers co-exposed to Nasopharynx Blair et al., 1987
particulates with cumulative formaldehyde
exposures of:
0 ppm-years SMR = 0: 0
<0.5 ppm-years SMR = 192: 1
0.5<5.5 ppm-years SMR = 403: 2
$5.5 ppm-years SMR = 746: 2
White male industrial workers: Nasopharynx Collins et al., 1988

exposed for <1 year SMR = 517 ( P # 0.05): 3
exposed for $1 year SMR = 218 ( P > 0.05): 3
exposed at one plant with particulates SMR = 1031 (P # 0.01): 4
White male workers, hired between 1947 and Nasopharynx Marsh et al., 1996
1956, employed at one specific plant for:
<1 year SMR = 768 ( P > 0.05): 2
$1 year SMR = 1049 (P < 0.05): 2
White male industrial workers exposed to $0.1 Lung SMR = 111 (96127): 210 Blair et al., 1986
ppm formaldehyde (4% of cohort exposed to $2
ppm [$2.4 mg/m3])
White male industrial workers with $20 years Lung SMR = 132 ( P # 0.05): 151 Blair et al., 1986
since first exposure (4% of cohort exposed to $2
ppm [$2.4 mg/m3])
White male industrial workers with cumulative Lung Blair et al., 1986
exposures of: (4% of cohort exposed to $2
0 ppm-years SMR = 68 (37113): 14 ppm [$2.4 mg/m3])
#0.5 ppm-years SMR = 122 (98150): 88
0.515.5 ppm-years SMR = 100 (80124): 86
>5.5 ppm-years SMR = 111 (85143): 62
Wage-earning white males in industrial cohort Lung SMR = 140 ( P # 0.05): 124 Blair et al., 1990a
exposed to formaldehyde and other substances
Wage-earning white males in industrial cohort Lung SMR = 100 ( P > 0.05): 88 Blair et al., 1990a
exposed to formaldehyde
Subjects in industrial cohort less than 65 years Lung Sterling & Weinkam, 1994
of age with cumulative exposures of:
<0.1 ppm-years RR = 1.0
0.10.5 ppm-years RR = 1.47 (1.032.12) b
0.52.0 ppm-years RR = 1.08 (0.671.70) b
>2.0 ppm-years RR = 1.83 (1.093.08) b
Males in industrial cohort less than 65 years of Lung Sterling & Weinkam, 1994
age with cumulative exposures of:
<0.1 ppm-years RR = 1.0
0.10.5 ppm-years RR = 1.50 (1.032.19) b
0.52.0 ppm-years RR = 1.18 (0.731.90) b
>2.0 ppm-years RR = 1.94 (1.133.34) b
White wage-earning males in industrial cohort with Lung Blair & Stewart, 1994
>2 ppm-years of cumulative exposure and
exposure durations of:
<1 year SMR = 0: 0
1<5 years SMR = 110 ( P > 0.05): 9
5<10 years SMR = 280 ( P < 0.05): 17
>10 years SMR = 100 ( P > 0.05): 10
White male workers employed at one specific Lung Marsh et al., 1996
plant for: (25% exposed to >0.7 ppm
<1 year SMR = 134 ( P < 0.05): 63 [>0.84 mg/m3])
$1 year SMR = 119 ( P > 0.05): 50
White males in industrial cohort with cumulative Lung Callas et al., 1996
exposures of:
0 ppm-years RR = 1.00
0.050.5 ppm-years RR = 1.46 (0.812.61)
0.515.5 ppm-years RR = 1.27 (0.722.26)
>5.5 ppm-years RR = 1.38 (0.772.48)
a Unless otherwise noted, values in parentheses are 95% confidence interval or level of statistical significance. Risk measures are
presented in the format reported in the references cited. Values in italics are the number of observed deaths or cases, when specified in
the reference cited. Abbreviations are as follows: SMR = standardized mortality ratio; SIR = standardized incidence ratio; PMR =
proportionate mortality ratio; SPIR = standardized proportionate incidence ratio; RR = relative risk.
b Values in parentheses represent 90% confidence interval.
30
Formaldehyde
excess of cancers of the buccal mucosa or pharynx in this al. (1990b) and Partanen (1993), Collins et al. (1997)
cohort. concluded that there was no evidence of increased risk of
nasopharyngeal cancer associated with exposure to
In the largest industrial cohort mortality study of formaldehyde; the differing results were attributed to
26 561 workers first employed before 1966 at 10 plants in inclusion of additional more recent studies for which
the USA (4% of cohort exposed to $2 ppm [$2.4 mg/m3]), results were negative (particularly Gardner et al., 1993) and
Blair et al. (1986) observed a slight but significant (1.3- correction for under-reporting of expected numbers. The
fold) excess of deaths due to lung cancer among the authors also considered that the previous analyses of
subcohort of white male industrial workers with $20 years exposureresponse were questionable, focusing on only
since first exposure. However, results of a number of one cohort study and combining the unquantified
follow-up studies within this industrial group have medium/high-level exposure groups from the casecontrol
provided little additional evidence of exposureresponse studies with the quantified highest exposure group in the
(i.e., cumulative, average, peak, duration, intensity), except one positive cohort study. Although an analysis of
in the presence of other substances (Blair et al., 1986, exposureresponse was not conducted by Collins et al.
1990a; Marsh et al., 1992, 1996; Blair & Stewart, 1994; (1997), the authors felt that the casecontrol data should
Callas et al., 1996). have been combined with the low-exposure cohort data.
Based upon the results of the cohort investigations of
Meta-analyses of data from epidemiological studies industrial workers, pathologists, and embalmers, the
published between 1975 and 1991 were conducted by Blair relative risks for lung cancer were 1.1 (95% CI = 1.01.2),
et al. (1990b) and Partanen (1993). Blair et al. (1990b) 0.5 (95% CI = 0.40.6), and 1.0 (95% CI = 0.91.1),
indicated that the cumulative relative risk of nasal cancer respectively; the relative risk for lung cancer derived from
was not significantly increased among those with lower the casecontrol studies was 0.8 (95% CI = 0.70.9).
(RR = 0.8) or higher (RR = 1.1) exposure to formaldehyde,
while Partanen (1993) reported that the cumulative relative 9.2.2 Genotoxicity
risk of sinonasal cancer among those with substantial
exposure to formaldehyde was significantly elevated (i.e., An increased incidence of micronucleated buccal or
RR = 1.75). In both meta-analyses, there was a nasal mucosal cells has been reported in some surveys of
significantly increased cumulative relative risk (ranging individuals occupationally exposed to formaldehyde
from 2.1 to 2.74) of nasopharyngeal cancer among those in (Ballarin et al., 1992; Suruda et al., 1993; Kitaeva et al.,
the highest category of exposure to formaldehyde; in the 1996; Titenko-Holland et al., 1996; Ying et al., 1997).
lower or low-medium exposure categories, the cumulative Evidence of genetic effects (i.e., chromosomal aberrations,
relative risks for nasopharyngeal cancer ranged from 1.10 sister chromatid exchanges) in peripheral lymphocytes
to 1.59 (Blair et al., 1990b; Partanen, 1993). The analysis of from individuals exposed to formaldehyde vapour has
exposureresponse in Blair et al. (1990b) and Partanen also been reported in some studies (Suskov & Sazonova,
(1993) was based on three and five studies, respectively, 1982; Bauchinger & Schmid, 1985; Yager et al., 1986;
in which increased risks of nasopharyngeal cancer had Dobi et al., 1988, 1989; Kitaeva et al., 1996), but not
been observed. others (Fleig et al., 1982; Thomson et al., 1984; Vasudeva
& Anand, 1996; Zhitkovich et al., 1996). Available data are
Both meta-analyses revealed no increased risk of consistent with a pattern of weak positive responses, with
lung cancer among professionals having exposure to good evidence of effects at the site of first contact and
formaldehyde; however, among industrial workers, the equivocal evidence of systemic effects, although
cumulative relative risk for lung cancer was marginally contribution of co-exposures cannot be precluded.
(but significantly) increased for those with lower and low-
medium (both RR = 1.2) exposure to formaldehyde, 9.2.3 Respiratory irritancy and function
compared with those with higher (RR = 1.0) or substantial
(RR = 1.1) exposure (Blair et al., 1990b; Partanen, 1993). Symptoms of respiratory irritancy and effects on
pulmonary function have been examined in studies of
More recently, Collins et al. (1997) determined the populations exposed to formaldehyde (and other com-
cumulative relative risks of death due to nasal, nasophar- pounds) in both the occupational and general environ-
yngeal, and lung cancer associated with potential expo- ments.
sure to formaldehyde, based upon a meta-analysis of data
from casecontrol and cohort investigations published In a number of studies of relatively small numbers of
between 1975 and 1995. For nasal cancer, cumulative workers (3884) in which exposure was monitored for
relative risks (designated as meta RR) were 0.3 (95% individuals, there was a higher prevalence of symptoms,
confidence interval [CI] = 0.10.9) and 1.8 (95% CI = primarily of irritation of the eye and respiratory tract, in
1.42.3), on the basis of the cohort and casecontrol workers exposed to formaldehyde in the production of
studies, respectively. In contrast to the findings of Blair et resin-embedded fibreglass (Kilburn et al., 1985a), chemi-
31
cals, and furniture and wood products (Alexandersson & samples collected in two rooms on one occasion were
Hedenstierna, 1988, 1989; Holmstrm & Wilhelmsson, conducted and classified as low (<0.1 ppm [<0.12
1988; Malaka & Kodama, 1990) or through employment in mg/m3]), medium (0.10.3 ppm [0.120.36 mg/m3]), and
the funeral services industry (Holness & Nethercott, high (>0.3 ppm [>0.36 mg/m3]), based on the average
1989), compared with various unexposed control groups. value for the two samples. Each of the respondents (who
Due to the small numbers of exposed workers, however, it were not aware of the results of the monitoring) was
was not possible to meaningfully examine exposure classified by four dependent variables for health effects
response in most of these investigations. In the one (yes/no for eye irritation, nose/throat irritation,
survey in which it was considered (Horvath et al., 1988), headaches, and skin rash) and four potentially
formaldehyde was a statistically significant predictor of explanatory variables age, sex, smoking status, and
symptoms of eye, nose, and throat irritation, phlegm, low, medium, or high exposure to formaldehyde. In all
cough, and chest complaints. Workers in these studies cases, the effects of formaldehyde were substantially
were exposed to mean formaldehyde concentrations of greater at concentrations above 0.3 ppm (0.36 mg/m3) than
0.17 ppm (0.20 mg/m3) and greater. for levels below 0.3 ppm (0.36 mg/m3). Reports of eye
irritation were most frequent, followed by nose and throat
Results of investigations of effects on pulmonary irritation, headaches, and skin rash. While proportions of
function in occupationally exposed populations are the population reporting eye, nose, and throat irritation or
somewhat conflicting. Pre-shift reductions (considered headaches at above 0.3 ppm (0.36 mg/m3) were high
indicative of chronic occupational exposure) of up to 12% (7199%), those reporting effects at below 0.1 ppm (0.12
in parameters of lung function (e.g., forced vital capacity, mg/m3) were low (12% for eye irritation, 011% for nose
forced expiratory volume, forced expiratory flow rate) were or throat irritation, and 210% for headaches). The
reported in a number of smaller studies of chemical, prevalence of skin rash was between 5% and 44% for >0.3
furniture, and plywood workers (Alexandersson & ppm (>0.36 mg/m3) and between 0% and 3% for <0.1 ppm
Hedenstierna, 1988, 1989; Holmstrm & Wilhelmsson, (<0.12 mg/m3).
1988; Malaka & Kodama, 1990; Herbert et al., 1994). In
general, these effects on lung function were small and There has been preliminary indication of effects on
transient over a workshift, with a cumulative effect over pulmonary function in children in the residential environ-
several years that was reversible after relatively short ment associated with relatively low concentrations of
periods without exposure (e.g., 4 weeks); effects were formaldehyde, of which further study seems warranted.
more obvious in non-smokers than in smokers Although there was no increase in symptoms (chronic
(Alexandersson & Hedenstierna, 1989). In the subset of cough and phlegm, wheeze, attacks of breathlessness)
these investigations in which exposure was monitored for indicated in self-administered questionnaires, the preva-
individuals (i.e., excluding only that of Malaka & Kodama, lence of physician-reported chronic bronchitis or asthma
1990), workers were exposed to mean concentrations of in 298 children aged 615 years exposed to concentrations
formaldehyde of 0.3 ppm (0.36 mg/m3) and greater. In the between 60 and 140 ppb (72 and 168 g/m3) in their homes
only study in which it was examined, there was a was increased, especially among those also exposed to
doseresponse relationship between exposure to ETS (Krzyzanowski et al., 1990). There was an association
formaldehyde and decrease in lung function between exposure and response based on subdivision of
(Alexandersson & Hedenstierna, 1989). However, the population into groups for which indoor
evidence of diminished lung function was not observed in concentrations were #40 ppb (#48 g/m3), 4160 ppb
other studies of larger numbers of workers (84254) (4872 g/m3), and >60 ppb (>72 g/m3), although the
exposed to formaldehyde through employment in wood proportions of the population in the mid- and highest
product (cross-shift decreases that correlated with exposure group were small (<10% and <4%, respectively).
exposure to formaldehyde but not pre-shift) (Horvath et Exposure to formaldehyde was characterized based on
al., 1988) or resin (Nunn et al., 1990) manufacturing or in monitoring in the kitchen, the main living area, and each
the funeral services industry (Holness & Nethercott, subjects bedroom for two 1-week periods. There was no
1989). These groups of workers were exposed to mean indication of whether respondents were blinded to the
concentrations of formaldehyde of up to >2 ppm (>2.4 results of the monitoring when responding to the
mg/m3). questionnaires. Levels of peak expiratory flow rates
(PEFR) also decreased linearly with exposure, with the
In a survey of residences in Minnesota, USA, decrease at 60 ppb (72 g/m3) equivalent to 22% of the
prevalences of nose and throat irritation among residents level of PEFR in non-exposed children; this value was
were low for exposures to concentrations of formaldehyde 10% at levels as low as 30 ppb (36 g/m3). Effects in a
less than 0.1 ppm (0.12 mg/m3) but considerable at levels larger sample of 613 adults were less evident, with no
greater than 0.3 ppm (0.36 mg/m3) (Ritchie & Lehnen, increase in symptoms or respiratory disease and small
1987). This study involved analysis of the relation transient decrements in PEFR only in the morning and
between measured levels of formaldehyde and reported mainly in smokers, the significance of which is unclear.
symptoms for nearly 2000 residents in 397 mobile and 494 Results of exposureresponse analyses in adults were not
conventional homes. Analyses for formaldehyde in presented.
32
Formaldehyde
9.2.5 Other effects

In a survey of 1726 occupants of homes containing
UFFI and 720 residents of control homes, health ques- Histopathological changes within the nasal epi-
tionnaires were administered and a series of objective thelium have been examined in surveys of workers
tests of pulmonary function, nasal airway resistance, occupationally exposed to formaldehyde vapour (Berke,
sense of smell, and nasal surface cytology conducted 1987; Edling et al., 1988; Holmstrm et al., 1989c; Boysen
(Broder et al., 1988). The distributions of the age groups in et al., 1990; Ballarin et al., 1992).
this population were 80%, 10%, and 10% for 16 and over,
<10, and 1015 years, respectively; only the questionnaire In all but one of the most limited of these investi-
was completed for children under the age of 10. gations (Berke, 1987), the prevalence of metaplasia of the
Monitoring for formaldehyde was conducted in the homes nasal epithelium was increased in populations exposed
of these residents during 2 successive days, one of which occupationally principally to formaldehyde compared with
included the day on which the occupants were examined, age-matched control populations; occasionally, also,
in a central location, in all bedrooms, and in the yard. dysplastic changes were reported in those exposed to
Upon analysis, there were increases in prevalences of formaldehyde. In the most extensive of these
symptoms primarily at values greater than 0.12 ppm (0.14 investigations and the only one in which there were
mg/m3) formaldehyde, although there was evidence of individual estimates of exposure based on personal and
interaction between UFFI and formaldehyde associated area sampling (Holmstrm et al., 1989c), mean histological
with these effects. There were no effects on other scores were increased in 70 workers principally exposed to
parameters investigated, with the exception of a small formaldehyde (mean 0.25 ppm, standard deviation 0.13
increase in nasal epithelial squamous metaplasia in UFFI ppm [mean 0.30 mg/m3, standard deviation 0.16 mg/m3])
subjects intending to have their UFFI removed. The compared with 36 unexposed controls. Where
median concentration of formaldehyde in the UFFI homes confounders were examined, they have not explained the
was 0.038 ppm (0.046 mg/m3) (maximum, 0.227 ppm [0.272 effects. For example, in the most extensive study by
mg/m3]); in the control homes, the comparable value was Holmstrm et al. (1989c), changes were not significant in a
0.031 ppm (0.037 mg/m3) (maximum, 0.112 ppm [0.134 population exposed to wood dustformaldehyde that was
mg/m3]). Notably, health complaints of residents in UFFI also examined. Edling et al. (1988) observed no variation in
homes were significantly decreased after remediation, mean histological score in workers exposed to both
although the levels of formaldehyde were unchanged. formaldehyde and wood dust compared with those
exposed only to formaldehyde. In cases where it was
9.2.4 Immunological effects examined, there was no relationship of histological scores
with duration of exposure, although this may be
Epidemiological studies on the effects of exposure attributable to the small numbers in the subgroups (Edling
to formaldehyde on the immune system have focused et al., 1988).
primarily upon allergic reactions (reviewed in Feinman,
1988; Bardana & Montanaro, 1991; Stenton & Hendrick, The available data are consistent, therefore, with the
1994). Case reports of systemic or localized allergic hypothesis that formaldehyde is primarily responsible for
reactions have been attributed to the formaldehyde induction of these histopathological lesions in the nose.
present in a wide variety of products. Formaldehyde is an The weight of evidence of causality is weak, however, due
irritant to the respiratory tract, and some reports have primarily to the limited number of investigations of
suggested that the development of bronchial asthma relatively small populations of workers that do not permit
following inhalation of formaldehyde may be due to adequate investigation of, for example,
immunological mechanisms. The specific conditions of exposureresponse.
exposure as well as idiosyncratic characteristics among
individuals are likely important factors in determining
whether inhalation exposure to formaldehyde can result in
adverse effects on pulmonary function mediated through
immunological means. Immune effects (e.g., contact
dermatitis) resulting from dermal exposure to
formaldehyde have been more clearly defined. The
concentration of formaldehyde likely to elicit contact
dermatitis reactions in hypersensitive individuals may be
as low as 30 mg/litre. Based on the results of surveys
conducted in North America, less than 10% of patients
presenting with contact dermatitis may be immunologi-
cally hypersensitive to formaldehyde.
33
Based upon epidemiological studies, there is no The 96-h no-observed-effect concentration (NOEC) and
clear evidence to indicate that maternal (Hemminki et al., lowest-observed-effect concentration (LOEC) (per cent
1985; John et al., 1994; Taskinen et al., 1994) or paternal mortality not specified) of 7-day-old embryos of the same
(Lindbohm et al., 1991) exposure to formaldehyde is species were reported as 1 and 10 mg/litre, respectively,
associated with an increased risk of spontaneous abor- indicating that older organisms are more tolerant (Burridge
tion.1 et al., 1995a). Concentrations of 0.1, 1, and 10 mg/litre also
reduced germination and growth rates of the zygotes and
There is little convincing evidence that formalde- embryos (Burridge et al., 1995b).
hyde is neurotoxic in occupationally exposed populations,
although it has been implicated as the responsible agent Freshwater algae may be slightly more tolerant of
in the development of neurobehavioural disorders such as formaldehyde, based on a cell multiplication inhibition test
insomnia, lack of concentration, memory loss, and mood (Bringmann & Khn, 1980a). The toxicity threshold (for a
and balance alterations, as well as loss of appetite in case mean extinction of $3% less than that in controls) was 0.9
reports and a series of cross-sectional surveys by the mg formaldehyde/litre (2.5 mg formalin/litre) (Bringmann &
same investigators (Kilburn et al., 1985a,b, 1987, 1989; Khn, 1980a).
Kilburn & Warshaw, 1992; Kilburn, 1994). However, the
reported effects, which included increases in self-reported Other freshwater microorganisms were similarly
symptoms (for which frequencies of behavioural, sensitive in analogous cell multiplication studies. A 48-h
neurological, and dermatological symptoms were toxicity threshold (5% below average cell counts of
sometimes combined for analyses), or impacts on more controls) of 1.6 mg formaldehyde/litre (4.5 mg formalin/li-
objective measures of neurobehavioural function were tre, 35% CH2O w/w) was determined for the saprozoic
confined primarily to histology workers. Attribution of the flagellate protozoan Chilomona paramaecium (Bring-
effects to formaldehyde in this group is complicated by mann et al., 1980), and a 72-h toxicity threshold ($3%
co-exposures; indeed, sampling and analyses in a small inhibition of cell multiplication, 25 C) of 7.7 mg/litre (22
number of histology laboratories confirmed the widely mg formalin/litre, 35% CH2O w/w) was reported for the
ranging concentrations of formaldehyde, xylene, protozoan Entosiphon sulcatum (Bringmann & Khn,
chloroform, and toluene to which such workers were likely 1980b). For bacteria, the 16-h toxicity threshold ($3%
exposed. Further, there was no verification of the crude inhibition of cell multiplication) was 4.9 mg
measures by which exposure to formaldehyde was formaldehyde/litre (14 mg formalin/litre, 35% CH2O w/w)
distinguished from that to solvents, which was based on for Pseudomonas putida (Bringmann & Khn, 1980a), and
worker recall of time spent conducting various tasks. a 25-min EC50 (light emission inhibition) of 2.5 mg
formaldehyde/litre (242 mol formalin/litre, 37% CH2O
w/w) was observed in the Photobacterium phosphoreum
Microtox test (Chou & Que Hee, 1992).
10. EFFECTS ON OTHER ORGANISMS IN
THE LABORATORY AND FIELD The sensitivity of freshwater invertebrates to form-
aldehyde varies widely. The seed shrimp Cypridopsis sp.
appears to be the most sensitive, with a 96-h EC50
10.1 Aquatic environment (immobility) of 0.36 mg formaldehyde/litre (1.05 l
formalin/litre, 37% CH2O w/w). The snail Helisoma sp.,
Data on the aquatic toxicity of formaldehyde are bivalve Corbicula sp., freshwater prawn Palaemonetes
numerous. The most sensitive aquatic effects identified hadiakensis, and backswimmer Notonecta sp. have 96-h
were observed for marine algae. Formaldehyde concen- EC50 values (immobility, delayed response to tactile
trations of 0.1 and 1 mg/litre in water caused 4050% stimuli) of 32, 43, 160, and 287 g/litre (93, 126, 465, and
mortality after 96 h in day-old zygotes of Phyllospora 835 l formalin/litre, 37% CH2O w/w), respectively,
comosa, a brown marine macroalga endemic to south- assuming 1 l formalin/litre = 0.34 mg formaldehyde/litre
eastern Australia. Total (100%) mortality resulted from (Bills et al., 1977). Reported 24-h LC50 values for Daphnia
exposures to 100 mg/litre for 24 h and 10 mg/litre for 96 h. magna range from 2 to 1000 mg/litre (IPCS, 1989).
The toxicity of formaldehyde for fish is also variable.

The most sensitive freshwater fish were fingerlings of
1
An epidemiological study on potential reproductive effects of striped bass (Roccus saxatilis). Reardon & Harrell (1990)
formaldehyde exposure in women (Taskinen et al., 1999) was reported 96-h LC50 values of 1.8, 5.0, 5.7, and 4.0 mg/litre
identified after the cut-off date for inclusion in the Canadian (4.96, 13.52, 15.48, and 10.84 mg formalin/litre, 37% CH2O
source document. Owing to the suggestion in this report that w/w) in water with 0, 5, 10, and 15 salinity, respectively.
occupational exposure of women to formaldehyde may be These values were calculated from nominal test
associated with adverse effects on fertility, this area should be a concentrations using probit analyses. Salinity may have
priority for consideration in any subsequent review of health an effect on the tolerance of striped bass to formaldehyde.
effects. Although the fish had been acclimated to water with a
34
Formaldehyde
salinity of 1030 prior to testing, they were most al., 1976). A 5-h exposure to 700 ppb (840 g/m3) caused
tolerant of formaldehyde in isosmotic medium (910). mild atypical signs of injury in alfalfa (Medico sativa), but
Since controls were not affected by the changes in no injury to spinach (Spinacia oleracea), beets (Beta
salinity, there may be a compounded effect of chemical vulgaris), or oats (Avena sativa) (Haagen-Smit et al.,
and environmental (e.g., salinity) interaction on fish 1952).
survival. Wellborn (1969) reported a 96-h LC50 of 6.7
mg/litre for striped bass under static conditions. Other Effects on plants were also investigated following
short-term (3- to 96-h) LC50s of between 10 and 10 000 exposure to formaldehyde in fog water. Seedlings of
mg/litre were reported for 19 species and three life stages winter wheat (Triticum aestivum), aspen (Populus
of freshwater fish (US EPA, 1985; IPCS, 1989). In some tremuloides), rapeseed (Brassica rapa), and slash pine
studies, formaldehyde caused disruption of normal gill (Pinus elliotti) were exposed to formaldehyde concentra-
function (Reardon & Harrell, 1990). tions of 0, 9000, or 27 000 g/litre in fog for 4.5 h/night, 3
nights/week, for 40 days. Based on an unspecified
The only data identified for marine fish were for the Henrys law constant, calculated corresponding atmos-
juvenile marine pompano (Trachinotus carolinus), with pheric gas-phase formaldehyde concentrations were 0, 15,
24-, 48-, and 72-h LC50 values of 28.8, 27.3, and 25.6 mg and 45 ppb (0, 18, and 54 g/m3), respectively. In rapeseed
formaldehyde/litre (78.0, 73.7, and 69.1 mg formalin/litre, grown in the formaldehyde fog, significant (P # 0.1)
assumed to contain 37% CH2O), respectively, in 30 reductions in leaf area, leaf dry weight, stem dry weight,
salinity. Salinity (10, 20, 30) did not significantly affect flower number, and number of mature siliques (seed pods
the tolerance of fish to formaldehyde (Birdsong & Avault, that produce seed) were observed compared with control
1971). plants. The slash pine showed a significant increase in
needle and stem growth. No effects were observed in the
The sensitivity of amphibians to formaldehyde is wheat or aspen at test concentrations (Barker &
similar to that of fish. The lowest 24-, 48-, and 72-h LC50 Shimabuku, 1992).
values were 8.4, 8.0, and 8.0 mg/litre, respectively, for
larvae of the leopard frog (Rana pipiens). Tadpoles of Formaldehyde is known to be an effective disinfec-
bullfrogs (Rana catesbeiana) appear more tolerant, tant that kills microorganisms such as bacteria, viruses,
with 24-, 48-, and 72-h LC50 values of 20.1, 17.9, and fungi, and parasites at relatively high concentrations
17.9 mg/litre, respectively. Larvae of the toad Bufo sp. had (IPCS, 1989). Exposure to 2 ppm (2400 g/m3) gaseous
72-h LC50 and LC100 values of 17.1 and 19.0 mg/litre, formaldehyde for 24 h killed 100% of spores from cultures
respectively (Helms, 1964). Mortality (13100%) in of various species of Aspergillus and Scopulariopsis, as
tadpoles of the Rio Grande leopard frog (Rana berlan- well as Penicillium crustosum (Dennis & Gaunt, 1974). In
dieri) was observed after 24 h in formaldehyde (9.2 a fumigation study, the death rate of spores of Bacillus
30.5 mg/litre) (Carmichael, 1983). A NOEC (mortality) of 6.0 globigii increased from low to high with formaldehyde
mg/litre was reported. concentrations ranging from 42 000 to 330 000 ppb (50 000
to 400 000 g/m3), respectively. Humidity (>50%) appeared
10.2 Terrestrial environment to shorten the delay before death (Cross & Lach, 1990).
The most sensitive effect for terrestrial organisms For terrestrial invertebrates, nematodes in peat were
resulting from exposure to formaldehyde in air was an killed by fumigation applications of 370 g/litre
increase in the growth of shoots, but not of roots, of the formaldehyde solutions at a rate of 179 ml/m3 (66 g/m3)
common bean (Phaseolus vulgaris) after exposure to (Lockhart, 1972). Solutions of 1% and 5% formalin (37%
average measured concentrations of 65, 107, 199, and 365 formaldehyde) destroyed the eggs and affected larvae,
ppb (78, 128, 239, and 438 g/m3) in air (day: 25 C, 40% respectively, of the cattle parasites Ostertagia ostertagi
humidity; night: 14 C, 60% humidity) for 7 h/day, 3 and Cooperia oncophora in liquid cow manure (Persson,
days/week, for 4 weeks, beginning at the appearance of 1973).
the first macroscopic floral bud, 20 days after emergence
(Mutters et al., 1993). Although the authors concluded No acute or chronic toxicity data were identified for
that there were no short-term harmful effects, it has been wild mammals, birds, reptiles, or terrestrial invertebrates.
suggested that an imbalance between shoot and root Effects on laboratory mammals are presented in section 8.
growth may increase the vulnerability of plants to
environmental stresses such as drought, because the root
system may not be large enough to provide water and
nutrients for healthy plant growth (Barker & Shimabuku,
1992). Other sensitive effects on terrestrial vegetation
include a significant reduction of the pollen tube length of
lily (Lilium longiflorum) following a 5-h exposure to 367
ppb (440 g/m3) in air; total inhibition of pollen tube
elongation occurred at 1400 ppb (1680 g/m3) (Masaru et
35
11. EFFECTS EVALUATION Formaldehyde also induces the formation of DNA

protein crosslinks in a variety of human and rat cell types
in vitro and in the epithelium of the nasal cavity of rats
11.1 Evaluation of health effects and respiratory tract of monkeys following inhalation,
which may contribute to the carcinogenicity of the
11.1.1 Hazard identification compound in the nasal cavity of rats through replication
errors, resulting in mutation.
Inhalation, the likely principal route of exposure
of the general population to formaldehyde, has been the Overall, formaldehyde is genotoxic, with effects
focus of most studies on the effects of this substance in most likely to be observed in vivo in cells from tissues or
humans and laboratory animals. Available data on effects organs with which the aldehyde first comes into contact.
following ingestion of or dermal exposure to formaldehyde
are limited. Since formaldehyde is water soluble, highly 11.1.1.2 Carcinogenicity
reactive with biological macromolecules, and rapidly
metabolized, adverse effects resulting from exposure are 11.1.1.2.1 Inhalation
observed primarily in those tissues or organs with which
formaldehyde first comes into contact (i.e., the respiratory In casecontrol studies, associations between
and aerodigestive tract, including oral and gastrointestinal cancers of the nasal or nasopharyngeal cavities and
mucosa, following inhalation and ingestion, respectively). formaldehyde exposure have been observed that fulfil, at
least in part, traditional criteria of causality; significantly
Effects following inhalation that occur primarily at elevated odds ratios of an association were found for
the site of contact are, therefore, the principal focus of workers with the highest level or duration of exposure. It
this section. should be noted, though, that measures of exposure in
these population-based investigations are rather less
11.1.1.1 Genotoxicity reliable than those in the larger, most extensive cohort
studies of occupationally exposed populations; moreover,
Results of epidemiological studies in occupationally methodological limitations complicate interpretation of
exposed populations are consistent with a pattern of weak several of the casecontrol studies. Excesses of cancers
positive responses for genotoxicity, with good evidence of the nasal or nasopharyngeal cavities have not been
of an effect at site of contact (e.g., micronucleated buccal observed consistently in cohort studies. Where there
or nasal mucosal cells). Evidence for distal (i.e., systemic) have been excesses, there has been little evidence of
effects is equivocal (chromosomal aberrations and sister exposureresponse, although the total number of
chromatid exchanges in peripheral lymphocytes). The observed tumours was small. In epidemiological studies of
contribution of co-exposures to observed effects cannot occupationally exposed populations, there has been little
be precluded. evidence of a causal association between exposure to
formaldehyde and lung cancer. Indeed, results of studies
The results of a large number of in vitro assays of in a rather extensive database of cohort and casecontrol
a variety of end-points indicate that formaldehyde is studies do not fulfil traditional criteria of causality in this
genotoxic at high concentrations in both bacterial and regard, such as consistency, strength, and
mammalian cells. The spectrum of mutation induced by exposureresponse. Increases in mortality or incidence
formaldehyde in vitro varies among cell types and have not been observed consistently, and, where
concentrations to which cells were exposed but includes examined, there has consistently been no evidence of
both point and large-scale changes. Formaldehyde exposureresponse.
induced in vitro DNAprotein crosslinks, DNA single-
strand breaks, chromosomal aberrations, sister chromatid Five carcinogenicity bioassays have provided con-
exchange, and gene mutations in human and rodent cells. sistent evidence that formaldehyde is carcinogenic in rats
It also induced cell transformation in rodent cells. The exposed via inhalation (Kerns et al., 1983; Sellakumar et
results of in vivo studies in animals are similar to those in al., 1985; Tobe et al., 1985; Monticello et al., 1996; Kamata
humans, with effects at site of contact being observed et al., 1997). The incidence of nasal tumours was not
(e.g., increased chromosomal anomalies in lung cells, significantly increased in mice exposed to formaldehyde
micronuclei in the gastrointestinal tract, and sperm by inhalation (Kerns et al., 1983). This has been attributed,
anomalies following inhalation or gavage to rats in vivo). at least in part, to the greater reduction in minute volume
Evidence of distal (systemic) effects is less convincing. in mice than in rats exposed to formaldehyde (Chang et al.,
Indeed, in the majority of studies of rats exposed to 1981; Barrow et al., 1983), resulting in lower exposures in
formaldehyde via inhalation, genetic effects within mice than in rats (Barrow et al., 1983).
peripheral lymphocytes or bone marrow cells have not
been observed. Observation of tumours at the site of contact is con-
sistent with toxicokinetic considerations. Formaldehyde is
a highly water-soluble, highly reactive gas that is locally
36
Formaldehyde
absorbed quickly at the site of contact. It is also rapidly tion, and DNAprotein crosslinking are all more closely
metabolized, such that exposure to even high related to the exposure concentration than to the total
concentrations of atmospheric formaldehyde does not cumulative intake or dose of formaldehyde (Swenberg et
result in an increase in formaldehyde concentrations in al., 1983; Casanova et al., 1994).
the blood.
While the respective roles of DNAprotein cross-
As described in section 8.7, the mechanisms by linking, mutation, and cellular proliferation in the induc-
which formaldehyde induces nasal tumours in rats are not tion of tumours in the rat nose are not fully delineated, the
fully understood. However, it has been hypothesized that hypothesized mode of carcinogenesis is in keeping with
a sustained increase in epithelial cell regenerative the growing body of evidence supporting the biological
proliferation resulting from cytotoxicity is a requisite plausibility that prolonged regenerative cell proliferation
precursor in the mode of induction of tumours. Mutation, can be a causal mechanism in chemical carcinogenesis.
for which the formation of DNAprotein crosslinks serves Regenerative cell proliferation following formaldehyde-
as a marker of potential, may also contribute to the induced cytotoxicity increases the number of DNA
carcinogenicity of the compound in the nasal cavity of replications and thus increases the probability of a
rats. Studies relevant to assessment of the mode of action DNAprotein crosslink initiating a DNA replication error,
include a cancer bioassay (Monticello et al., 1996) in resulting in a mutation. This proposed mode of action is
which intermediate end-points (proliferative response in consistent with the observed inhibition of DNA
various regions of the nasal epithelium) have been replication in the rat nose at elevated concentrations
investigated. The relevant database also includes (Heck & Casanova, 1995) and point mutations in the p53
numerous shorter-term studies in which proliferative tumour suppressor gene in tumours from the noses of rats
response and the formation of DNAprotein crosslinks in exposed to formaldehyde (Recio et al., 1992) as well as
the nasal epithelium of rats and other species have been increased p53 expression in preneoplastic lesions (Wolf et
examined following exposure via regimens often similar to al., 1995).
those in the cancer bioassays (Swenberg et al., 1983;
Casanova & Heck, 1987; Heck & Casanova, 1987; The hypothesized mode of induction of formalde-
Casanova et al., 1989, 1991, 1994; Monticello et al., 1989, hyde-induced tumours that satisfies several criteria for
1991). It should be noted, though, that due to the limited weight of evidence, including consistency, concordance
data on intermediate end-points in most of the cancer of exposureresponse relationships across intermediate
bioassays, information available as a basis for direct end-points, and biological plausibility and coherence of
comparison of the incidence of intermediate lesions (i.e., the database, is likely relevant to humans, at least quali-
proliferative response as a measure of cytotoxicity and tatively. Increased cell proliferation (Monticello et al.,
DNAprotein crosslinking) and tumours is limited to that 1989) and DNAprotein crosslink formation (Casanova et
presented in Table 8. al., 1991) within epithelia of the upper respiratory tract
have been observed in monkeys exposed to formaldehyde
However, as would be expected for essential but not vapour. Although not sufficient in itself as a basis for
necessarily sufficient precursor events, cancer is not inferring causality, direct evidence on histopathological
always associated with sustained cytotoxicity and lesions in the nose of humans exposed primarily to
regenerative proliferation (Monticello et al., 1991, 1996). formaldehyde in the occupational environment is
Similarly, tumours have been observed only at consistent with a qualitatively similar response of the
concentrations at which increases in DNAprotein upper respiratory tract in humans and experimental
crosslinks have been observed in shorter-term studies in animals to formaldehyde. Increased human epithelial cell
the same strain (Casanova & Heck, 1987; Heck & proliferation following in situ exposure to formaldehyde
Casanova, 1987; Casanova et al., 1989, 1994). has also been observed in a model system in which rat
trachea populated with human tracheobronchial epithelial
In addition, where proliferative response (Monti- cells were xenotransplanted into athymic mice (Ura et al.,
cello et al., 1991, 1996) and DNAprotein crosslinking 1989).
(Casanova et al., 1994) have been examined in various
regions of the nasal passages, sites at which there are Because formaldehyde is highly reactive at the site
increases are similar to those where tumours have been of contact, dosimetry is of critical importance when
observed. The concentrationresponse relationships for extrapolating across species that have significantly
DNAprotein crosslinking, cytotoxicity, proliferative different anatomical features of the nasal and respiratory
response, and tumours are highly non-linear, with signi- passages and patterns of flow of inhaled air. Since
ficant increases in all end-points being observed at con- humans as well as other primates are oronasal breathers,
centrations of 4 ppm (4.8 mg/m3) and above (Table 8). This compared with rats, which are obligate nose breathers,
correlates well with the concentration at which effects associated with the inhalation of formaldehyde are
mucociliary clearance is inhibited and glutathione- likely to be observed in a larger area, including deeper
mediated metabolism saturated (i.e., 4 ppm [4.8 mg/m3]). parts of the respiratory tract. Indeed, in rats exposed to
Histological changes, increased epithelial cell prolifera- moderate levels of formaldehyde, histopathological
37
changes, increased epithelial cell proliferation, and biological plausibility for weight of evidence of causality
DNAprotein crosslink formation are restricted to the is also satisfied by the convincing evidence in monkeys
nasal cavity; in formaldehyde-exposed monkeys (as (Rusch et al., 1983) and rodents of histopathological
surrogates for humans), on the other hand, these effects alterations (degenerative changes consistent with
have been observed further along within the upper cytotoxicity) within the upper respiratory tract. Other than
respiratory tract. While the epidemiological studies taken damage to the gastric epithelium observed following the
as a whole do not provide strong evidence for a causal acute ingestion of large amounts of formaldehyde
association between formaldehyde exposure and human (Kochhar et al., 1986; Nishi et al., 1988; IPCS, 1989),
cancer, the possibility of increased risk of respiratory studies on potential changes within the aerodigestive
cancers, particularly those of the upper respiratory tract, tract, including oral and gastrointestinal mucosa, in
cannot be excluded on the basis of available data. humans following the long-term ingestion of this
substance were not identified. However, histological
Based primarily upon data derived from laboratory changes within the surface epithelium of the aerodigestive
studies, therefore, the inhalation of formaldehyde under tract, including oral and gastrointestinal mucosa of rats
conditions that induce cytotoxicity and sustained regen- (e.g., erosions and/or ulcers, hyperkeratosis, hyperplasia,
erative proliferation is considered to present a carcino- gastritis), have been observed following long-term oral
genic hazard to humans. exposure to formaldehyde administered in drinking-water
at high concentrations (Til et al., 1989; Tobe et al., 1989).
11.1.1.2.2 Oral exposure
Formaldehyde is not likely to affect reproduction or
Epidemiological studies of potential carcinogenic development at levels of exposure lower than those
hazards associated with the ingestion of formaldehyde associated with adverse health effects at the site of
were not identified. Currently, there is no definitive contact. Based upon recent epidemiological studies of
evidence to indicate that formaldehyde is carcinogenic occupationally exposed individuals, there is no clear
when administered orally to laboratory animals. However, evidence indicating that either maternal or paternal
consistent with the known reactivity of this substance inhalation exposure to formaldehyde is associated with an
with biological macromolecules in the tissue or organ of increased risk of spontaneous abortion (Hemminki et al.,
first contact, histopathological and cytogenetic changes 1985; Lindbohm et al., 1991; John et al., 1994; Taskinen et
within the aerodigestive tract, including oral al., 1994). In studies of laboratory animals exposed via
and gastrointestinal mucosa, have been observed in rats inhalation (Saillenfait et al., 1989; Martin, 1990) or oral
administered formaldehyde orally. These observations administration (Seidenberg & Becker, 1987;
and additional consideration of the mode of induction of Wickramaratne, 1987), formaldehyde had no effect on
tumours by formaldehyde lead to the conclusion that reproduction or fetal development at levels of exposure
under certain conditions of exposure, potential carcino- less than those causing notable adverse health effects at
genic hazard associated with the ingestion of formalde- the site of contact.
hyde cannot be eliminated.
Based upon the available although limited data,
11.1.1.3 Non-neoplastic effects exposure to formaldehyde is unlikely to be associated
with suppression of the immune response. Indeed, the
Sensory irritation of the eyes and respiratory tract dermal hypersensitivity of some individuals to formalde-
by formaldehyde has been observed consistently in hyde as well as the results of studies in animals indicate
clinical studies and epidemiological (primarily cross- heightened immune responses linked to formaldehyde
sectional) surveys in occupational and residential exposure. Information from epidemiological studies on
environments. The pattern of effects is consistent suppression of the immune response associated with
with increases in symptoms being reported at lowest exposure to formaldehyde was not identified. Adverse
concentrations, with the eye generally being most sensi- effects on either cell- or humoral-mediated immune
tive. responses have not been consistently observed in
studies conducted in laboratory animals (Dean et al., 1984;
At concentrations higher than those generally asso- Adams et al., 1987; Holmstrm et al., 1989b; Jakab, 1992;
ciated with sensory irritation, generally small, reversible Vargov et al., 1993). Although suggested in case reports
effects on lung function have been noted, although evi- for some individuals, no clear evidence that
dence of cumulative decrement in pulmonary function is formaldehyde-induced asthma was attributable to
limited. immunological mechanisms has been identified. However,
studies with laboratory animals have revealed that
Results are consistent with the increased prevalence formaldehyde may enhance their sensitization to inhaled
of histological changes in the nasal epithelium in cross- allergens (Tarkowski & Gorski, 1995; Riedel et al., 1996).
sectional studies of workers being attributable to
formaldehyde (Edling et al., 1988; Holmstrm et al., 1989c; For the general population, dermal exposure to
Boysen et al., 1990; Ballarin et al., 1992). The criterion of concentrations of formaldehyde in the vicinity of 12%
38
Formaldehyde
(10 00020 000 mg/litre) is likely to cause skin irritation; methodology due to incorporation of as many biological
however, in hypersensitive individuals, contact dermatitis data as possible.
can occur following exposure to formaldehyde at
concentrations as low as 0.003% (30 mg/litre). In North The preferred biologically based approach incor-
America, less than 10% of patients presenting with porates two-stage clonal growth modelling and dosimetry
contact dermatitis may be immunologically hypersensitive calculations from computational fluid dynamics modelling
to formaldehyde. of formaldehyde flux in various regions of the nose and
single-path modelling for the lower respiratory tract.
11.1.2 Exposureresponse analysis
Sensitivity analysis conducted to determine which
The weight of evidence indicates that formaldehyde of the model parameters has greatest impact on risk
is carcinogenic only at concentrations that induce the estimates or to identify which parameters are known with
obligatory precursor lesion of proliferative regenerative the highest degree of certainty for this biologically moti-
response associated with cytotoxicity, although vated case-specific model was limited to a few parameters
interaction with DNA must also be taken into account. For of the clonal growth (i.e., time delay, division rate at
consistency with other assessments and for ease of maximum flux into the nose of the rat, the relationship
presentation, cancer and non-cancer effects are consid- between DNAprotein crosslink concentration, and the
ered separately here, although, based on consideration of probability of mutation per cell generation) and dosimetry
mode of action, they are inextricably linked. (number of flux bins) components. However, output of the
model is considered adequate as a basis to ensure that
11.1.2.1 Inhalation measures taken to prevent sensory irritation1 in human
populations are sufficiently protective with respect to
11.1.2.1.1 Non-neoplastic effects carcinogenic potential.
There are considered to be sufficient data from The outcome of the biologically motivated dose
clinical studies and cross-sectional surveys of human response model is compared with that derived based on
populations, as well as supporting observations from empirical default methodology for estimation of tumori-
experimental studies conducted with laboratory animals, genic concentrations in the experimental range (Health
to indicate that the irritant effects of formaldehyde on the Canada, 1998). Moreover, in view of the clear emphasis
eyes, nose, and throat occur at lowest concentration. herein and preference for the biologically motivated case-
Although individual sensitivity and exposure conditions specific model, there has been no attempt to incorporate
such as temperature, humidity, duration, and co-exposure more of the biological data in the calculation of
to other irritants are likely to influence response levels, in tumorigenic concentrations by default methodology (e.g.,
well conducted studies, only a very small proportion of dose and time dependence to derive an empirical dose
the population experiences symptoms of irritation metric for rats).
following exposure to #0.1 ppm (#0.12 mg/m3) formal-
dehyde. This is less than the levels that reduce mucocili- 1) Biologically motivated case-specific model
ary clearance in the anterior portion of the nasal cavity in
available clinical studies in human volunteers (0.25 ppm There is indisputable evidence that formaldehyde is
[0.30 mg/m3]) and induce histopathological effects in the carcinogenic in rats following inhalation, with the
nasal epithelium in cross-sectional studies of formalde- carcinogenic response being limited to the site of contact
hyde-exposed workers (0.25 ppm [0.30 mg/m3]). Additional (e.g., the nasal passages of rodents). While the mecha-
investigation of preliminary indication of effects on nism of action is not well understood, based primarily
pulmonary function in children in the residential upon data derived from laboratory studies, regenerative
environment associated with lower concentrations of proliferation associated with cytotoxicity appears to be an
formaldehyde (4060 ppb [4872 g/m3]) (Krzyzanowski et obligatory intermediate step in the induction of cancer by
al., 1990) is warranted. formaldehyde. Interaction with genetic material, the
potential for which is indicated by DNAprotein cross-
11.1.2.1.2 Carcinogenicity linking, likely also contributes, although the probability of
mutation resulting from DNAprotein crosslinking is
There are two approaches to doseresponse unknown.
modelling presented here a biologically motivated
case-specific model and default, curve-fitting method- However, since formaldehyde is highly reactive at
ology. It is the biologically motivated case-specific model the site of contact, dosimetry is of critical importance in
that is considered to provide the most defensible
estimates of cancer risk. While this model entails simpli-
fication of cancer biology, which requires selection of a 1
Occurs at lower concentrations than effects on
number of parameters and use of simplifying assumptions,
mucociliary clearance or histopathological damage to the
it is considered to offer improvement over default
nose of humans.
39
predicting interspecies variations in response, as a func- Lack of evidence for the potential carcinogenicity of
tion of flux to the tissue and regional tissue susceptibility, ingested formaldehyde precludes an analysis of expo-
due to the significantly different anatomical features of sureresponse for this effect.
the nasal and respiratory passages between experimental
animals and humans. Data on non-neoplastic effects associated with the
ingestion of formaldehyde are much more limited than for
The biologically motivated case-specific model inhalation. Owing to its high reactivity, non-neoplastic
incorporates regenerative cell proliferation as a required effects in the tissue of first contact following ingestion
step in the induction of tumours by formaldehyde and a (i.e., the aerodigestive tract, including oral and
contribution from mutagenicity (not defined specifically gastrointestinal mucosa) are more likely related to the
by DNAprotein crosslinking) that has greatest impact at concentration of the formaldehyde consumed, rather than
low exposures through modelling of complex functional to its cumulative (total) intake. Information from studies
relationships for cancer due to actions of formaldehyde on humans is inadequate to identify putative exposure
on mutation, cell replication, and exponential clonal response relationships with respect to toxicological
expansion. The incorporated clonal growth modelling is effects associated with the long-term ingestion of formal-
identical to other biologically based, two-stage clonal dehyde. However, a tolerable concentration (TC) for
growth models (also known as MVK models), incor- formaldehyde in ingested products may be derived on the
porating information on normal growth, cell cycle time, basis of the NOEL for the development of histological
and cells at risk (in various regions of the respiratory changes in the aerodigestive tract, including oral and
tract). Species variations in dosimetry are taken into gastrointestinal mucosa of rats, as follows:
account by computational fluid dynamics modelling of
formaldehyde flux in various regions of the nose and a TC = 260 mg/litre
single-path model for the lower respiratory tract of 100
humans (CIIT, 1999).
= 2.6 mg/litre
Derivation of the doseresponse model and selec-
tion of various parameters are summarized in Appendix 4 where:
and presented in greater detail in CIIT (1999). Although
development of the biologically motivated case-specific # 260 mg/litre is the NOEL for effects (i.e., histopatho-
model required analysis of only the nasal cavity, for logical changes) in the aerodigestive tract, including
humans, carcinogenic risks were based on estimates of oral and gastrointestinal mucosa, of rats
formaldehyde dose to regions (i.e., regional flux) along the administered formaldehyde in drinking-water for
entire respiratory tract. 2 years in the most comprehensive study conducted
(Til et al., 1989), and
2) Default modelling # 100 is the uncertainty factor (10 for interspecies
variation, 10 for intraspecies variation).2
For comparison, a tumorigenic concentration05
(TC05) (i.e., the concentration associated with a 5% 11.1.3 Sample human health risk characterization
increase in tumour incidence over background) of 7.9 ppm
(9.5 mg/m3) (95% lower confidence limit [LCL] = 6.6 ppm Characterization of human health risks associated
[7.9 mg/m3]) formaldehyde was derived from data on the with exposure to formaldehyde is based upon analysis of
incidence of nasal squamous tumours in rats exposed to the concentrations of this substance in air and some food
this substance in the single study (i.e., Monticello et al., products, rather than estimates of total daily intake per se,
1996) in which exposureresponse was best since effects are observed primarily in the tissue of first
characterized.1 Information on estimation of the TC05 is contact and are related to the level of exposure rather than
presented in greater detail in Appendix 5. to total systemic intake.
11.1.2.2 Oral exposure Emphasis for the characterization of health risks

associated with the inhalation of formaldehyde in the
environment in the sample country (i.e., Canada) is on
1
Based upon the incidence of nasal tumours in rats 2
Available data are inadequate to further address
exposed to formaldehyde, combined from the studies toxicokinetic and toxicodynamic aspects of components
conducted by Kerns et al. (1983) and Monticello et al. of uncertainty with values derived on the basis of
(1996), the concentration of formaldehyde associated with compound-specific data, and guidance is not explicit,
a 5% increase in tumour incidence (maximum likelihood currently (IPCS, 1994), on more generalized replacement of
estimate) was approximately 6.1 ppm (7.3 mg/m3) (CIIT, kinetic components for effects related to delivered
1999). concentration.
40
Formaldehyde
non-neoplastic effects that occur at lowest concentrations which effects (i.e., sensory irritation) occur, although
(i.e., sensory irritation). The adequacy of this approach to additional investigation of an unconfirmed report of
protect for potential carcinogenicity is considered in the effects on respiratory function in children exposed to
context of the biologically motivated case-specific model lower levels of formaldehyde is desirable.
described above in section 11.1.2.1.2.
The degree of confidence in the database that
In humans (as well as laboratory animals), signs of supports an obligatory role of regenerative proliferation in
ocular and upper respiratory tract sensory irritation have the induction of nasal tumours in rats is moderate to high,
been observed at exposures typically greater than 100 ppb although the mechanism of carcinogenicity of
[120 g/m3]). The estimated median (2024 ppb [2429 formaldehyde is unclear. Although the biologically
g/m3]) and mean (2830 ppb [3436 g/m3]) 24-h time- motivated case-specific model for estimation of cancer
weighted average exposures to formaldehyde in air in risks is clearly preferred due to incorporation of as many
Canada are, at most, one-third of this value. This value is biological data as possible, there are a number of uncer-
also greater than the estimated time-weighted average tainties described in more detail in CIIT (1999) and
exposure (6778 ppb [8094 g/m3]) to which 95% of the summarized briefly here, although sensitivity analyses
population is exposed. In some indoor locations, however, were not conducted. For dosimetry, sources of uncer-
concentrations may approach the level associated with tainty for which sensitivity analyses would have been
signs of eye and respiratory tract sensory irritation in appropriate include the use of individual rat, primate, and
humans. human nasal anatomies as representative of the general
population, the use of a typical-path human lung structure
Based upon the biologically motivated case-specific to represent people with compromised lungs, the sizes of
model, the predicted additional risk of upper respiratory specific airways, the use of a symmetric Weibel model for
tract cancer for non-smoking workers with an 80-year the lung, the estimation of the location and extent of
lifetime continous exposure to 0.004 ppm (0.0048 mg/m3) squamous and olfactory epithelium and of mucus- and
formaldehyde and having 40 years of occupational non-mucus-coated nasal regions in the human, and the
exposure (8 h/day, 5 days/week) to 1 ppm (1.2 mg/m3) values of mass transfer and dispersion coefficients. The
formaldehyde was 8.8 106 (CIIT, 1999). For the general lack of human data on formaldehyde-related changes in
population, the predicted additional risks of upper the values of key parameters of the clonal growth
respiratory tract cancer for non-smokers, associated with component accounts for much of the uncertainty in the
an 80-year continuous exposure to levels of formaldehyde biologically motivated case-specific model.
between 0.001 and 0.1 ppm (1.2 and 120 g/m3), range from
2.3 1010 to 2.7 108, respectively (CIIT, 1999). The risks In order to better define the mode of action of
of upper respiratory tract cancer predicted by the induction of tumours, elaboration of the quantitative
biologically motivated case-specific model to be relationship between DNAprotein crosslinks and
associated with exposure to the median, mean, and 95th mutation and the time course of loss of DNAprotein
percentile concentrations of formaldehyde in air in Canada crosslinks is desirable. Additional characterization of the
are also exceedingly low (i.e., <2.7 108). shape of the concentrationresponse relationship for
regenerative proliferative response would also be
Available information is considered insufficient to informative.
fully characterize the exposure of individuals in Canada or
elsewhere to formaldehyde in foodstuffs. However, based Comparison of the output of the biologically
upon limited information, the levels of formaldehyde in motivated case-specific model with that for the com-
drinking-water (i.e., up to 10 g/litre) appear to be more parable value for default methodology (i.e., estimation of
than 2 orders of magnitude less than the tolerable tumorigenic concentrations close to the experimental
concentration (2.6 mg/litre). Although the concentration range) indicates that values for the former are at least
of formaldehyde in some food products would appear to 3 orders of magnitude less than that for the latter.
exceed the tolerable concentration, the extent of its
bioavailability therein is unknown. 11.2 Evaluation of environmental effects
11.1.4 Uncertainties in the evaluation of health 11.2.1 Assessment end-points

effects
Formaldehyde enters the Canadian environment
With respect to toxicity, the degree of confidence mainly from natural and anthropogenic combustion
that critical effects are well characterized is high. A sources, from industrial on-site releases, from off-gassing
relatively extensive database in both humans and animals of formaldehyde products, and through secondary
indicates that critical effects occur at the initial site of formation as a result of oxidation of anthropogenic and
exposure to this substance. The database in humans is natural organic compounds in air. Almost all releases and
also sufficiently robust to serve as a basis for confident formation in the ambient environment are in air, with small
conclusion concerning the consistently lowest levels at amounts released to water.
41
Given its physical/chemical properties, formalde- Therefore, although limited, the available toxicity
hyde is degraded by various processes in air, with very studies cover an array of organisms from different taxa
small amounts transferring into water. When released to and ecological niches and are considered adequate for an
water or soil, formaldehyde is expected to remain primarily assessment of risks to terrestrial biota. The single most
in the original compartment of release, where it undergoes sensitive response for all of these end-points will be used
various biological and physical degradation processes. as the critical toxicity value (CTV) for the risk character-
Formaldehyde is not bioaccumulative or persistent in any ization for terrestrial effects.
compartment of the environment.
11.2.2 Sample environmental risk characterization
Based on the sources and fate of formaldehyde in
the ambient environment, biota are expected to be Results of second-tier (i.e., conservative) anal-
exposed to formaldehyde primarily in air and, to a lesser yses are presented below, since hyperconservative
extent, in water. Little exposure of soil or benthic analyses based on comparison of an estimated exposure
organisms is expected. While formaldehyde occurs value (EEV) with an estimated no-effects value (ENEV),
naturally in plants and animals, it is readily metabolized determined by dividing a CTV by an application factor,
and does not bioaccumulate in organisms. Therefore, the resulted in hyperconservative quotients (EEV/ENEV)
focus of the environmental risk characterization will be on greater than 1. Additional information related to the
terrestrial and aquatic organisms exposed directly to sample environmental risk characterization is presented in
ambient formaldehyde in air and water. Appendix 6.
11.2.1.1 Aquatic end-points 11.2.2.1 Aquatic organisms
Data on aquatic toxicity are available for a variety of Environmental exposure to formaldehyde in water is
algae, microorganisms, invertebrates, fish, and amphibians expected to be greatest near areas of high atmospheric
(section 10.1). Identified sensitive end-points include concentrations (where some formaldehyde can partition
effects on the development and survival of algae and from air into water) and near spills or effluent outfalls.
invertebrates (Bills et al., 1977; Bringmann & Khn, 1980a; Measured concentrations are available in Canada for
Burridge et al., 1995a,b), inhibition of cell multiplication in effluents and groundwater.
protozoa (Bringmann & Khn, 1980a), immobilization of
crustaceans (Bills et al., 1977), and mortality in fish 11.2.2.1.1 Effluent analysis
(Reardon & Harrell, 1990).
The highest 1-day concentration identified in an
Algae are primary producers in aquatic systems, industrial effluent was 325 g/litre (Environment Canada,
forming the base of the aquatic food-chain, while zoo- 1997b). The effluent EEV was based on the conservative
plankton, including protozoans and crustaceans, are assumption that organisms could be living at the point of
consumed by many species of invertebrates and verte- discharge.
brates. Fish are consumers in aquatic communities and
themselves feed piscivorous fish, birds, and mammals. For a conservative analysis, dilution can be con-
sidered. Hence, the hyperconservative EEV of 325 g/litre
11.2.1.2 Terrestrial end-points can be divided by a generic and conservative dilution
factor of 10 derived for all types of water bodies to
Data on terrestrial toxicity are available for a variety estimate ambient concentrations of formaldehyde near
of microorganisms, plants, and invertebrates (section outfalls. This results in a conservative effluent EEV of 32.5
10.2), as well as from mammalian toxicology studies g/litre.
(section 8). The most sensitive identified end-points
include primarily effects on the growth and development For aquatic organisms, a CTV of 360 g/litre (96-h
of plants (Haagen-Smit et al., 1952; Barker & Shimabuku, EC50 for immobility in seed shrimp Cypridopsis sp.) (Bills
1992; Mutters et al., 1993). et al., 1977) was selected as the most sensitive end-point
from a large data set composed of toxicity studies
Bacteria and fungi are ubiquitous in terrestrial conducted on at least 34 freshwater species of aquatic
ecosystems and, as saprophytes, are essential for nutrient algae, microorganisms, invertebrates, fish, and
cycling. Terrestrial plants are primary producers, provide amphibians. For the conservative analysis, the ENEV is
food and cover for animals, and provide soil cover to derived by dividing the CTV by a factor of 10. This factor
reduce erosion and moisture loss. Invertebrates are an accounts for the uncertainty surrounding the
important component of the terrestrial ecosystem, con- extrapolation from the EC50 to a chronic no-effects value,
suming both plant and animal matter while serving as the extrapolation from laboratory to field conditions, and
forage for other animals. Vertebrate wildlife species are interspecies and intraspecies variations in sensitivity. The
key consumers in most terrestrial ecosystems. resulting ENEV is 36 g/litre.
42
Formaldehyde
The conservative quotient is calculated by dividing ponding amount in fog (9000 g/litre) that affects the
the EEV by the ENEV as follows: growth and reproduction potential of the brassica plant
(Brassica rapa) exposed 4.5 h/night, 3 nights/week, for 40
Quotient = EEV days (Barker & Shimabuku, 1992). This value is the lowest
ENEV from a moderate data set composed of acute and chronic
toxicity studies conducted on at least 18 species of
= 32.5 g/litre
36 g/litre terrestrial plants, microorganisms, invertebrates, and
mammals exposed to air and/or fog water. Application of a
factor of 2 to the CTV of 18 g/m3 results in an ENEV for
= 0.9
the conservative analysis of the exposure scenario for
terrestrial organisms of 9 g/m3.
Since the conservative quotient is less than 1, it is
unlikely that exposure to concentrations in water resulting
The conservative quotient is calculated by dividing
from effluent discharge are causing adverse effects on
the EEV by the ENEV as follows:
populations of aquatic organisms in Canada.
Quotient = EEV
11.2.2.1.2 Groundwater analysis ENEV
A realistic representation of groundwater quality = 7.48 g/m3

can be achieved using a median concentration in ground- 9 g/m3
water of 100 g/litre. The groundwater EEV was based on
the conservative assumption that the groundwater could = 0.83
recharge directly to surface water at its full concentration.
Assuming some degree of dilution similar to that of Alternatively, for a conservative analysis, it may
effluent in receiving water bodies, the median value can also be more realistic to use a CTV from a toxicity study
be divided by the generic and conservative dilution factor involving exposure to formaldehyde in gas phase in air
of 10 to obtain a conservative estimate of possible rather than back-calculating from exposure in fog. For the
concentrations in the event of surface recharge. As a conservative analysis of the exposure of terrestrial
result, the conservative EEV for groundwater is 10 g/litre. organisms to formaldehyde in air, the CTV is 78 g/m3,
based on the lowest average concentration in air that
The conservative quotient is calculated by dividing caused a slight imbalance in the growth of shoots and
the EEV by the ENEV (as described above) as follows: roots in the common bean (Phaseolus vulgaris) exposed
for 7 h/day, 3 days/week, for 4 weeks in air (day: 25 C,
Quotient = EEV 40% humidity; night: 14 C, 60% humidity) (Mutters et al.,
ENEV 1993). This value was selected as the most sensitive end-
point from a moderate data set composed of acute and
= 10 g/litre
36 g/litre chronic toxicity studies conducted on at least 18 species
of terrestrial plants, microorganisms, invertebrates, and
= 0.28 mammals exposed to air and/or fog water.
Since the conservative quotient is less than 1, it is Dividing the CTV by a factor of 10 to account for
unlikely that concentrations of formaldehyde in ground- the uncertainty surrounding the conversion of the effect
concentration to a no-effect value, the extrapolation from
water are causing adverse effects on populations of
laboratory to field conditions, and interspecies and intra-
aquatic organisms in Canada.
species variations in sensitivity, the resulting ENEV is
11.2.2.2 Terrestrial organisms 7.8 g/m3. This yields the following conservative quotient:
Quotient = EEV
Environmental exposure to formaldehyde in air is
ENEV
expected to be greatest near sites of continuous release or
formation of formaldehyde, namely in urban centres and 7.48 g/m3
=
near industrial facilities releasing formaldehyde. For a 7.8 g/m3
conservative analysis, the concentration selected as the
EEV was 7.48 g/m3, representing the highest 90th = 0.96
percentile value calculated from 354 measurements made
in Toronto, Ontario, Canada, between 6 December 1989 This quotient is very close to 1.
and 18 December 1997.
Given the arguments for reducing the application
For the exposure of terrestrial organisms to formal- factor of the hyperconservative CTV for rapeseed and the
dehyde in air, the CTV is 18 g/m3, based on the corres- even milder effects observed for the common bean plant
43
(Mutters et al. [1993] themselves did not conclude any ill 12. PREVIOUS EVALUATIONS BY
effects from formaldehyde), the application factor can be INTERNATIONAL BODIES
reduced from 10 to 2 for a more realistic ENEV of 39 g/m3.
This results in a lower conservative quotient:
The International Agency for Research on Cancer
Quotient = EEV
(IARC, 1995) has classified formaldehyde in group 2A
ENEV
(probably carcinogenic to humans), based on limited
7.48 g/m3 evidence in humans and sufficient evidence in animals.
=
39 g/m3
An air quality guideline of 0.1 mg/m3 has been
= 0.19 derived based upon the development of nose and throat
irritation in humans; this guidance value is to be used
Since all three conservative quotients are less than with a 30-min averaging time (WHO, 2000). A drinking-
1, it is unlikely that formaldehyde in air causes adverse water guideline for formaldehyde of 900 g/litre has been
effects on terrestrial organisms in Canada. derived based on a no-observed-adverse-effect level
(NOAEL) of 15 mg/kg body weight divided by an
11.2.2.3 Discussion of uncertainty uncertainty factor of 100, and assuming 20% intake from
water (IPCS, 1996).
There are a number of potential sources of uncer-
tainty in this environmental risk assessment. Regarding
effects of formaldehyde on terrestrial and aquatic
organisms, uncertainty surrounds the extrapolation from
available toxicity data to potential ecosystem effects.
While the toxicity data set included studies on organisms
from a variety of ecological niches and taxa, there are
relatively few good long-term exposure studies available.
To account for these uncertainties, application factors
were used in the environmental risk analysis to derive
ENEVs.
For exposure in air, the measurements used in this

assessment are considered acceptable because they were
selected from an extensive set of recent air monitoring
data of urban and other sites, including from sites at or
near industrial facilities that use and release formaldehyde
in Canada. These sites can also be associated with high
concentrations of VOCs associated with secondary
formation of formaldehyde. Thus, available data on
atmospheric concentrations are considered representative
of the highest concentrations likely to be encountered in
air in Canada.
Only limited data are available for water, although

concentrations of formaldehyde are expected to be low
because of the limited releases to these media that have
been identified and the limited partitioning of formalde-
hyde to these compartments from air. The available data
on concentrations in groundwater include data from
industrial sites of the users of formaldehyde. Since data
are not available regarding surface recharge of the con-
taminated groundwater, the assessment very conserva-
tively assumed that recharge occurred at concentrations
equivalent to those measured in the groundwater with
minimal dilution.
44
Formaldehyde
REFERENCES Atkinson R, Arey J, Aschmann SM, Long WD, Tuazon EC, Winer
AM (1990) Lifetimes and fates of toxic air contaminants in
Californias atmosphere, March 1990. Sacramento, CA, California
Environmental Protection Agency, Air Resources Board, Research
Adams DO, Hamilton TA, Lauer LD, Dean JH (1987) The effect of Division (Contract No. A732-107).
formaldehyde exposure upon the mononuclear phagocyte system
of mice. Toxicology and applied pharmacology, 88:165174. Atkinson R, Arey J, Harger WP, Kwok ESC, Long WD (1993) Life-
times and fates of toxic air contaminants in Californias
Alexandersson R, Hedenstierna G (1988) Respiratory hazards atmosphere, June 1993. Sacramento, CA, California
associated with exposure to formaldehyde and solvents in acid- Environmental Protection Agency, Air Resources Board, Research
curing paints. Archives of environmental health, 43:222227. Division (Contract No. A032-055).
Alexandersson R, Hedenstierna G (1989) Pulmonary function in ATSDR (1999) Toxicological profile for formaldehyde. Atlanta,
wood workers exposed to formaldehyde: a prospective study. GA, US Department of Health and Human Services, Agency for
Archives of environmental health, 44:511. Toxic Substances and Disease Registry.
Altshuller AP, Cohen IR (1964) Atmospheric photooxidation of the Baker DC (1994) Projected emissions of hazardous air pollutants
ethylene nitric oxide system. International journal of air and water from a Shell coal gasification process-combined-cycle power
pollution, 8:611632. plant. Fuel, 73(7):10821086.
Andersen I, Mlhave L (1983) Controlled human studies with Ballarin C, Sarto F, Giacomelli L, Bartolucci GB, Clonfero E
formaldehyde. In: Gibson JE, ed. Formaldehyde toxicity. (1992) Micronucleated cells in nasal mucosa of
Washington, DC, Hemisphere Publishing, pp. 155165. formaldehyde-exposed workers. Mutation research, 280:17.
Andersen M (1999) Final report: Review of revised edition(s) of Baraniak Z, Nagpal DS, Neidert E (1988) Gas chromatographic
the formaldehyde hazard characterization and doseresponse determination of formaldehyde in maple syrup as 2,4-dinitro-
assessment. Fort Collins, CO, Colorado State University phenylhydrazone derivative. Journal of the Association of Official
(unpublished). Analytical Chemists, 71(4):740741.
Anderson WB, Huck PM, Douglas IP, Van Den Oever J, Hutcheon Bardana EJ Jr, Montanaro A (1991) Formaldehyde: an analysis of
BC, Fraser JC, Jasim SY, Patrick RJ, Donison HE, Uza MP (1995) its respiratory, cutaneous, and immunologic effects. Annals of
Ozone byproduct formation in three different types of surface allergy, 66:441452.
water. In: Proceedings of the 1994 Water Quality Technology
Conference, November 610, 1994, San Francisco, CA. Vol. 2. Barker JR, Shimabuku RA (1992) Formaldehyde-contaminated fog
Denver, CO, American Water Works Association, pp. 871908. effects on plant growth. Presented at the 85th Annual Meeting
and Exhibition of the Air and Waste Management Association,
Andjelkovich DA, Shy CM, Brown MH, Jansen DB, Richardson RB 2126 June 1992, Kansas City, MO, 13 pp. (Air and Waste
(1994) Mortality of iron foundry workers. III. Lung cancer case Management Association Report 92-150.01).
control study. Journal of occupational medicine, 36:13011309.
Barrow CS, Steinhagen WH, Chang JF (1983) Formaldehyde
Andjelkovich DA, Jansen DB, Brown MH, Richardson RB, Miller FJ sensory irritation. In: Gibson JE, ed. Formaldehyde toxicity.
(1995) Mortality of iron foundry workers. IV. Analysis of a subcohort Washington, DC, Hemisphere Publishing, pp. 1625.
exposed to formaldehyde. Journal of occupational and environ-
mental medicine, 36:13011309. Bauchinger M, Schmid E (1985) Cytogenetic effects in
lymphocytes of formaldehyde workers of a paper factory. Mutation
Appelman LM, Woutersen RA, Zwart A, Falke HE, Feron VJ (1988) research, 158:195199.
One-year inhalation toxicity study of formaldehyde in male rats
with a damaged or undamaged nasal mucosa. Journal of applied Berke JH (1987) Cytologic examination of the nasal mucosa in
toxicology, 8:8590. formaldehyde-exposed workers. Journal of occupational medicine,
29:681684.
ASTM (1990) Standard test method for determining formaldehyde
levels from wood products under defined test conditions using a Bermudez E, Delehanty LL (1986) The effects of in vitro formalde-
large chamber (Method E 1333-90). Philadelphia, PA, American hyde treatment on the cells of the rat nasal epithelium.
Society for Testing and Materials. Environmental mutagenesis, 8(Suppl. 6):11.
Atkinson R (1985) Kinetics and mechanisms of the gas-phase Bertazzi PA, Pesatori A, Guercilena S, Consonni D, Zocchetti C
reactions of the hydroxyl radicals with organic compounds under (1989) [Cancer risk among workers producing formaldehyde-based
atmospheric conditions. Chemical reviews, 85:69201. resins: extension of follow-up.] Medicina del Lavoro , 80:111122
(in Italian).
Atkinson R (1989) Atmospheric lifetimes and fate of acetaldehyde.
Sacramento, CA, California Environmental Protection Agency, Air Betterton EA, Hoffmann MR (1988) Henrys law constants of some
Resources Board, Research Division; Riverside, CA, University of environmentally important aldehydes. Environmental science and
California, Statewide Air Pollution Research Center (Contract No. technology, 22:361367.
A732-107).
Bhalla DK, Mahavni V, Nguyen T, McClure T (1991) Effects of
Atkinson R (1990) Gas-phase tropospheric chemistry of organic acute exposure to formaldehyde on surface morphology of nasal
compounds: A review. Atmospheric environment, 24A:141. epithelia in rats. Journal of toxicology and environmental health,
33:171188.
Atkinson R, Aschmann SM, Tuazon EC, Arey J, Zielinska B (1989)
Formation of 3-methylfuran from the gas-phase reaction of OH Bhatt HS, Lober SB, Combes B (1988) Effect of glutathione
radicals with isoprene and the rate constant for its reaction with depletion on aminopyrine and formaldehyde metabolism.
the OH radical. International journal of chemical kinetics, Biochemical pharmacology, 37:15811589.
21:593604.
45
BIBRA Toxicology International (1994) Formaldehyde. Contract Bringmann G, Khn R (1980b) [Determination of the harmful
report prepared for Health Canada, Ottawa, Ontario, 181 pp. effect on protozoa of substances endangering water quality. II.
Bacteria-consuming ciliates.] Zeitschrift fr Wasser und Abwasser
Bierbach A, Barnes I, Becker KH, Klotz B, Wiesen E (1994) OH- Forschung, 1:2631 (in German).
radical initiated degradation of aromatic hydrocarbons. In:
Angeletti G, Restelli G, eds. Physico-chemical behaviour of Bringmann G, Khn R, Winter A (1980) Determination of
atmospheric pollutants. Proceedings of the 6th European biological damage from water pollutants to protozoa. III.
Symposium, Varese, 1822 October 1993. Brussels, Commission Saprozoic flagellates. Zeitschrift fr Wasser und Abwasser
of the European Communities, pp. 129136 (CEC Report EUR Forschung, 13(5):170173.
15609/1 EN).
British Standards Institution (1989) Standard No. 22.
Billings RE, Ku RH, Brower ME, Dallas CE, Theiss JC (1984) Determination of extractable formaldehyde (BS 5669:1989).
Disposition of formaldehyde (CH2O) in mice. Toxicologist, 4:29. London, British Standards Institution, pp. 3137.
Bills D, Marking L, Chandler H Jr (1977) Investigation in fish Broder I, Corey P, Cole P, Lipa M, Mintz S, Nethercott JR (1988)
control. 73. Formalin: Its toxicity to nontarget aquatic organisms, Comparison of health of occupants and characteristics of houses
persistence and counteraction. Washington, DC, US Department among control homes and homes insulated with urea
of the Interior, Fish and Wildlife Service, pp. 17. formaldehyde foam. II. Initial health and house variables and
exposureresponse relationships. Environmental research,
Birdsong CL, Avault JV Jr (1971) Toxicity of certain chemicals to 45:156178.
juvenile pompano. The progressive fish-culturist, 33(2):7680.
Brownson RC, Alavanja MCR, Chang JC (1993) Occupational risk
Blair A, Stewart PA (1994) Comments on the Sterling and factors for lung cancer among nonsmoking women: a casecontrol
Weinkam analysis of data from the National Cancer Institute study in Missouri (United States). Cancer causes and control,
formaldehyde study. American journal of industrial medicine, 4:449454.
25:603606.
Brunn W, Klostermeyer H (1984) [Detection and determination of
Blair A, Stewart P, OBerg M, Gaffey W, Walrath J, Ward J, Bales formaldehyde in foods.] Lebensmittelchemie und Gerichtliche
R, Kaplan S, Cubit D (1986) Mortality among industrial workers Chemie, 38:1617 (in German) [cited in Buckley et al., 1988].
exposed to formaldehyde. Journal of the National Cancer
Institute, 76:10711084. Buckley KE, Fisher LJ, Mackay VG (1986) Electron capture gas
chromatographic determination of traces of formaldehyde in milk
Blair A, Stewart PA, Hoover RN, Fraumeni JF, Walrath J, OBerg as the 2,4-dinitrophenylhydrazone. Journal of the Association of
M, Gaffey W (1987) Cancers of the nasopharynx and oropharynx Official Analytical Chemists, 69(4):655657.
and formaldehyde exposure. Journal of the National Cancer
Institute, 78:191192. Buckley KE, Fisher LJ, Mackay VG (1988) Levels of formaldehyde
in milk, blood, and tissues of dairy cows and calves consuming
Blair A, Stewart PA, Hoover RN (1990a) Mortality from lung formalin-treated whey. Journal of agricultural and food chemistry,
cancer among workers employed in formaldehyde industries. 36:11461150.
American journal of industrial medicine, 17:683699.
Burridge TR, Lavery T, Lam PKS (1995a) Effects of tributyltin and
Blair A, Saracci R, Stewart PA, Hayes RB, Shy C (1990b) formaldehyde on the germination and growth of Phyllospora
Epidemiologic evidence on the relationship between comosa (Labillardiere) C. Agardh (Phaeophyta: Fucales). Bulletin
formaldehyde exposure and cancer. Scandinavian journal of of environmental contamination and toxicology, 55:525532.
work, environment and health, 16:381393.
Burridge TR, Lavery T, Lam PKS (1995b) Acute toxicity tests
Blair A, Linos A, Stewart PA, Burmeister LF, Gibson R, Everett G, using Phyllospora comosa (Labillardiere) C. Agardh (Phaeophyta:
Schuman L, Cantor KP (1993) Evaluation of risks for Fucales) and Allorchestes compressa Dana (Crustacea: Amphi-
non-Hodgkins lymphoma by occupation and industry exposures poda). Bulletin of environmental contamination and toxicology,
from a casecontrol study. American journal of industrial medicine, 55:621628.
23:301312.
California Air Resources Board (1993) Acetaldehyde as a toxic air
Boffetta P, Stellman SD, Garfinkel L (1989) A casecontrol study contaminant. Part A. Exposure assessment. Sacramento, CA,
of multiple myeloma nested in the American Cancer Society pros- California Environmental Protection Agency, Air Resources Board,
pective study. International journal of cancer, 43:554559. Stationary Source Division, November.
Bond GG, Flores GH, Shellenberger RJ, Cartmill JB, Fishbeck WA, Callas PW, Pastides H, Hosmer DW (1996) Lung cancer mortality
Cook RR (1986) Nested casecontrol study of lung cancer among among workers in formaldehyde industries. Journal of
chemical workers. American journal of epidemiology, 124:5366. occupational and environmental medicine, 38:747748.
Boysen M, Zadig E, Digernes V, Abeler V, Reith A (1990) Nasal Calvert JG, Kerr JA, Demerjian KL, McQuigg RD (1972) Photolysis
mucosa in workers exposed to formaldehyde: a pilot study. British of formaldehyde as a hydrogen atom source in the lower atmos-
journal of industrial medicine, 47:116121. phere. Science, 175:751752.
Bracamonte BG, Ortiz de Frutos FJ, Diez LI (1995) Occupational Cantoni C, Milva E, Bazzani M (1987) [Formaldehyde content in
allergic contact dermatitis due to formaldehyde and textile finish foods of animal origin.] Industrie Alimentari , 26(2):123126, 132
resins. Contact dermatitis, 33:139140. (in Italian).
Bringmann G, Khn R (1980a) Comparison of the toxicity thresh- Carmichael G (1983) Use of formalin to separate tadpoles from
olds of water pollutants to bacteria, algae and protozoa in the cell large-mouth bass fingerlings after harvesting. The progressive
multiplication inhibition test. Water research, 14:231241. fish-culturist, 45:105106.
46
Formaldehyde
Casanova M, Heck H dA (1987) Further studies of the metabolic Craft TR, Bermudez E, Skopek TR (1987) Formaldehyde muta-
incorporation and covalent binding of inhaled [ 3H]- and genesis and formation of DNA protein crosslinks in human lympho-
[14C]formaldehyde in Fischer-344 rats: effects of glutathione blasts in vitro . Mutation research, 176:147155.
depletion. Toxicology and applied pharmacology, 89:105121.
Crosby RM, Richardson KK, Craft TR, Benforado KB, Liber HL,
Casanova M, Heck H dA, Everitt JI, Harrington WW Jr, Popp JA Skopek TR (1988) Molecular analysis of formaldehyde-induced
(1988) Formaldehyde concentrations in the blood of rhesus mutations in human lymphoblasts and E. coli. Environmental and
monkeys after inhalation exposure. Food and chemical toxicology, molecular mutagenesis, 12:155166.
26:715716.
Cross GLC, Lach VH (1990) The effects of controlled exposure to
Casanova M, Deyo DF, Heck H dA (1989) Covalent binding of formaldehyde vapours on spores of Bacillus globigii nctc 10073.
inhaled formaldehyde to DNA in the nasal mucosa of Fischer 344 Journal of applied bacteriology, 68(5):461470.
rats: analysis of formaldehyde and DNA by high-performance
liquid chromatography and provisional pharmacokinetic Crump DR, Yu CWF, Squire RW, Atkinson M (1996) Small
interpretation. Fundamental and applied toxicology, 12:397417. chamber methods for characterizing formaldehyde emission from
particleboard. In: Tichenor BA, ed. Characterizing sources of
Casanova M, Morgan KT, Steinhagen WH, Everitt JI, Popp JA, indoor air pollution and related sink effects. Philadelphia, PA,
Heck H dA (1991) Covalent binding of inhaled formaldehyde to American Society for Testing and Materials, pp. 211214 (ASTM
DNA in the respiratory tract of rhesus monkeys: pharmacokinetics, Special Technical Publication 1287).
rat-to-monkey interspecies scaling, and extrapolation to man.
Fundamental and applied toxicology, 17:409428. Daisey JM, Mahanama KRR, Hodgson AT (1994) Toxic volatile
organic compounds in environmental tobacco smoke: Emission
Casanova M, Morgan KT, Gross EA, Moss OR, Heck H dA (1994) factors for modelling exposures of California populations.
DNAprotein cross-links and cell replication at specific sites in the Prepared for Research Division, Air Resources Board, California
nose of F344 rats exposed subchronically to formaldehyde. Environmental Protection Agency, Sacramento, CA, 109 pp.
Fundamental and applied toxicology, 23:525536. (Contract No. A133-186).
Cassee FR, Groten JP, Feron VJ (1996) Changes in the nasal Dalbey WE (1982) Formaldehyde and tumours in hamster respira-
epithelium of rats exposed by inhalation to mixtures of formal- tory tract. Toxicology, 24:914.
dehyde, acetaldehyde, and acrolein. Fundamental and applied
toxicology, 29:208218. Dallas CE, Scott MJ, Ward JB Jr, Theiss JC (1992) Cytogenetic
analysis of pulmonary lavage and bone marrow cells of rats after
Chan GS, Scafe M, Emami S (1992) Cemeteries and repeated formaldehyde inhalation. Journal of applied toxicology,
groundwater: An examination of the potential contamination of 12:199203.
groundwater by preservatives containing formaldehyde. Toronto,
Ontario, Ontario Ministry of the Environment, Water Resources Day JH, Lees REM, Clark RH, Pattee PL (1984) Respiratory
Branch. response to formaldehyde and off-gas of urea formaldehyde foam
insulation. Canadian Medical Association journal,
Chang JCF, Steinhagen WH, Barrow CS (1981) Effect of single or 131:10611065.
repeated formaldehyde exposure on minute volume of B6C3F1
mice and F-344 rats. Toxicology and applied pharmacology, Dean J (1985) Langes handbook of chemistry, 13th ed. New York,
61:451459. NY, McGraw-Hill.
Chapman PM, Fairbrother A, Brown D (1998) A critical evaluation Dean JH, Lauer LD, House RB, Murray MJ, Stillman WS, Irons RD,
of safety (uncertainty) factors for ecological risk assessment. Steinhagen WH, Phelps MC, Adams DO (1984) Studies of
Environmental toxicology and chemistry, 17(1):99108. immune function and host resistance in B6C3F1 mice exposed to
formaldehyde. Toxicology and applied pharmacology,
Chou CC, Que Hee SS (1992) Microtox EC50 values for drinking 72:519529.
water by-products produced by ozonolysis. Ecotoxicology and
environmental safety, 23:355363. de Andrade JB, Bispo MS, Rebouas MV, Carvalho MLSM,
Pinheiro HLC (1996) Spectrofluorimetric determination of formal-
CIIT (1999) Formaldehyde: Hazard characterization and dose dehyde in liquid samples. American laboratory, 28(12):5658.
response assessment for carcinogenicity by the route of
inhalation, rev. ed. Research Triangle Park, NC, Chemical Decisioneering, Inc. (1996) Crystal Ball Version 4.0. User manual.
Industry Institute of Toxicology. Denver, CO, Decisioneering, Inc., 286 pp.
Collins JJ, Caporossi JC, Utidjian HMD (1988) Formaldehyde Deneer JW, Seinen W, Hermens W (1988) The acute toxicity of
exposure and nasopharyngeal cancer: re-examination of the aldehydes to the guppy. Aquatic toxicology, 12:185192.
National Cancer Institute study and an update of one plant.
Journal of the National Cancer Institute, 80:376377. Dennis C, Gaunt H (1974) Effect of formaldehyde on fungi from
broiler houses. Journal of applied bacteriology, 37:595601.
Collins JJ, Acquavella JF, Esmen NA (1997) An updated meta-
analysis of formaldehyde exposure and upper respiratory cancers. De Serves C (1994) Gas phase formaldehyde and peroxide
Journal of occupational and environmental medicine, measurements in the Arctic atmosphere. Journal of geophysical
39:639651. research, 99(D12):25 39125 398.
Cosma GN, Jamasbi R, Marchok AC (1988) Growth inhibition and DMER, AEL (1996) Pathways analysis using fugacity modelling of
DNA damage induced by benzo[a]pyrene and formaldehyde in formaldehyde for the second Priority Substances List. Prepared
primary cultures of rat tracheal epithelial cells. Mutation research, for Chemicals Evaluation Division, Commercial Chemicals
201:161168. Evaluation Branch, Environment Canada, by Don Mackay
Environmental Research, Peterborough, Ontario, and Angus
Environmental Limited, Don Mills, Ontario, March.
47
Dobi L, Hanzl J, Rssner P, Jana L, Rulkov H, And.l ov S, Environment Canada (1999b) Summary report 1997. National
Klementov H (1988) [Evaluation of the clastogenic effect of Pollutant Release Inventory (NPRI). Canadian Environmental
formaldehyde in children in preschool and school facilities.] Protection Act. Hull, Quebec, Environment Canada.
Ceskoslovenska Hygiena, 33:596604 (in Czechoslovakian).
Environment Canada, Health Canada (2001) Canadian Environ-
Dobi L, Jan a L, Lochman I, Lochmanova A (1989) Genotoxic mental Protection Act. Priority Substances List assessment report
action of formaldehyde in exposed children. Mutation research, Formaldehyde. Ottawa, Ontario, Minister of Public Works and
216:310. Government Services.
Dong S, Dasgupta PK (1986) Solubility of gaseous formaldehyde Etkin DS (1996) Volatile organic compounds in indoor environ-
in liquid water and generation of trace standard gaseous formal- ments. Arlington, MA, Cutter Information Corp., 426 pp.
dehyde. Environmental science and technology, 20:637640.
European Commission (1989) Formaldehyde emission for wood
Eberhardt MA, Sieburth J (1985) A colorimetric procedure for the based materials: Guideline for the determination of steady state
determination of aldehydes in seawater and in cultures of methyl- concentrations in test chambers. Luxembourg, European
otrophic bacteria. Marine chemistry, 17:199212. Commission (EUR 12196 EN; Report No. 2 of the European
concerted action: Indoor air quality and its impact on man, COST
Ebner H, Kraft D (1991) Formaldehyde-induced anaphylaxis after Project 613).
dental treatment? Contact dermatitis, 24:307309.
Fan Q, Dasgupta PK (1994) Continuous automated determination
Edling C, Jarvholm B, Andersson L, Axelson O (1987) Mortality of atmospheric formaldehyde at the parts per trillion level.
and cancer incidence among workers in an abrasive Analytical chemistry, 66(4):551556.
manufacturing industry. British journal of industrial medicine,
44:5759. Feinman SE, ed. (1988) Formaldehyde sensitivity and toxicity.
Boca Raton, FL, CRC Press.
Edling C, Hellquist H, dkvist L (1988) Occupational exposure to
formaldehyde and histopathological changes in the nasal Feron VJ, Bruyntjes JP, Woutersen RA, Immel HR, Appelman LM
mucosa. British journal of industrial medicine, 45:761765. (1988) Nasal tumours in rats after short-term exposure to a cyto-
toxic concentration of formaldehyde. Cancer letters, 39:101111.
Eller PM, ed. (1989a) Method 3500. In: NIOSH manual of
analytical methods, 3rd ed. Supplement 3. Washington, DC, US Figley DA, Makohon JT (1993) Efficacy of post-manufacture
Government Printing Office, pp. 3500-1 3500-5 (DHHS (NIOSH) surface coatings to reduce formaldehyde emissions from
Publication No. 84-100). composite wood products. In: Proceedings of the 86th Annual
Meeting of the Air and Waste Management Association, Denver,
Eller PM, ed. (1989b) Method 2541. In: NIOSH manual of CO, June 1993. Vol. 11A. Health risk: human and ecological.
analytical methods, 3rd ed. Supplement 3. Washington, DC, US Pittsburgh, PA, Air and Waste Management Association, 11 pp.
Government Printing Office, pp. 2541-1 2541-4 (DHHS (NIOSH) (Paper No. 93-MP-3.01).
Publication No. 84-100).
Fisher PW, Foster JA, Deb K (1991) Development of toxic air
El Sayed F, Seite-Bellezza D, Sans B, Bayle-Lebey P, Marguery pollutant emissions for thirteen pulp and paper mills in Wisconsin.
MC, Bazex J (1995) Contact urticaria from formaldehyde in a root- In: TAPPI Proceedings 1991 Environmental Conference. Atlanta,
canal dental paste. Contact dermatitis, 33:353. GA, Technical Association of the Pulp and Paper Industry, pp.
469481.
Environment Canada (1995) Technical briefing note on composite
wood panels. Report prepared for Environmental Choice Fleig I, Petri N, Stocker WG, Theiss AM (1982) Cytogenetic
Program, Environment Canada, Ottawa, Ontario, 18 May 1995. analysis of blood lymphocytes of workers exposed to formaldehyde
in formaldehyde manufacturing and processing. Journal of
Environment Canada (1996) Summary report 1994. National occupational medicine, 24:10091012.
Pollutant Release Inventory (NPRI). Hull, Quebec, Environment
Canada, Pollution Data Branch. Fletcher JS, Johnson FL, McFarlane JC (1990) Influence of
greenhouse versus field testing and taxonomic differences on
Environment Canada (1997a) Notice respecting the second plant sensitivity to chemical treatment. Environmental toxicology
Priority Substances List and di(2-ethylhexyl) phthalate. Canada and chemistry, 9:769776.
Gazette, Part I, 15 February 1997, pp. 366368.
Florence E, Milner DF (1981) Determination of free and loosely
Environment Canada (1997b) Results of the CEPA Section 16 protein-bound formaldehyde in the tissues of pigs fed formalin-
Notice to Industry respecting the second Priority Substances List treated skim milk as a protein supplement. Journal of the science
and di(2-ethylhexyl) phthalate. Hull, Quebec, Environment of food and agriculture , 32:288292.
Canada, Commercial Chemicals Evaluation Branch, Use Patterns
Section. Flyvholm M-A, Andersen P (1993) Identification of formaldehyde
releasers and occurrence of formaldehyde and formaldehyde
Environment Canada (1997c) VOC emissions survey of releasers in registered chemical products. American journal of
adhesives, sealants and adhesive tape manufacturers in Canada. industrial medicine, 24:533552.
Draft report prepared for Pollution Data Branch, Environment
Canada, Hull, Quebec. Flyvholm M-A, Menn T (1992) Allergic contact dermatitis from
formaldehyde. Contact dermatitis, 27:2736.
Environment Canada (1999a) Canadian Environmental Protection
Act Priority Substances List Supporting document for the Fontignie-Houbrechts N (1981) Genetic effects of formaldehyde in
environmental assessment of formaldehyde. Hull, Quebec, the mouse. Mutation research, 88:109114.
Environment Canada, Commercial Chemicals Evaluation Branch.
Fowler JF, Skinner SM, Belsito DV (1992) Allergic contact derma-
titis from formaldehyde resins in permanent press clothing: An
48
Formaldehyde
underdiagnosed cause of generalized dermatitis. Journal of the Grosjean D (1991b) Atmospheric chemistry of toxic contaminants.
American Academy of Dermatology, 27:962968. 5. Unsaturated halogenated aliphatics: Allyl chloride,
chloroprene, hexachlorocyclopentadiene, vinylidene chloride.
Fredberg JJ, Wohl ME, Glass GM, Dorkin HL (1980) Airway area Journal of the Air and Waste Management Association,
by acoustic reflections measured at the mouth. Journal of applied 41(2):182189.
physiology, 48(5):749758.
Grosjean D (1991c) Atmospheric fate of toxic aromatic
Gardner MJ, Pannett B, Winter PD, Cruddas AM (1993) A cohort compounds. The science of the total environment, 100:367414.
study of workers exposed to formaldehyde in the British chemical
industry: an update. British journal of industrial medicine, Grosjean D, Swanson R, Ellis C (1983) Carbonyls in Los Angeles
50:827834. air: contribution of direct emissions and photochemistry. The
science of the total environment, 28:6585.
Gay BW Jr, Bufalini JJ (1971) Nitric acid and the nitrogen balance
of irradiated hydrocarbons in the presence of oxides of nitrogen. Grosjean D, Grosjean E, Williams EL II (1993a) Atmospheric
Environmental science and technology, 5:422425. chemistry of unsaturated alcohols. Environmental science and
technology, 27:24782485.
Georghiou PE, Winsor L, Sliwinski JF, Shirtliffe CJ (1993) Method
11. Determination of formaldehyde in indoor air by a liquid Grosjean D, Grosjean E, Williams EL (1993b) The reaction of
sorbent technique. In: Seifert B, van de Wiel H, Dodet B, ONeill ozone with MPAN, CH2=C(CH3)C(O)OONO2. Environmental science
IK, eds. Environmental carcinogens: Methods of analysis and and technology, 27:25482552.
exposure measurement. Vol. 12. Indoor air contaminants. Lyon,
International Agency for Research on Cancer, pp. 245249 (IARC Grosjean E, Grosjean D, Seinfeld JH (1996a) Atmospheric chem-
Scientific Publications No. 109). istry of 1-octene, 1-decene cyclohexene: gas-phase carbonyl and
peroxyacyl nitrate products. Environmental science and
Grin M, Siemiatycki J, Nadon L, Dewar R, Krewski D (1989) technology, 30(3):10381047.
Cancer risks due to occupational exposure to formaldehyde:
results of a multi-site casecontrol study in Montreal. International Grosjean E, de Andrade JB, Grosjean D (1996b) Carbonyl
journal of cancer, 44:5358. products of the gas-phase reaction of ozone with simple alkenes.
Environmental science and technology, 30(3):975983.
Gocke E, King M-T, Eckhardt K, Wild D (1981) Mutagenicity of
cosmetics ingredients by the European Communities. Mutation Guerin MR, Jenkins RA, Tomkins BA (1992) The chemistry of
research, 90:91109. environmental tobacco smoke: composition and measurement.
Boca Raton, FL, Lewis Publishers.
Godish T (1988) Residential formaldehyde contamination:
sources and levels. Comments on toxicology, 2(3):115134. Guski ME, Raczynski DT (1994) Evaluation of air toxic emissions
and impacts from an urban wood waste to energy facility.
Godish T (1989) Formaldehyde exposures from tobacco smoke: a Presented at the 87th Annual Meeting and Exhibition of the Air
review. American journal of public health, 79(8):10441045. and Waste Management Association, Cincinnati, OH, 15 pp.
(Presentation 94-RP130.04).
Green DJ, Sauder LR, Kulle TJ, Bascom R (1987) Acute response
to 3.0 ppm formaldehyde in exercising healthy nonsmokers and Haagen-Smit AJ, Darley EE, Zaitlin M, Hull H, Noble WM (1952)
asthmatics. American review of respiratory disease, 135:1261 Investigation on injury to plants from air pollution in the Los
1266. Angeles area. Plant physiology, 27:1834.
Green DJ, Bascom R, Healey EM, Hebel JR, Sauder LR, Kulle TJ Hansch C, Leo A (1979) Substituent constants for correlation
(1989) Acute pulmonary response in healthy, nonsmoking adults analysis in chemistry and biology. New York, NY, John Wiley and
to inhalation of formaldehyde and carbon. Journal of toxicology Sons.
and environmental health, 28:261275.
Hansch C, Leo AJ (1981) MEDCHEM Project. Claremont, CA,
Groah WJ, Bradfield J, Gramp G, Rudzinski R, Heroux G (1991) Pomona College (Issue No. 19).
Comparative response of reconstituted wood products to European
and North American test methods for determining formaldehyde Hansen J, Olsen JH (1995) Formaldehyde and cancer morbidity
emissions. Environmental science and technology, 25:117122. among male employees in Denmark. Cancer causes and control,
6:354360.
Grosjean D (1982) Formaldehyde and other carbonyls in Los
Angeles ambient air. Environmental science and technology, Harley RA, Cass GR (1994) Modeling the concentrations of gas-
16:254262. phase toxic organic air pollutants: direct emissions and
atmospheric formation. Environmental science and technology,
Grosjean D (1990a) Atmospheric chemistry of toxic contaminants. 28(1):8898.
2. Saturated aliphatics: acetaldehyde, dioxane, ethylene glycol
ethers, propylene oxide. Journal of the Air and Waste Harving H, Korsgaard J, Pedersen OF, Mlhave L, Dahl R (1990)
Management Association, 40(11):15221531. Pulmonary function and bronchial reactivity in asthmatics during
low-level formaldehyde exposure. Lung, 168:1521.
Grosjean D (1990b) Gas-phase reaction of ozone with 2-methyl-2-
butene: Dicarbonyl formation from Criegee biradicals. Hatch KL, Maibach HI (1995) Textile dermatitis: an update (I).
Environmental science and technology, 24:14281432. Resins, additives and fibers. Contact dermatitis, 32:319326.
Grosjean D (1991a) Atmospheric chemistry of toxic contaminants. Hayashi T, Reece CA, Shibamoto T (1986) Gas chromatographic
4. Saturated halogenated aliphatics: methyl bromide, determination of formaldehyde in coffee via thiazolidine
epichlorhydrin, phosgene. Journal of the Air and Waste derivative. Journal of the Association of Official Analytical
Management Association, 41(1):5661. Chemists, 69(1):101105.
49
Hayes RB, Raatgever JW, de Bruyn A, Gerin M (1986) Cancer of hyde of workers manufacturing oriented strand board. Archives of
the nasal cavity and paranasal sinuses, and formaldehyde expo- environmental health, 49:465470.
sure. International journal of cancer, 37:487492.
Holly EA, Aston DA, Ahn DK, Smith AH (1996) Intraocular mela-
Hayes RB, Blair A, Stewart PA, Herrick RF, Mahar H (1990) noma linked to occupations and chemical exposures.
Mortality of U.S. embalmers and funeral directors. American Epidemiology, 7:5561.
journal of industrial medicine, 18:641652.
Holmstrm M, Wilhelmsson B (1988) Respiratory symptoms and
Health Canada (1997) Health Canada 1994 Survey on Smoking pathophysiological effects of occupational exposure to formalde-
in Canada. Chronic diseases in Canada, 18(3):120129. hyde and wood dust. Scandinavian journal of work, environment
and health, 14:306311.
Health Canada (1998) Report of Health Canada/U.S. EPA
External Peer Review Workshop on Formaldehyde. Ottawa, Holmstrm M, Wilhelmsson B, Hellquist H (1989a) Histological
Ontario, Health Canada (unpublished). changes in the nasal mucosa in rats after long-term exposure to
formaldehyde and wood dust. Acta Oto-laryngologica,
Health Canada (2000) Draft supporting documentation for PSL2 108:274283.
assessments. Human exposure assessment for formaldehyde.
Ottawa, Ontario, Health Canada, Health Protection Branch, Holmstrm M, Rynnel-Dag B, Wilhelmsson B (1989b) Antibody
Priority Substances Section, January 2000. production in rats after long-term exposure to formaldehyde.
Toxicology and applied pharmacology, 100:328333.
Heck H dA, Casanova M (1987) Isotope effects and their implica-
tions for the covalent binding of inhaled [ 3H]- and Holmstrm M, Wilhelmsson B, Hellquist H, Rosn G (1989c)
[14C]formaldehyde in the rat nasal mucosa. Toxicology and Histological changes in the nasal mucosa in persons
applied pharmacology, 89:122134. occupationally exposed to formaldehyde alone and in
combination with wood dust. Acta Oto-laryngologica,
Heck H dA, Casanova M (1995) Nasal dosimetry of formaldehyde: 107:120129.
Modeling site specificity and the effects of preexposure. In: Miller
FJ, ed. Nasal toxicity and dosimetry of inhaled xenobiotics: Holness DL, Nethercott JR (1989) Health status of funeral service
Implications for human health. Washington, DC, Taylor & Francis, workers exposed to formaldehyde. Archives of environmental
pp. 159175. health, 44:222228.
Heck H dA, Chin TY, Schmitz MC (1983) Distribution of Horton AW, Tye R, Stemmer KL (1963) Experimental carcinogen-
[14C]formaldehyde in rats after inhalation exposure. In: Gibson JE, esis of the lung. Inhalation of gaseous formaldehyde or an aerosol
ed. Formaldehyde toxicity. Washington, DC, Hemisphere of coal tar by C3H mice. Journal of the National Cancer Institute,
Publishing, pp. 2637. 30:3143.
Heck H dA, Casanova-Schmitz M, Dodd PB, Schachter EN, Witek Horvath EP Jr, Anderson H Jr, Pierce WE, Hanrahan L, Wendlick
TJ, Tosun T (1985) Formaldehyde (CH2O) concentrations in the JD (1988) Effects of formaldehyde on the mucous membranes and
blood of humans and Fischer-344 rats exposed to CH2O under lungs. A study of an industrial population. Journal of the American
controlled conditions. American Industrial Hygiene Association Medical Association, 259:701707.
journal, 46:13.
Hose JE, Lightner DV (1980) Absence of formaldehyde residues in
Heikkil P, Priha E, Savela A (1991) [Formaldehyde.] Helsinki, penaeid shrimp exposed to formalin. Aquaculture , 21(2):197202.
Finnish Institute of Occupational Health and Finnish Work
Environment Fund (Exposures at Work No. 14) (in Finnish) [cited in Howard PH (1989) Handbook of environmental fate and exposure
IARC, 1995]. data for organic chemicals. Vol. 1. Large production and priority
pollutants. Chelsea, MI, Lewis Publishers, pp. 101106.
Heineman EF, Olsen JH, Pottern LM, Gomez M, Raffn E, Blair A
(1992) Occupational risk factors for multiple myeloma among Howard PH, Boethling RS, Jarvis WF, Meylan WM, Michalenko
Danish men. Cancer causes and control, 3:555568. EM (1991) Handbook of environmental degradation rates.
Chelsea, MI, Lewis Publishers.
Hellebust JA (1974) Extracellular products. In: Stewart WDP, ed.
Algal physiology and biochemistry. Oxford, Blackwell Scientific Howe RB, Crump KS (1982) GLOBAL82: A computer program to
Publications, pp. 838863. extrapolate quantal animal toxicity data to low doses. Ruston, LA,
Science Research Systems.
Helms DR (1964) The use of formalin to control tadpoles in
hatchery ponds. M.Sc. Thesis. Carbondale, IL, Southern Illinois HSDB (1999) Hazardous Substances Data Bank. Bethesda, MD,
University, 28 pp. US National Library of Medicine, National Toxicology Information
Program, 3 March 1999.
Helrich K, ed. (1990) Method 931.08. In: Official methods of
analysis of the Association of Official Analytical Chemists, 15th Huck PM, Anderson WB, Rowley SM, Daignault SA (1990)
ed. Vol. 2. Arlington, VA, Association of Official Analytical Formation and removal of selected aldehydes in a biological
Chemists, pp.10371038, 1149. drinking-water treatment process. Journal of water supply research
and technology Aqua, 39(5):321333.
Hemminki K, Kyyrnen P, Lindbohm M-L (1985) Spontaneous
abortions and malformations in the offspring of nurses exposed to IARC (1981) Wood, leather and some associated industries. Lyon,
anaesthetic gases, cytostatic drugs, and other potential hazards in International Agency for Research on Cancer, pp. 1412 (IARC
hospitals, based on registered information of outcome. Journal of Monographs on the Evaluation of Carcinogenic Risk of Chemicals
epidemiology and community health, 39:141147. to Humans, Volume 25).
Herbert FA, Hessel PA, Melenka LS, Yoshida K, Nakaza M (1994) IARC (1995) Wood dust and formaldehyde. Lyon, International
Respiratory consequences of exposure to wood dust and formalde- Agency for Research on Cancer, pp. 217375 (IARC Monographs
on the Evaluation of Carcinogenic Risks to Humans, Volume 62).
50
Formaldehyde
ICRP (1994) Human respiratory tract model for radiological protec- Kaminski J, Atwal AS, Mahadevan S (1993) Determination of
tion. Annals of the International Commission on Radiological formaldehyde in fresh and retail milk by liquid column
Protection, 24(13) (ICRP Publication 66). chromatography. Journal of the Association of Official Analytical
Chemists international, 76(5):10101013.
IPCS (1989) Formaldehyde. Geneva, World Health Organization,
International Programme on Chemical Safety, 219 pp. Kao AS (1994) Formation and removal reactions of hazardous air
(Environmental Health Criteria 89). pollutants. Journal of the Air and Waste Management Association,
44:683696.
IPCS (1994) Assessing human health risks of chemicals:
derivation of guidance values for health-based exposure limits. Karickhoff SW, Brown DS, Scott TA (1979) Sorption of
Geneva, World Health Organization, International Programme on hydrophobic pollutants on natural sediments. Water research,
Chemical Safety, 73 pp. (Environmental Health Criteria 170). 13:241248.
IPCS (1996) Guidelines for drinking-water quality. Vol. 2. Health Kauppinen T, Niemel R (1985) Occupational exposure to
criteria and other supporting information. Geneva, World Health chemical agents in the particleboard industry. Scandinavian
Organization, International Programme on Chemical Safety, 973 journal of work, environment and health, (14):161167 [cited in
pp. IARC, 1995].
IPCS (1997) Methanol. Geneva, World Health Organization, Inter- Keefer LK, Streeter AJ, Leung LY, Perry WC, Hu HS-W, Baillie TA
national Programme on Chemical Safety, 180 pp. (Environmental (1987) Pharmacokinetic and deuterium isotope effect studies on
Health Criteria 196). the metabolism of formaldehyde and formate to carbon dioxide in
rats in vivo. Drug metabolism and disposition, 15:300304.
IPCS (2000) International Chemical Safety Card Formaldehyde.
Geneva, World Health Organization, International Programme on Kelly TJ, Smith DL, Satola J (1999) Emission rates of
Chemical Safety (ICSC 0275). formaldehyde from materials and consumer products found in
California homes. Environmental science and technology,
Iversen OH (1988) Formaldehyde and skin tumorigenesis in 33(1):8188.
Sencar mice. Environment international, 14:2327 [cited in IPCS,
1989]. Kenaga EE (1980) Predicted bioconcentration factors and soil
sorption coefficients of pesticides and other chemicals.
Jakab GJ (1992) Relationship between carbon black particulate- Ecotoxicology and environmental safety, 4:2638.
bound formaldehyde, pulmonary antibacterial defenses, and
alveolar macrophage phagocytosis. Inhalation toxicology, Kenaga EE, Goring CAI (1980) Relationship between water solu-
4:325342. bility, soil sorption, octanolwater partitioning, and concentration
of chemicals in biota. In: Eaton JG, Parish PR, Hendricks AC, eds.
Jann O (1991) Present state and developments in formaldehyde Aquatic toxicology. Philadelphia, PA, American Society for
regulations and testing methods in Germany. In: Proceedings of Testing and Materials, pp. 78115 (ASTM Special Technical
the 25th International Particleboard/Composite Materials Publication 707).
Symposium. Pullman, WA, Washington State University.
Kennedy ER, Hull D (1986) Evaluation of Du Pont Pro-Tek
Jass HE (1985) History and status of formaldehyde in the Formaldehyde Badge and the 3M Formaldehyde Monitor.
cosmetics industry. In: Turoski V, ed. Formaldehyde analytical American Industrial Hygiene Association journal, 47:94105.
chemistry and toxicology. Washington, DC, American Chemical
Society, pp. 229236 (Advances in Chemistry Series 210). Kepler GM, Richardson RB, Morgan KT, Kimbell JS (1998) Com-
puter simulation of inspiratory nasal airflow and inhaled gas
Jermini C, Weber A, Grandjean E (1976) [Quantitative determina- uptake in a rhesus monkey. Toxicology and applied pharmacology,
tion of various gas-phase components of the side-stream smoke of 150:111.
cigarettes in the room air as a contribution to the problem of
passive smoking.] International archives of occupational and Kerns WD, Pavkov KL, Donofrio DJ, Gralla EJ, Swenberg JA
environmental health, 36:169181 (in German). (1983) Carcinogenicity of formaldehyde in rats and mice after
long-term inhalation exposure. Cancer research, 43:43824392.
Johannsen FR, Levinskas GJ, Tegeris AS (1986) Effects of formal-
dehyde in the rat and dog following oral exposure. Toxicology Kieber RJ, Zhou X, Mopper K (1990) Formation of carbonyl com-
letters, 30:16. pounds from UV-induced photodegradation of humic substances
in natural waters: Fate of riverine carbon in the sea. Limnology
Johansson EB, Tjlve H (1978) Distribution of [14C]dimethylnitroso- and oceanography, 35(7):15031515.
amine in mice. Autoradiographic studies in mice with inhibited
and noninhibited dimethylnitrosoamine metabolism and Kilburn KH (1994) Neurobehavioral impairment and seizures from
comparison with the distribution of [14C]formaldehyde. Toxicology formaldehyde. Archives of environmental health, 49:3744.
and applied pharmacology, 45:565575.
Kilburn KH, Warshaw RH (1992) Neurobehavioral effects of form-
John EM, Savitz DA, Shy CM (1994) Spontaneous abortions aldehyde and solvents on histology technicians: repeated testing
among cosmetologists. Epidemiology, 5:147155. across time. Environmental research, 58:134146.
Kamata E (1966) Aldehydes in lake and seawater. Bulletin of the Kilburn KH, Warshaw R, Boylen CT, Johnson S-JS, Seidman B,
Chemical Society of Japan, 36:1227. Sinclair R, Takaro T Jr (1985a) Pulmonary and neurobehavioral
effects of formaldehyde exposure. Archives of environmental
Kamata E, Nakadate M, Uchida O, Ogawa Y, Suzuki S, Kaneko T, health, 40:254260.
Saito M, Kurokawa Y (1997) Results of a 28-month chronic
inhalation toxicity study of formaldehyde in male Fischer-344 rats. Kilburn KH, Seidman BC, Warshaw R (1985b) Neurobehavioral
Journal of toxicological science, 22:239254. and respiratory symptoms of formaldehyde and xylene exposure in
histology technicians. Archives of environmental health, 40:229
233.
51
Kilburn KH, Warshaw R, Thornton JC (1987) Formaldehyde hprt DNA sequence and mRNA expression. Mutation research,
impairs memory, equilibrium, and dexterity in histology 226:3137.
technicians: effects which persist for days after exposure. Archives
of environmental health, 42:117120. Lindbohm M-L, Hemminki K, Bonhomme MG, Anttila A, Rantala
K, Heikkil P, Rosenberg MJ (1991) Effects of paternal
Kilburn KH, Warshaw R, Thornton JC, Husmark I (1989) An occupational exposure on spontaneous abortions. American
examination of factors that could affect choice reaction time in journal of public health, 81:10291033.
histology technicians. American journal of industrial medicine,
15:679686. Lipari F, Dasch JM, Scruggs WF (1984) Aldehyde emissions from
wood-burning fireplaces. Environmental science and technology,
Kimbell JS, Godo MN, Gross EA, Joyner DR, Richardson RB, 18:326330.
Morgan KT (1997) Computer simulation of inspiratory airflow in
all regions of the F344 rat nasal passages. Toxicology and Little JC, Hodgson AT, Gadgil AJ (1994) Modeling emissions of
applied pharmacology, 145:388398. volatile organic compounds from new carpets. Atmospheric
environment, 28(2):227234.
Kirschner EM (1995) Production of top 50 chemicals rose in 1994.
Chemical & engineering news, April 10, 1995, pp. 1620. Lockhart CL (1972) Control of nematodes in peat with formalde-
hyde. Canadian plant disease survey, 52:104.
Kitaeva LV, Kitaeva EM, Pimenova MN (1990) [Cytopathic and
cytogenetic effects of chronic inhalation of formaldehyde on the Lowe DC, Schmidt U (1983) Formaldehyde measurements in the
female rats germ and marrow cells.] Tsitologiya, 32:12121216 nonurban atmosphere. Journal of geophysical research,
(in Russian). 88:10 84410 858.
Kitaeva LV, Mikheeva EA, Shelomova LF, Shvartsman P Ya Lowe DC, Schmidt U, Ehhalt DH (1980) A new technique for
(1996) [Genotoxic effect of formaldehyde in somatic human cells measuring tropospheric formaldehyde. Geophysical research
in vivo.] Genetika, 32:12871290 (in Russian). letters, 7:825828.
Kitchens JF, Casner RE, Edwards GS, Harward WE, Macri BJ Luce D, Grin M, Leclerc A, Morcet J-F, Brugre J, Goldberg M
(1976) Investigation of selected potential environmental contami- (1993) Sinonasal cancer and occupational exposure to formalde-
nants: formaldehyde. Washington, DC, US Environmental Protec- hyde and other substances. International journal of cancer,
tion Agency, 204 pp. (EPA 560/2-76-009). 53:224231.
Kligerman AD, Phelps MC, Erexson GL (1984) Cytogenetic Mackay D (1991) Multimedia environmental models: the fugacity
analysis of lymphocytes from rats following formaldehyde approach. Chelsea, MI, Lewis Publishers.
inhalation. Toxicology letters, 21:241246.
Mackay D, Paterson S (1991) Evaluating the multimedia fate of
Klus H, Kuhn H (1982) [Distribution of different components of organic chemicals: a Level III fugacity model. Environmental
tobacco smoke between main-current and side-current smoke.] science and technology, 25:427436.
Beitrge zur Tabakforschung International, 11:229265 (in
German). Mackay D, Shiu W-Y, Ma K-C (1995) Illustrated handbook of
physical-chemical properties and environmental fate of organic
Kochhar R, Nanda V, Nagi B, Mehta SK (1986) Formaldehyde- compounds. Vol. IV. Chelsea, MI, Lewis Publishers.
induced corrosive gastric cicatrization: case report. Human
toxicology, 5:381382. Malaka T, Kodama AM (1990) Respiratory health of plywood
workers occupationally exposed to formaldehyde. Archives of
Krasner SW, McGuire MJ, Jacangelo JG, Patania NL, Reagan environmental health, 45:288294.
KM, Aieta EM (1989) The occurrence of disinfection by-products
in US drinking water. Journal of the American Water Works Maldotti AC, Chionboli C, Bignozzi CA, Bartocci C, Carassiti V
Association, 81(8):4153. (1980) Photo-oxidation of 1,3-butadiene containing systems
rate constant determination for the reaction of acrolein with OH
Krivanek ND, McAlack JW, Chromey NC (1983) Mouse skin radicals. International journal of chemical kinetics,
painting-initiation-promotion study with formaldehyde solutions 12(12):905919.
preliminary results. Toxicologist, 3:144 [cited in IPCS, 1989].
Marsh GM, Stone RA, Henderson VL (1992) Lung cancer mortality
Kroschwitz JI, ed. (1991) Kirk-Othmer encyclopedia of chemical among industrial workers exposed to formaldehyde: a Poisson
technology, 4th ed. Vol. 11. New York, NY, John Wiley and Sons. regression analysis of the National Cancer Institute study.
American Industrial Hygiene Association journal, 53:681691.
Krzyzanowski M, Quackenboss JJ, Lebowitz MD (1990) Chronic
respiratory effects of indoor formaldehyde exposure. Marsh GM, Stone RA, Esmen NA, Henderson VL, Lee K (1996)
Environmental research, 52:117125. Mortality among chemical workers in a factory where
formaldehyde was used. Occupational and environmental
Kulle TJ (1993) Acute odor and irritation response in healthy non- medicine, 53:613627.
smokers with formaldehyde exposure. Inhalation toxicology,
5:323332. Martin WJ (1990) A teratology study of inhaled formaldehyde in
the rat. Reproductive toxicology, 4:237239.
Lawrence JF, Iyengar JR (1983) The determination of
formaldehyde in beer and soft drinks by HPLC of the 2,4- Masaru N, Syozo F, Saburo K (1976) Effects of exposure to various
dinitrophenylhydrazone derivative. International journal of injurious gases on germination of lily pollen. Environmental pollu-
environmental analytical chemistry, 15:4752. tion, 11:181188.
Liber HL, Benforado K, Crosby RM, Simpson D, Skopek TR (1989) Matanoski GM (1989) Risks of pathologists exposed to formalde-
Formaldehyde-induced and spontaneous alterations in human hyde. Cincinnati, OH, National Institute for Occupational Safety
and Health, 45 pp. (PB91-173682).
52
Formaldehyde
Maurice F, Rivory J-P, Larsson PH, Johansson SGO, Bousquet J Morgan KT, Gross EA, Patterson DL (1986b) Distribution, progres-
(1986) Anaphylactic shock caused by formaldehyde in a patient sion, and recovery of acute formaldehyde-induced inhibition of
undergoing long-term hemodialysis. Journal of allergy and nasal mucociliary function in F-344 rats. Toxicology and applied
clinical immunology, 77:594597. pharmacology, 86:448456.
McCrillis RC, Howard EM, Guo Z, Krebs KA, Fortmann R, Lao H-C Morgan KT, Jiang X-Z, Starr TB, Kerns WD (1986c) More precise
(1999) Characterization of curing emissions from conversion localization of nasal tumors associated with chronic exposure of F-
varnishes. Journal of the Air and Waste Management Association, 344 rats to formaldehyde gas. Toxicology and applied pharmacol-
49:7075. ogy, 82:264271.
McMartin KE, Martin-Amat G, Noker PE, Tephly TR (1979) Lack of Mutters RG, Madore M, Bytnerowicz A (1993) Formaldehyde
a role for formaldehyde in methanol poisoning in the monkey. exposure affects growth and metabolism of common bean.
Biochemical pharmacology, 28:645649. Journal of the Air and Waste Management Association,
43:113116.
Meek ME, Atkinson A, Sitwell J (1985) Background paper on
formaldehyde prepared for WHO working group on indoor air Natarajan AT, Darroudi F, Bussman CJM, van Kesteren-van
quality: radon and formaldehyde. Ottawa, Ontario, Health and Leeuwen AC (1983) Evaluation of the mutagenicity of
Welfare Canada, Health Protection Branch, Bureau of Chemical formaldehyde in mammalian cytogenetic assays in vivo and vitro .
Hazards, pp. 1124. Mutation research, 122:355360.
Merletti F, Boffetta P, Ferro G, Pisani P, Terracini B (1991) National Particleboard Association (1983) Small scale test method
Occupation and cancer of the oral cavity or oropharynx in Turin, for determining formaldehyde emissions from wood products
Italy. Scandinavian journal of work, environment and health, Two hour desiccator test. Gaithersburg, MD, National
17:248254. Particleboard Association (Formaldehyde Test Method 1-1983).
Meyer B, Hermanns K (1985) Formaldehyde release from pressed NCASI (1994) Evaluation of methods to estimate releasable
wood products. In: Turoski V, ed. Formaldehyde analytical formaldehyde from formaldehyde resin containing wood and paper
chemistry and toxicology. Washington, DC, American Chemical product dusts. Research Triangle Park, NC, National Council of
Society, pp. 101116 (Advances in Chemistry Series 210). the Paper Industry for Air and Stream Improvement (NCASI
Technical Bulletin No. 664).
Migliore L, Ventura L, Barale R, Loprieno N, Castellino S, Pulci R
(1989) Micronuclei and nuclear anomalies induced in the gastro- Nishi K, Yamada M, Wakasugi C (1988) Formaldehyde poisoning:
intestinal epithelium of rats treated with formaldehyde. report of an autopsy case. Nippon Hoigaku Zasshi, 42:8589.
Mutagenesis, 4:327334.
Norton LA (1991) Common and uncommon reactions to formalde-
Miyake T, Shibamoto T (1995) Quantitative analysis by gas chro- hyde-containing nail hardeners. Seminars in dermatology, 10:29
matography of volatile carbonyl compounds in cigarette smoke. 33.
Journal of chromatography, A 693:376381.
Novamann International (1997) SWARU incinerator emission
Mhler K, Denbsky G (1970) [Determination of formaldehyde in characterization for compliance with certificate of approval.
foods.] Zeitschrift fr Lebensmittel-Untersuchung und -Forschung, Prepared by Novamann (Ontario) Inc. for Regional Municipality of
142:109 (in German) [cited in IPCS, 1989, but not listed among Hamilton-Wentworth and Laidlaw Technologies, Mississauga,
references; cited in Owen et al., 1990, as Mohler, K. and Denby, Ontario.
G. (1970), as reported in Cantoni et al. (1987)].
Nuccio J, Seaton PJ, Kieber RJ (1995) Biological production of
Monteiro-Riviere NA, Popp JA (1986) Ultrastructural evaluation of formaldehyde in the marine environment. Limnology and
acute nasal toxicity in the rat respiratory epithelium in response to oceanography, 40(3):521527.
formaldehyde gas. Fundamental and applied toxicology,
6:251262. Nunn AJ, Craigen AA, Darbyshire JH, Venables KM, Newman
Taylor AJ (1990) Six year follow up of lung function in men
Monticello TM, Morgan KT (1994) Cell proliferation and occupationally exposed to formaldehyde. British journal of
formaldehyde-induced respiratory carcinogenesis. Risk analysis, industrial medicine, 47:747752.
14:313319.
OConnor B, Voss R (1997) Guidance with respect to PSL2 survey.
Monticello TM, Morgan KT, Everitt JI, Popp JA (1989) Effects of Pointe-Claire, Quebec, Pulp and Paper Research Institute of
formaldehyde gas on the respiratory tract of rhesus monkeys. Canada, 2 April 1997.
Pathology and cell proliferation. American journal of pathology,
134:515527. Olin KL, Cherr GN, Rifkin E, Keen CL (1996) The effects of some
redox-active metals and reactive aldehydes on DNAprotein cross-
Monticello TM, Miller FJ, Morgan KT (1991) Regional increases links in vitro . Toxicology, 110:18.
in rat nasal epithelial cell proliferation following acute and
subchronic inhalation of formaldehyde. Toxicology and applied Olsen JH, Asnaes S (1986) Formaldehyde and the risk of squa-
pharmacology, 111:409421. mous cell carcinoma of the sinonasal cavities. British journal of
industrial medicine, 43:769774.
Monticello TM, Swenberg JA, Gross EA, Leininger JR, Kimbell
JS, Seilkop S, Starr TB, Gibson JE, Morgan KT (1996) Correlation Owen BA, Dudney CS, Tan EL, Easterly CE (1990) Formaldehyde
of regional and nonlinear formaldehyde-induced nasal cancer in drinking water: Comparative hazard evaluation and an
with proliferating populations of cells. Cancer research, approach to regulation. Regulatory toxicology and pharmacology,
56:10121022. 11:200236.
Morgan KT, Patterson DL, Gross EA (1986a) Responses of the Partanen T (1993) Formaldehyde exposure and respiratory cancer
nasal mucociliary apparatus of F-344 rats to formaldehyde gas. a meta-analysis of the epidemiologic evidence. Scandinavian
Toxicology and applied pharmacology, 82:113. journal of work, environment and health, 19:815.
53
Partanen T, Kauppinen T, Hernberg S, Nickels J, Luukkonen R, Restani P, Restelli AR, Galli CL (1992) Formaldehyde and hexa-
Hakulinen T, Pukkala E (1990) Formaldehyde exposure and res- methylenetetramine as food additives: chemical interactions and
piratory cancer among woodworkers an update. Scandinavian toxicology. Food additives and contaminants, 9(5):597605.
journal of work, environment and health, 16:394400.
Reuzel PGJ, Wilmer JWGM, Woutersen RA, Zwart A, Rombout
Patterson DL, Gross EA, Bogdanffy MS, Morgan KT (1986) Reten- PJA, Feron VJ (1990) Interactive effects of ozone and formalde-
tion of formaldehyde gas by the nasal passages of F-344 rats. hyde on the nasal respiratory lining epithelium in rats. Journal of
Toxicologist, 6:55. toxicology and environmental health, 29:279292.
Pazdrak K, Grski P, Krakowiak A, Ruta U (1993) Changes in nasal Riedel F, Hasenauer E, Barth PJ, Koziorowski A, Rieger CHL
lavage fluid due to formaldehyde inhalation. International (1996) Formaldehyde exposure enhances inhalative allergic sensi-
archives of occupational and environmental health, 64:515519. tization in the guinea pig. Allergy, 51:9496.
Perry RH, Green DW, eds. (1984) Perrys chemical engineers Rietbrock N (1969) [Kinetics and pathways of methanol
handbook, 6th ed. New York, NY, McGraw-Hill. metabolism in rats.] Experimental pathology and pharmacology,
263:88105 (in German) [cited in IPCS, 1989].
Persson L (1973) Studies on the influence of lime, formalin,
formic acid and ammonium persulphate on the eggs and larvae Ritchie IM, Lehnen RG (1987) Formaldehyde-related health com-
of Ostertagia ostertagi and Cooperia oncophora in liquid cattle plaints of residents living in mobile and conventional homes.
manure. Zentralblatt fr Veterinaermedizin, 20:729740. American journal of public health, 77:323328.
Piersol P (1995) Build Green and conventional materials off- RIVM (1992) Exploratory report for formaldehyde. Bilthoven,
gassing tests. Prepared by ORTECH Corporation for Canada National Institute of Public Health and the Environment (RIVM
Mortgage and Housing Corporation, 6 February 1995, 24 pp. Report No. 710401018).
(Report No. 94-G53-B0106).
Ross JS, Rycroft JG, Cronin E (1992) Melamine-formaldehyde
Piletta-Zanin PA, Pasche-Koo F, Auderset PC, Huggenberger D, contact dermatitis in orthopaedic practice. Contact dermatitis,
Saurat J-H, Hauser C (1996) Detection of formaldehyde in ten 26:203204.
brands of moist baby toilet tissue by the acetylacetone methods
and high-performance liquid chromatography. Dermatology, Roush GC, Walrath J, Stayner LT, Kaplan SA, Flannery JT, Blair
193:170. A (1987) Nasopharyngeal cancer, sinonasal cancer, and
occupations related to formaldehyde: A casecontrol study.
Pottern LM, Heineman EF, Olsen JH, Raffn E, Blair A (1992) Journal of the National Cancer Institute, 79:12211224.
Multiple myeloma among Danish women: employment history
and workplace exposures. Cancer causes and control, 3:427432. Rusch GM, Bolte HF, Rinehart WE (1983) A 26-week inhalation
toxicity study with formaldehyde in the monkey, rat and hamster.
Preuss PW, Dailey RL, Lehman ES (1985) Exposure to formal- In: Gibson JE, ed. Formaldehyde toxicity. Washington, DC, Hemi-
dehyde. In: Turoski V, ed. Formaldehyde analytical chemistry sphere Publishing, pp. 98110.
and toxicology. Washington, DC, American Chemical Society, pp.
247259 (Advances in Chemistry Series 210). Saillenfait AM, Bonnet P, de Ceaurriz J (1989) The effects of
maternally inhaled formaldehyde on embryonal and foetal
Priha E (1995) Are textile formaldehyde regulations reasonable? development in rats. Food and chemical toxicology, 8:545548.
Experiences from the Finnish textile and clothing industries.
Regulatory toxicology and pharmacology, 22:243249. Saladino AJ, Willey JC, Lechner JF, Grafstrom RC, LaVeck M,
Harris CC (1985) Effects of formaldehyde, acetaldehyde, benzoyl
Priha E, Riipinen H, Korhonen K (1986) Exposure to peroxide, and hydrogen peroxide on cultured normal human
formaldehyde and solvents in Finnish furniture factories in bronchial epithelial cells. Cancer research, 45:25222526.
19751984. Annals of occupational hygiene, 30:289294 [cited
in IARC, 1995]. Sangster J (1989) Octanolwater partition coefficients of simple
organic compounds. Journal of physical and chemical reference
Ramdahl T, Alfheim I, Rustad S, Olsen T (1982) Chemical and data, 18:11111230.
biological characterization of emissions from small residential
stove burning wood and charcoal. Chemosphere , 11(4):601611. Satsumabayashi H, Kurita H, Chang YS, Carmichael GR, Ueda H
(1995) Photochemical formations of lower aldehydes and lower
Reardon IS, Harrell RM (1990) Acute toxicity of formalin and fatty acids under long-range transport in central Japan.
copper sulfate to striped bass fingerlings held in varying salinities. Atmospheric environment, 29(2):255266.
Aquaculture , 87(3/4):255270.
Sauder LR, Chatham MD, Green DJ, Kulle TJ (1986) Acute pul-
Recio L, Sisk S, Pluta L, Bermudez E, Gross EA, Chen Z, Morgan monary response to formaldehyde exposure in healthy
K, Walker C (1992) p53 mutations in formaldehyde-induced nasal nonsmokers. Journal of occupational medicine, 28:420424.
squamous cell carcinomas in rats. Cancer research,
52:61136116. Sauder LR, Green DJ, Chatham MD, Kulle TJ (1987) Acute pul-
monary response of asthmatics to 3.0 ppm formaldehyde. Toxicol-
Rehbein H (1986) [Formation of formaldehyde in fish products.] ogy and industrial health, 3:569578.
Lebensmittelchemie und Gerichtliche Chemie, 40:147118 (in
German) [cited in IPCS, 1989]. Schachter EN, Witek TJ Jr, Tosun T, Leaderer BP, Beck GJ (1986)
A study of respiratory effects from exposure to 2 ppm
Reinhardt TE (1991) Monitoring firefighter exposure to air toxins formaldehyde in healthy subjects. Archives of environmental
at prescribed burns of forest and range biomass. Portland, OR, US health, 41:229239.
Department of Agriculture, Forest Service, Pacific Northwest
Research Station, 8 pp. (Research Paper PNW-RP-441). Schachter EN, Witek TJ Jr, Brody DJ, Tosun T, Beck GJ, Leaderer
BP (1987) A study of respiratory effects from exposure to 2.0 ppm
54
Formaldehyde
formaldehyde in occupationally exposed workers. Environmental Stills JB, Allen JL (1979) Residues of formaldehyde undetected in
research, 44:188205. fish exposed to formalin. The progressive fish-culturist, 41(2):67
68.
Schauer JJ, Kleeman ML, Cass GR, Simoneit BRT (1999) Mea-
surement of emissions from air pollution sources. 1. C1 through C29 Stroup NE, Blair A, Erikson GE (1986) Brain cancer and other
organic compounds from meat charbroiling. Environmental causes of death in anatomists. Journal of the National Cancer
science and technology, 33:15661577. Institute, 77:12171224.
Scheman AJ, Carrol PA, Brown KH, Osburn AH (1998) Formalde- Subramaniam RP, Richardson RB, Morgan KT, Guilmette RA,
hyde-related textile allergy: an update. Contact dermatitis, Kimbell JS (1998) Computational fluid dynamics simulations of
38:332336. inspiratory airflow in the human nose and nasopharynx. Inhalation
toxicology, 10:92120.
Scheuplein RJ (1985) Formaldehyde: The Food and Drug
Administrations perspective. In: Turoski V, ed. Formaldehyde Suruda A, Schulte P, Boeniger M, Hayes RB, Livingston GK,
analytical chemistry and toxicology. Washington, DC, American Steenland K, Stewart P, Herrick R, Douthit D, Fingerhut MA (1993)
Chemical Society, pp. 237245 (Advances in Chemistry Series Cytogenetic effects of formaldehyde exposure in students of
210). mortuary science. Cancer epidemiology, biomarkers and preven-
tion, 2:453460.
Schlitt H, Knppel H (1989) Carbonyl compounds in mainstream
and sidestream cigarette smoke. In: Bieva C, Courtois Y, Govaerts Suskov II, Sazonova LA (1982) Cytogenetic effects of epoxy,
M, eds. Present and future of indoor air quality. Amsterdam, phenol-formaldehyde and polyvinylchloride resins in man.
Excerpta Medica, pp. 197206. Mutation research, 104:137140.
Schriever E, Marutzky R, Merkel D (1983) [Examination of emis- Sverdrup GM, Riggs KB, Kelly TJ, Barrett RE, Peltier RG, Cooper
sions from small wood-fired combustion furnaces.] Staub- JA (1994) Toxic emissions from a cyclone burner boiler with an
Reinhaltung der Luft, 43:6265 (in German). ESP and with the SNOX demonstration and from a pulverized
coal burner boiler with an ESP/wet flue gas desulfurization
Seidenberg JM, Becker RA (1987) A summary of the results of 55 system. Presented at the 87th Annual Meeting and Exhibition of
chemicals screened for developmental toxicity in mice. Terato- the Air and Waste Management Association, Cincinnati, OH,
genesis, carcinogenesis, mutagenesis, 7:1728. 1924 June 1994 (94-WA73.02).
Sellakumar AR, Snyder CA, Solomon JJ, Albert RE (1985) Car- Swenberg JA, Kerns WD, Mitchell RI, Gralla EJ, Pavkov KL (1980)
cinogenicity of formaldehyde and hydrogen chloride in rats. Induction of squamous cell carcinomas of the rat nasal cavity by
Toxicology and applied pharmacology, 81:401406. inhalation exposure to formaldehyde vapor. Cancer research,
40:33983402.
Skov H, Hjorth J, Lohse C, Jensen NR, Restelli G (1992) Products
and mechanisms of the reactions of the nitrate radical (NO3) with Swenberg JA, Gross EA, Martin J, Popp JA (1983) Mechanisms of
isoprene, 1,3-butadiene and 2,3-dimethyl-1,3-butadiene in air. formaldehyde toxicity. In: Gibson JE, ed. Formaldehyde toxicity.
Atmospheric environment, 26A(15):27712783. Washington, DC, Hemisphere Publishing, pp. 132147.
Snyder RD, van Houten B (1986) Genotoxicity of formaldehyde Swenberg JA, Gross EA, Martin J, Randall HA (1986) Localization
and an evaluation of its effects on the DNA repair process in and quantitation of cell proliferation following exposure to nasal
human diploid fibroblasts. Mutation research, 165:2130. irritants. In: Barrow CS, ed. Toxicology of the nasal passages.
Washington, DC, Hemisphere Publishing, pp. 291300.
Soffritti M, Maltoni C, Maffei F, Biagi R (1989) Formaldehyde: an
experimental multipotential carcinogen. Toxicology and Tabor RG (1988) Control of formaldehyde release from wood
industrial health, 5:699730. products adhesives. Comments on toxicology, 2(3):191200.
Sotelo CG, Pieiro C, Prez-Martn RI (1995) Denaturation of fish Tanner RL, Zielinska B, Ueberna E, Harshfield G (1994) Measure-
protein during frozen storage: role of formaldehyde. Zeitschrift fr ments of carbonyls and the carbon isotopy of formaldehyde at a
Lebensmittel-Untersuchung und -Forschung, 200:1423. coastal site in Nova Scotia during NARE. Final report. Prepared
by Desert Research Institute, Reno, NV, for the Office of Global
Staudinger J, Roberts PV (1996) A critical review of Henrys law Programs, National Oceanic and Atmospheric Administration,
constants for environmental applications. Critical reviews in Silver Spring, MD, 25 pp. (DRI Document 3910-IFI).
environmental science and technology, 26:205297.
Tarkowski M, Gorski P (1995) Increased IgE antiovalbumin level in
Stayner LT, Elliott L, Blade L, Keenlyside R, Halperin W (1988) A mice exposed to formaldehyde. International archives of allergy
retrospective cohort mortality study of workers exposed to and immunology, 106:422424.
formaldehyde in the garment industry. American journal of
industrial medicine, 13:667681. Tashkov W (1996) Determination of formaldehyde in foods, bio-
logical media and technological materials by head space gas
Stenton SC, Hendrick DJ (1994) Formaldehyde. Immunology and chromatography. Chromatographia, 43(11/12):625627.
allergy clinics of North America, 14:635657.
Taskinen H, Kyyrrnen P, Hemminki K, Hoikkala M, Lajunen K,
Sterling TD, Weinkam JJ (1994) Mortality from respiratory cancers Lindbohm M-L (1994) Laboratory work and pregnancy outcome.
(including lung cancer) among workers employed in formaldehyde Journal of occupational medicine, 36:311319.
industries. American journal of industrial medicine, 25:593602.
Taskinen HK, Kyyrnen P, Sallmn M, Virtanen SV, Liukkonen
Stewart PA, Cubit DA, Blair A, Spirtas R (1987) Performance of TA, Huida O, Lindbohm M-L, Anttila A (1999) Reduced fertility
two formaldehyde passive dosimeters. Applied industrial hygiene, among female wood workers exposed to formaldehyde. American
2:6165. journal of industrial medicine, 36:206212.
55
Thomson EJ, Shackleton S, Harrington JM (1984) Chromosome TO11-38 (EPA Report No. EPA-600/4-89-017; US NTIS PB90-
aberrations and sister-chromatid exchange frequencies in 116989).
pathology staff occupationally exposed to formaldehyde. Mutation
research, 141:8993. US EPA (1990) Evaluation of emission factors for formaldehyde
from certain wood processing operations. Final report,
Tiemstra E (1989) Gas pipeline contaminants. Washington, DC, MayAugust 1989. Research Triangle Park, NC, US
American Gas Association, pp. 545548 (89-DT-84). Environmental Protection Agency, Office of Research and
Development, Air and Energy Engineering Research Laboratory
Til HP, Woutersen RA, Feron VJ (1988) Evaluation of the oral (EPA/600/8-90/052).
toxicity of acetaldehyde and formaldehyde in a 4-week drinking
water study in rats. Food and chemical toxicology, 26:447452. US EPA (1993) Motor vehicle-related air toxics study. Ann Arbor,
MI, US Environmental Protection Agency, Office of Mobile
Til HP, Woutersen RA, Feron VJ, Hollanders VHM, Falke HE Sources, Emission Planning and Strategies Division, April (EPA
(1989) Two-year drinking-water study of formaldehyde in rats. 420-R-93-005).
Food and chemical toxicology, 27:7787.
US NRC (1981) Formaldehyde and other aldehydes. Washington,
Titenko-Holland N, Levine AJ, Smith MT, Quintana PJE, DC, US National Research Council, National Academy Press, 340
Boeniger M, Hayes R, Suruda A, Schulte P (1996) Quantification pp.
of epithelial cell micronuclei by fluorescence in situ hybridization
(FISH) in mortuary science students exposed to formaldehyde. US OSHA (1990) Method 52. In: OSHA analytical methods
Mutation research, 371:237248. manual, 2nd ed. Part 1, Vol. 2 (Methods 2954). Salt Lake City,
UT, US Occupational Safety and Health Administration, pp. 52-1
Tobe M, Kaneko T, Uchida Y, Kamata E, Ogawa Y, Ikeda Y, 52-38.
Saito M (1985) Studies on the inhalation toxicity of formaldehyde.
Tokyo, National Sanitary and Medical Laboratory Service, Vargov M, Wagnerov J, Liskov A, Jakubovsk J, Gajdov M,
Toxicity, 43 pp. (TR-85-0236) [cited in IPCS, 1989]. Stolcov E, Kubov J, Tulinsk J, Stenclov R (1993) Subacute
immunotoxicity study of formaldehyde in male rats. Drug and
Tobe M, Naito K, Kurokawa Y (1989) Chronic toxicity study on chemical toxicology, 16:255275.
formaldehyde administered orally to rats. Toxicology, 56:7986.
Vasudeva N, Anand C (1996) Cytogenetic evaluation of medical
TRI (1994) 1992 Toxics Release Inventory, public data release. students exposed to formaldehyde vapor in the gross anatomy
Washington, DC, US Environmental Protection Agency, Office of dissection laboratory. Journal of the American College of Health,
Pollution Prevention and Toxics, p. 236. 44:177179.
Tsuchiya K, Hayashi Y, Onodera M, Hasegawa T (1975) Toxicity Vaughan TL, Strader C, Davis S, Daling JR (1986a)
of formaldehyde in experimental animals concentrations of the Formaldehyde and cancers of the pharynx, sinus and nasal cavity:
chemical in the elution from dishes of formaldehyde resin in some I. Occupational exposures. International journal of cancer,
vegetables. Keio journal of medicine, 24:1937. 38:677683.
Tsuchiya H, Ohtani S, Yamada K, Akagiri M, Takagi N, Sato M Vaughan TL, Strader C, Davis S, Daling JR (1986b)
(1994) Determination of formaldehyde in reagents and beverages Formaldehyde and cancers of the pharynx, sinus and nasal cavity:
using flow injection. Analyst, 119:14131416. II. Residential exposures. International journal of cancer,
38:685688.
Tsuda M, Frank N, Sato S, Sugimura T (1988) Marked increase in
the urinary level of N-nitrosothioproline after ingestion of cod with Veith GD, Macek KJ, Petrocelli SR, Carroll J (1980) An evaluation
vegetables. Cancer research, 48:40494052. of using partition coefficients and water solubility to estimate bio-
concentration factors for organic chemicals in fish. In: Eaton JG,
Upreti RK, Farooqui MYH, Ahmed AE, Ansari GAS (1987) Toxico- Parrish PR, Hendricks AC, eds. Aquatic toxicology. Philadelphia,
kinetics and molecular interaction of [ 14C]-formaldehyde in rats. PA, American Society for Testing and Materials, pp. 116129
Archives of environmental contamination and toxicology, 16:263 (ASTM Special Technical Publication 707).
273.
Verschueren K (1983) Handbook of environmental data on organic
Ura H, Nowak P, Litwin S, Watts P, Bonfil RD, Klein-Szanto AJ chemicals, 2nd ed. New York, NY, Van Nostrand Reinhold.
(1989) Effects of formaldehyde on normal xenotransplanted
human tracheobronchial epithelium. American journal of Vincenzi C, Guerra L, Peluso AM, Zucchelli V (1992) Allergic
pathology, 134:99106. contact dermatitis due to phenol-formaldehyde resins in a knee-
guard. Contact dermatitis, 27:54.
US EPA (1985) Health and environmental effects profile for
formaldehyde. Cincinnati, OH, US Environmental Protection Walker BL, Cooper CD (1992) Air pollution emission factors for
Agency, Environmental Criteria and Assessment Office, Office of medical waste incinerators. Journal of the Air and Waste Manage-
Health and Environmental Assessment, Office of Research and ment Association, 42:784791.
Development (EPA/600/X-85/362).
Wantke F, Hemmer W, Haglmuller T, Gotz M, Jarisch R (1995)
US EPA (1988a) Method TO5. In: Compendium of methods for the Anaphylaxis after dental treatment with a formaldehyde-
determination of toxic organic compounds in ambient air. containing tooth filling material. Allergy, 50:274276.
Research Triangle Park, NC, US Environmental Protection
Agency, Office of Research and Development, pp. TO5-1 TO5- Warneck P, Klippel W, Moortgat GK (1978) [Formaldehyde in
22 (EPA Report No. EPA-600/4-89-017; US NTIS PB90-116989). tropospheric clean air.] Berichte der Bunsengesellschaft fr
Physikalische Chemie, 82:11361142 (in German).
US EPA (1988b) Method TO11. In: Compendium of methods for
the determination of toxic organic compounds in ambient air. Weast RC, ed. (19821983) Handbook of chemistry and physics,
Research Triangle Park, NC, US Environmental Protection 62th ed. Boca Raton, FL, CRC Press.
Agency, Office of Research and Development, pp. TO11-1
56
Formaldehyde
Wellborn TL (1969) Toxicity of nine therapeutic and herbicidal Zafiriou OC, Alford J, Herrera M, Peltzer ET, Gagosian RB, Liu SC
compounds to striped bass. The progressive fish-culturist, (1980) Formaldehyde in remote marine air and rain: flux
31(1):2732. measurements and estimates. Geophysical research letters,
7:341344.
West S, Hildesheim A, Dosemeci M (1993) Non-viral risk factors for
nasopharyngeal carcinoma in the Philippines: Results from a Zhitkovich A, Lukanova A, Popov T, Taioli E, Cohen H, Costa M,
casecontrol study. International journal of cancer, 55:722727. Toniolo P (1996) DNAprotein crosslinks in peripheral
lymphocytes of individuals exposed to hexavalent chromium
WHO (2000) Air quality guidelines for Europe, 2nd ed. Copen- compounds. Biomarkers, 1:8693.
hagen, World Health Organization, Regional Office for Europe
(WHO Regional Publications, European Series, No. 91). Internet Zhou X, Mopper K (1990) Apparent partition coefficients of 15
address: http://www.who.dk carbonyl compounds between air and seawater and between air
and freshwater: Implications for airsea exchange. Environmental
Wickramaratne GA de S (1987) The Chernoff-Kavlock assay: its science and technology, 24(12):18641869.
validation and application in rats. Teratogenesis, carcinogenesis,
mutagenesis, 7:7383. Zimmermann PR, Chatfield RB, Fishman J, Crutzen PJ, Hanst PL
(1978) Estimates on the production of CO and H2 from the
Wilmer JWGM, Woutersen RA, Appelman LM, Leeman WR, Feron oxidation of hydrocarbon emissions from vegetation. Geophysical
VJ (1987) Subacute (4-week) inhalation toxicity study of formalde- research letters, 5:679682.
hyde in male rats: 8-hour intermittent versus 8-hour continuous
exposures. Journal of applied toxicology, 7:1516. Zwart A, Woutersen RA, Wilmer JWGM, Spit BJ, Feron VJ (1988)
Cytotoxic and adaptive effects in rat nasal epithelium after 3-day
Wilmer JWGM, Woutersen RA, Appelman LM, Leeman WR, Feron and 13-week exposure to low concentrations of formaldehyde
VJ (1989) Subchronic (13-week) inhalation toxicity study of formal- vapour. Toxicology, 51:8799.
dehyde in male rats: 8-hour intermittent versus 8-hour continuous
exposures. Toxicology letters, 47:287293.
Witek TJ Jr, Schachter EN, Tosun T, Beck GJ, Leaderer BP (1987)

An evaluation of respiratory effects following exposure to 2.0 ppm
formaldehyde in asthmatics: lung function, symptoms, and airway
reactivity. Archives of environmental health, 42:230237.
Wolf DC, Gross EA, Lyght O, Bermudez E, Recio L, Morgan KT

(1995) Immunohistochemical localization of p53, PCNA, and
TFG-" proteins in formaldehyde-induced rat nasal squamous cell
carcinomas. Toxicology and applied pharmacology, 132:2735.
Wolverton BC, McDonald RC, Watkins EA Jr (1984) Foliage plants

for removing indoor air pollutants from energy efficient homes.
Economic botany, 38:224228.
Wortley P, Vaughan TL, Davis S, Morgan MS, Thomas DB (1992)

A casecontrol study of occupational risk factors for laryngeal
cancer. British journal of industrial medicine, 49:837844.
Woutersen RA, Appelman LM, Wilmer JWGM, Falke HE, Feron VJ

(1987) Subchronic (13-week) inhalation toxicity study of formalde-
hyde in rats. Journal of applied toxicology, 7:4349.
Woutersen RA, van Garderen-Hoetmer A, Bruijntjes JP, Zwart A,

Feron VJ (1989) Nasal tumours in rats after severe injury to the
nasal mucosa and prolonged exposure to 10 ppm formaldehyde.
Journal of applied toxicology, 9:3946.
Yager JW, Cohn KL, Spear RC, Fisher JM, Morse L (1986)
Sister-chromatid exchanges in lymphocytes of anatomy students
exposed to formaldehyde-embalming solution. Mutation research,
174:135139.
Yamada H, Matsui S (1992) Formation characteristics of formalde-

hyde and the formaldehyde precursors which release formal-
dehyde through thermal decomposition in water. Water science
and technology, 25(11):371378.
Yasuhara A, Shibamoto T (1995) Quantitative analysis of volatile

aldehydes formed from various kinds of fish flesh during heat
treatment. Journal of agricultural and food chemistry, 43:9497.
Ying C-J, Yan W-S, Zhao M-Y, Ye X-L, Xie H, Yin S-Y, Zhu X-S
(1997) Micronuclei in nasal mucosa, oral mucosa and
lymphocytes in students exposed to formaldehyde vapor in
anatomy class. Biomedical and environmental sciences,
10:451455.
57
APPENDIX 1 SOURCE DOCUMENT The product of this joint effort was a draft document
entitled Formaldehyde: Hazard Characterization and
DoseResponse Assessment for Carcinogenicity by the Route of
Inhalation (CIIT, 1999). This report, which was developed
Environment Canada & Health Canada (2001) primarily by CIIT (with input from J. Overton, US EPA), was
reviewed at an external peer review workshop of the following
Copies of the Canadian Environmental Protection Act invitees, convened by Health Canada and the US EPA on 1820
Priority Substances List assessment report (Environment Canada & March 1998, in Ottawa, Ontario, Canada (Health Canada, 1998):
Health Canada, 2001) and unpublished supporting
B. Allen, RAS Associates
documentation for formaldehyde may be obtained from:
M. Andersen, ICF Kaiser Engineering (Chair)
Commercial Chemicals Evaluation Branch D. Blakey, Health Canada
Environment Canada A. Dahl, Lovelace Respiratory Research Institute
14th floor, Place Vincent Massey D. Gaylor, US Food and Drug Administration
351 St. Joseph Blvd. Hull, J. Harkema, Michigan State University
D. Jacobson-Kram, MA BioServices
Quebec
Canada K1A 0H3 D. Krewski, Health Canada
R. Maronpot, National Institute of Environmental Health
or Sciences
G. Marsh, University of Pittsburgh
Environmental Health Centre J. Siemiatycki, Institut Armand-Frappier
J. Ultman, Pennsylvania State University
Health Canada
Address Locator: 0801A
Tunneys Pasture Written comments were also provided by S. Moolgavkar (Fred
Ottawa, Ontario Hutchinson Cancer Research Center).
Canada K1A 0L2
Following the workshop, the report was revised to reflect
Initial drafts of the supporting documentation and assess- comments of the external reviewers and recirculated; written
ment report for formaldehyde were prepared by staff of Health comments on the subsequently revised draft were submitted by all
Canada and Environment Canada. H. Hirtle, Health Canada, members of the external review panel (November 1998). The final
assisted in the preparation of the draft CICAD through inclusion of draft (dated 28 September 1999) (CIIT, 1999) was reviewed by the
additional relevant information. Chair of the workshop (M. Andersen) to ensure that comments had
been adequately addressed (Andersen, 1999).
The environmental assessment was led by R. Chnier,
R. Vincent, Environmental Toxicology Division, Health
Environment Canada, and coordinated by A. Bobra (AMBEC
Environmental Consultants) on behalf of Environment Canada. Canada, provided comments on the assessment report. Accuracy
of reporting, adequacy of coverage, and defensibility of
The sections of the assessment report relevant to the conclusions with respect to hazard characterization and
environmental assessment and the environmental supporting doseresponse analyses were considered in written review by M.
documentation were externally reviewed by A. Day (Celanese Andersen (Colorado State University), V. Feron, (TNO-Nutrition
Canada Inc.), D. Mackay (University of Toronto), and P. Makar and Food Research Institute), and J. Swenberg (University of North
(Environment Canada). Carolina).
M. Walker and J. Zielenski, Division of Biostatistics and

Research Coordination, Health Canada, and D. Blakey and G.
Douglas, Environmental and Occupational Toxicology Division,
Health Canada, contributed to the preparation of sections on
doseresponse analyses for cancer and genotoxicity, respectively.
In the first stage of external review, background sections of

the supporting documentation pertaining to human health were
reviewed primarily to address adequacy of coverage. Written
comments were provided by J. Acquavella (Monsanto Company),
S. Felter (Toxicology Excellence for Risk Assessment), O.
Hernandez (US EPA), R. Keefe (Imperial Oil Limited), N. Krivanek
(Dupont Haskell Laboratory), J. Martin (consultant), and F. Miller
(CIIT) (June 1997).
In 1996, a governmentprivate Steering Committee was

formed in the USA to develop a model for doseresponse
analyses for formaldehyde that takes into account as much of the
biological database on formaldehyde as possible. This
partnership involved primarily the CIIT and the US EPA.
Toxicology Excellence for Risk Assessment, commissioned by the
Formaldehyde Epidemiology, Toxicology, and Environmental
Group, Inc., also participated, preparing sections of draft
documentation related to hazard assessment. Health Canada
joined this partnership later, contributing by organizing, in
collaboration with the US EPA, an external peer review workshop
and revising some sections of the draft documentation related to
hazard assessment (in particular, those addressing
epidemiological data).
58
Formaldehyde
APPENDIX 2 CICAD PEER REVIEW APPENDIX 3 CICAD FINAL REVIEW

BOARD
The draft CICAD on formaldehyde was sent for review to Geneva, Switzerland, 812 January 2001
institutions and organizations identified by IPCS after contact with
IPCS national contact points and Participating Institutions, as well
as to identified experts. Comments were received from:
Members
A. Aitio, International Programme on Chemical Safety,
World Health Organization, Switzerland Dr A.E. Ahmed, Molecular Toxicology Laboratory, Department of
Pathology, University of Texas Medical Branch, Galveston, TX,
A. Bartholomaeus, Therapeutic Goods Administration, USA
Health and Aged Care, Australia
Mr R. Cary, Health and Safety Executive, Merseyside, United
R. Benson, Drinking Water Program, US Environmental Kingdom (Chairperson)
Protection Agency, USA
Dr R.S. Chhabra, General Toxicology Group, National Institute of
R. Cary, Health and Safety Executive, United Kingdom Environmental Health Sciences, National Institutes of Health,
Research Triangle Park, NC, USA
R. Chhabra, National Institute of Environmental Health
Sciences, National Institutes of Health, USA Dr S. Czerczak, Department of Scientific Information, Nofer
Institute of Occupational Medicine, Lodz, Poland
E. Dybing, National Institute of Public Health, Norway
Dr S. Dobson, Centre for Ecology and Hydrology, Cambridgeshire,
H. Gibb, National Centre for Environmental Assessment, US United Kingdom
Environmental Protection Agency, USA
Dr O.M. Faroon, Division of Toxicology, Agency for Toxic
R.C. Grafstrom, Karolinksa Institute, Institute of Substances and Disease Registry, Atlanta, GA, USA
Environmental Medicine, Sweden
Dr H. Gibb, National Center for Environmental Assessment, US
I. Gut, National Institute of Public Health, Center of Environmental Protection Agency, Washington, DC, USA
Occupational Diseases, Czech Republic
Dr R.F. Hertel, Federal Institute for Health Protection of
O. Harris, Agency for Toxic Substances and Disease Consumers and Veterinary Medicine, Berlin, Germany
Registry, USA
Dr A. Hirose, Division of Risk Assessment, National Institute of
R. Hertel, Federal Institute for Health Protection of Health Sciences, Tokyo, Japan
Consumers and Veterinary Medicine, Germany
Dr P.D. Howe, Centre for Ecology and Hydrology, Cambridgeshire,
C. Hiremath, Environmental Carcinogenesis Division, US United Kingdom (Rapporteur)
Dr D. Lison, Industrial Toxicology and Occupational Medicine
H. Nagy, National Institute of Occupational Safety and Unit, Universit Catholique de Louvain, Brussels, Belgium
Health, USA
Dr R. Liteplo, Existing Substances Division, Bureau of Chemical
E.V. Ohanian, Office of Water, US Environmental
Hazards, Health Canada, Ottawa, Ontario, Canada
Protection Agency, USA
Dr I. Mangelsdorf, Chemical Risk Assessment, Fraunhofer Institute
R.J. Preston, Environmental Carcinogenesis Division, US for Toxicology and Aerosol Research, Hanover, Germany
Ms M.E. Meek, Existing Substances Division, Safe Environments
J. Sekizawa, National Institute of Health Sciences, Japan Program, Health Canada, Ottawa, Ontario, Canada (Vice-
Chairperson)
R. Touch, Agency for Toxic Substances and Disease
Registry, USA Dr S. Osterman-Golkar, Department of Molecular Genome
Research, Stockholm University, Stockholm, Sweden
D. Willcocks, National Industrial Chemicals Notification and
Assessment Scheme, Australia Dr J. Sekizawa, Division of Chem-Bio Informatics, National
Institute of Health Sciences, Tokyo, Japan
D.C. Wolf, Environmental Carcinogenesis Division, US
Environmental Protection Agency, USA Dr S. Soliman, Department of Pesticide Chemistry, Faculty of
Agriculture, Alexandria University, El-Shatby, Alexandria, Egypt
K. Ziegler-Skylakakis, Advisory Committee for Existing
Chemicals of Environmental Relevance (BUA), Germany Dr M. Sweeney, Education and Information Division, National
Institute for Occupational Safety and Health, Cincinnati, OH, USA
Professor M. van den Berg, Environmental Sciences and

Toxicology, Institute for Risk Assessment Sciences, University of
Utrecht, Utrecht, The Netherlands
59
Observers APPENDIX 4 BIOLOGICALLY

MOTIVATED CASE-SPECIFIC MODEL FOR
Dr W.F. ten Berge, DSM Corporate Safety and Environment,
Heerlen, The Netherlands CANCER
Dr K. Ziegler-Skylakakis, Commission of the European

Communities, Luxembourg Derivation of the doseresponse model and selection of
various parameters are presented in greater detail in CIIT (1999);
only a brief summary is provided here. The clonal growth compo-
Secretariat nent is identical to other biologically based, two-stage clonal
growth models (Figure A-1) (also known as MVK models),
incorporating information on normal growth, cell cycle time, and
Dr A. Aitio, International Programme on Chemical Safety, World
cells at risk (in various regions of the respiratory tract).
Health Organization, Geneva, Switzerland
Formaldehyde is assumed to act as a direct mutagen, with
Dr Y. Hayashi, International Programme on Chemical Safety,
the effect considered proportional to the estimated tissue concen-
World Health Organization, Geneva, Switzerland
tration of DNAprotein crosslinks. The concentrationresponse
curve for DNAprotein crosslink formation is linear at low exposure
Dr P.G. Jenkins, International Programme on Chemical Safety,
concentrations and increases in a greater than linear manner at
World Health Organization, Geneva, Switzerland high concentrations, similar to those administered in the rodent
carcinogenicity bioassays. For cytotoxicity and subsequent
Dr M. Younes, International Programme on Chemical Safety, regenerative cellular proliferation associated with exposure to
World Health Organization, Geneva, Switzerland formaldehyde, the non-linear, disproportionate increase in
response at higher concentrations is incorporated. Values for
parameters related to the effects of formaldehyde exposure upon
the mutagenic (i.e., DNAprotein crosslink formation) and
proliferative response (i.e., regenerative cell proliferation resulting
from formaldehyde-induced cytotoxicity) were derived from a two-
stage clonal growth model developed for rats (Figure A-2), which
describes the formation of nasal tumours in animals exposed to
formaldehyde.
Species-specific dosimetry within various regions of the

respiratory tract in laboratory animals and humans was also
incorporated. Regional dose is a function of the amount of formal-
dehyde delivered by inhaled air and the absorption characteristics
of the lining within various regions of the respiratory tract. The
amount of formaldehyde delivered by inhaled air depends upon
major airflow patterns, air-phase diffusion, and absorption at the
airlining interface. The dose (flux) of formaldehyde to cells
depends upon the amount absorbed at the airlining interface,
mucus/tissue-phase diffusion, chemical interactions such as reac-
tions and solubility, and clearance rates. Species differences in
these factors influence the site-specific distribution of lesions.
The F344 rat and rhesus monkey nasal surface for one side
of the nose and the nasal surface for both sides of the human nose
were mapped at high resolution to develop three-dimensional,
anatomically accurate computational fluid dynamics (CFD)
models of rat, primate, and human nasal airflow and inhaled gas
uptake (Kimbell et al., 1997; Kepler et al., 1998; Subramaniam et
al., 1998). The approximate locations of squamous epithelium
and the portion of squamous epithelium coated with mucus were
mapped onto the reconstructed nasal geometry of the CFD
models. These CFD models provide a means for estimating the
amount of inhaled gas reaching any site along the nasal passage
walls and allow the direct extrapolation of exposures associated
with tissue damage from animals to humans via regional nasal
uptake. Although development of the two-stage clonal growth
modelling for rats required analysis of only the nasal cavity, for
humans, carcinogenic risks were based on estimates of
formaldehyde dose to regions (i.e., regional flux) along the entire
respiratory tract.
The human clonal growth modelling (Figure A-3) predicts

the additional risk of formaldehyde-induced cancer within the
respiratory tract under various exposure scenarios.
Two of the parameters in the human clonal growth model

the probability of mutation per cell division and the growth
advantage for preneoplastic cells, both in the absence of
formaldehyde exposure were estimated statistically by fitting
60
Formaldehyde
the model to human 5-year age group lung cancer incidence data To account for oronasal breathing, there were two simula-
for non-smokers. 1 The parameter representing the time for a tions. In one simulation, the nasal airway model represented the
malignant cell to expand clonally into a clinically detectable proximal upper respiratory tract, while in the other simulation, the
tumour was set at 3.5 years. mouth cavity model was used for this region. In both simulations,
the fractional airflow rate in the mouth cavity or in the nasal
In addition to the human nasal CFD model, a typical-path, airway was taken into account. For each segment distal to the
one-dimensional model (see CIIT, 1999) of formaldehyde uptake proximal upper respiratory tract, the doses (fluxes) of
was developed for the lower respiratory tract. This latter model formaldehyde from both simulations were added to obtain the
consisted of the tracheobronchial and pulmonary regions in which estimated dose for oronasal breathing. The site-specific
uptake was simulated for four ventilatory states, based on an ICRP deposition of formaldehyde along the human respiratory tract
(1994) activity pattern for a heavy-working adult male. Nasal coupled with data on effects upon regional DNAprotein crosslinks
uptake in the lower respiratory model was calibrated to match and cell proliferation (derived from studies in animals) (Casanova
overall nasal uptake predicted by the human CFD model. While et al., 1994; Monticello et al., 1996) were reflected in calculations
rodents are obligate nasal breathers, humans switch to oronasal of carcinogenic risks associated with the inhalation of
breathing when the level of activity requires a minute ventilation formaldehyde in humans.
of about 35 litres/min. Thus, two anatomical models for the upper
respiratory tract encompassing oral and nasal breathing were Estimates of carcinogenic risks using the human clonal
developed, each of which consisted basically of a tubular growth model were developed for typical environmental
geometry. For the mouth cavity, the choice of tubular geometry exposures (i.e., continuous exposure throughout an 80-year
was consistent with Fredberg et al. (1980). The rationale for using lifetime to concentrations of formaldehyde ranging from 0.001 to
the simple tubular geometry for the nasal airway was based 0.1 ppm [0.0012 to 0.12 mg/m 3]). The human clonal growth
primarily upon the need to remove formaldehyde from the model describes a low-dose, linear carcinogenic response for
inhaled air at the same rate as in a corresponding three- humans exposed to levels of formaldehyde of #0.1 ppm (#0.12
dimensional CFD simulation. However, in calculations of mg/m 3), where cytotoxicity and sustained cellular regenerative
carcinogenic risk, the nasal airway fluxes predicted by the CFD proliferation do not appear to play a role in tumour induction.
simulations, and not those predicted by the single-path model, Indeed, the effect of formaldehyde upon regenerative cellular
were used to determine upper respiratory tract fluxes. proliferation did not have a significant impact upon the predicted
carcinogenic risks at exposures between 0.001 and 0.1 ppm
(0.0012 and 0.12 mg/m 3). No excess risk was predicted by the
human clonal growth model in a cohort exposed to formaldehyde
at a specific plant examined in two epidemiological studies (Blair
et al., 1986; Marsh et al., 1996). This was consistent with the
observed number of cases of respiratory tract cancer (113 observed
deaths; 120 expected) in the cohort. Thus, the outcome of the
model was consistent with the results of the epidemiological
studies.
1
Data on predicted risks of upper respiratory tract cancers
for smokers are also presented in CIIT (1999).
61
Division
(N) Mu I)
( Mu
tatio tatio
n n
( (
N) )
Normal Initiated Cancer
cells (N) cells (I) cell
(delay)
Death/
differentiation I)
(
N)
(
Tumor
31
Figure A-1: Two-stage clonal growth model (reproduced from CIIT, 1999).
ROADMAP FOR THE RAT CLONAL

Inhaled
formaldehyde
GROWTH MODEL
exposure site-specific
scenario flux into nasal
epithelium
CFD nasal mode of action

dosimetry cell replication
dose-response
mode l dose-response submodels
data
2-STAGE maximum
CLONAL likelihood
DPX dose-response nasal SCC data
estimation of
data GROWTH
parameter
MODEL
values
cells at risk
in nose
rat tumor
incidence
Figure A-2: Roadmap for the rat clonal growth model.

CFD = computational fluid dynamics; DPX = DNAprotein crosslinking; SCC = squamous cell carcinoma
(reproduced from CIIT, 1999).
62
Figure A-3 Road map for the human clonal growth model. Reproduced from CIIT 1999.
Inhaled ROADMAP FOR THE HUMAN

formaldehyde
CLONAL GROWTH MODEL
exposure scenario
site-specific flux into
respiratory tract epithelium
CFD nasal
dosimetry model
cell replication
mode of action
dose-response (rat)
single-path lung dose-response
dosimetry model submodels
DPX dose-response 2-STAGE

prediction (scale-up
CLONAL
cell replication from rat and monkey)
GROWTH
in control rats
MODEL
2-STAGE
cells at risk in maximum likelihood
CLONAL
respiratory tract estimation of baseline
GROWTH parameter values human tumor
MODEL
incidence
respiratory tract
tumor data
(control only)
APPENDIX 5 ESTIMATION OF groundwater at a single sampling station would recharge directly

to surface water. A more realistic representation of groundwater
TUMORIGENIC CONCENTRATION05 quality at the site could be achieved using the median
(TC05) concentration in groundwater at all sampling stations. The
median was 100 g/litre for measurements taken at five wells at
the contaminated site during 19961997.
The TC05 is calculated by first fitting a multistage model to

For a conservative analysis, an end-point should be
the exposureresponse data. The multistage model is given by selected that is more appropriate than that for the CTV used in
the hyperconservative analysis, which was based on toxicity to a
! e !q 0 ! q 1d ! ... ! q kd
k
P(d) = 1 marine alga endemic to Australia. A more meaningful value can
be derived by considering toxicity to the seed shrimp Cypridopsis
where d is dose, k is the number of dose groups in the study minus sp., a common freshwater ostracod, yielding a CTV of 360 g/litre.
one, P(d) is the probability of the animal developing a tumour at
dose d, and q i > 0, i = 1, ..., k are parameters to be estimated.
Terrestrial organisms
The model was fit using GLOBAL82 (Howe & Crump,
1982), and the TC05 was calculated as the concentration C that Environmental exposure to formaldehyde in air is expected
satisfies to be greatest near sites of continuous release or formation of
formaldehyde, namely in urban centres and near industrial
P(C) ! P(0) = 0.05 facilities releasing formaldehyde. Extensive recent data for
1 ! P(0) concentrations in air are available for 27 sites, covering a range of
industrial, urban, suburban, rural, and remote locations in
A chi-square lack of fit test was performed for each of the Canada.
three model fits. The degrees of freedom for this test are equal to
k minus the number of q is whose estimates are non-zero. A P- For a conservative analysis, a realistic estimate of long-term
value less than 0.05 indicates a significant lack of fit. In this case, terrestrial exposure would be the highest of 90th percentile values
chi-square = 3.7, df = 4, and P = 0.45. calculated for each monitored site. A highest 90th percentile
value is still representative of high-end concentrations at the site
of greatest concern, yet it also excludes unusually high
measurements, some of which may have been caused by rare
APPENDIX 6 ADDITIONAL INFORMATION ambient conditions or undetected analytical error. Analysis of the
abundant data available shows that only once in the last 10 years
ON ENVIRONMENTAL RISK
were such high air concentrations measured in Canada for as long
CHARACTERIZATION a period (1 month) as that from which the mean was selected for
the hyperconservative EEV. Based on these data, the highest 90th
percentile value is 7.48 g/m 3, calculated from 354
measurements made in Toronto, Ontario, between 6 December
Aquatic organisms 1989 and 18 December 1997. This value will be used as the EEV
for the conservative analysis of the exposure scenario for terrestrial
Environmental exposure to formaldehyde in water is organisms. For comparison, the 90th percentile value calculated
expected to be greatest near areas of high atmospheric concen- for all 3842 National Air Pollution Surveillance programme
trations (where some formaldehyde can partition from air into measurements available between 1997 and 1998 is 5.50 g/m 3.
water) and near spills or effluent outfalls. Measured concentrations The overall mean and median are 2.95 and 2.45 g/m 3,
are available in Canada for surface waters, effluents, and respectively.
groundwater. For surface water, data are available on limited
sampling at four drinking-water treatment plants in urban areas of For the exposure of terrestrial organisms to formaldehyde in
Ontario and Alberta. Measured concentrations in effluent are air, the CTV is 18 g/m 3, based on the corresponding amount in
available for one of the four industrial plants reporting releases of fog (9000 g/litre) that affects the growth and reproduction
formaldehyde to water. Groundwater data are available for three potential of the brassica plant (Brassica rapa) exposed 4.5
industrial sites associated with spills or chronic contamination and h/night, 3 nights/week, for 40 days (Barker & Shimabuku, 1992).
six cemeteries in Ontario. This value is the lowest from a moderate data set composed of
acute and chronic toxicity studies conducted on at least 18
The highest concentration of formaldehyde reported in species of terrestrial plants, microorganisms, invertebrates, and
surface water is 9.0 g/litre, obtained for a sample collected from mammals exposed to air and/or fog water.
the North Saskatchewan River near a treatment plant in
Edmonton, Alberta (Huck et al., 1990). The highest 1-day According to Fletcher et al. (1990), there is remarkable
concentration identified in an industrial effluent was 325 g/litre agreement between field and laboratory EC50 values for plant
(Environment Canada, 1997b). In various groundwater samples, species. In a study of sensitivity to pesticides in a wide range of
the highest concentration of formaldehyde was 690 000 g/litre at plants, only 3 of 20 field EC50 values were 2-fold higher than
an industrial site (Environment Canada, 1997b). These values laboratory EC50 values, and only 3 of 20 laboratory EC50 values
were used as the EEVs in the hyperconservative analysis of were 2-fold higher than field EC50 values. Therefore, no
aquatic organisms in surface water, effluent, and groundwater, application factor may be necessary for laboratory to field
respectively. The effluent EEV was based on the conservative extrapolations for plant effects. Furthermore, data indicated that
assumption that organisms could be living at the point of extrapolations among plant species within a genus can be
discharge. The groundwater EEV was based on the conservative confidently made without uncertainty factors. When extrapolating
assumption that the groundwater could recharge directly to from one genus to another within a family, an uncertainty factor of
surface water at its full concentration. 2 captured 80% of the potential variability. Extrapolations across
families within an order or across orders within a class should be
In the case of groundwater, the very high concentrations at discouraged, but, if necessary, factors of 15 and 300 should be
one contaminated site were related to a recognized historical used for intraorder and intraclass extrapolations, respectively, to
contamination that has since been contained and remediated capture 80% of the variability (Chapman et al., 1998). In the case
(Environment Canada, 1999a). The next highest concentration of the Barker & Shimabuku (1992) study from which the CTV was
reported for groundwater was for an industrial site in New selected, the four test species consisted of a deciduous tree
Brunswick (maximum of 8200 g/litre). It is highly unlikely that the
64
Formaldehyde
(aspen), a coniferous tree (slash pine), a grain crop (wheat), and a ecological impacts could be for sensitive effects such as
seed crop (rapeseed), representing diverse growth forms and imbalance in growth of roots and shoots. Based on the toxicity
morphology from four orders and two classes (monocots and data set available, it appears that plants are most sensitive during
dicots). In two of these, there were no adverse effects at test their early life stages. In Canada, sensitive early life stages of
concentrations, while in a third species (slash pine), there was an plants usually occur in the spring. Highest air concentrations of
arguably adverse increase in top growth at the lowest formaldehyde have generally been measured in late summer
concentration. Other studies indicate that other acute and chronic (August) (Environment Canada, 1999a), when atmospheric
effects begin to occur only at airborne concentrations clearly formaldehyde formation and photochemical smog formation are
higher than for the rapeseed in fog, even in developmental stages greatest. It would therefore appear that only the more tolerant
(e.g., lily pollen LOEC of 440 g/m 3). The rapeseed seedling adult plants would be exposed to the highest concentrations. In
therefore appears to be by far the most sensitive of a variety of addition, in studies other than those used in the hyperconservative
species tested. Given the diversity of the data set, only a minimal and conservative scenarios above, there has been considerably
application factor may be required for interspecies extrapolation. more tolerance to exposure to formaldehyde (e.g., no injury at
Regarding the extrapolation from effect concentration to no-effect concentrations below 840 g/m3 for alfalfa; Haagen-Smit et al.,
concentration, it should be noted that Barker & Shimabuku (1992) 1952), with no effects on plants at a concentration of 44 mg/m3
used a relatively low threshold of statistical significance (" = 0.1), (Wolverton et al., 1984).
and effects on the rapeseed did not include any of the visual
symptoms such as necrosis observed in other liquid- and gas-
phase formaldehyde studies. This may therefore allow for a
smaller application factor to be used on the CTV for rapeseed.
Therefore, application of a factor of 2 to the CTV of 18 g/m 3
results in an ENEV for the conservative analysis of the exposure
scenario for terrestrial organisms of 9 g/m3.
Alternatively, for a conservative analysis, it may also be

more realistic to use a CTV from a toxicity study involving
exposure to formaldehyde in gas phase in air rather than back-
calculating from exposure in fog. Reasons to do this include the
exploratory nature of the fog study (Barker & Shimabuku, 1992)
from which the hyperconservative CTV was selected. The
conversion of fog water concentrations to expected air
concentrations in the study could not be verified because
variables (temperature, vapour pressure, water solubility, Henrys
law constant) required for the conversion were not specified in the
study. Reported exposure concentrations represented an
estimated average based on the observed rate of degradation in
the experimental system. Since formaldehyde in the fog water
readily undergoes hydration and degradation, it is not certain how
its properties may change its toxicity. Analysis of the terrestrial
data set available indicates no other reports of studies on effects
of fog or effects as sensitive as those in Barker & Shimabuku
(1992). In addition, no data on concentrations of formaldehyde in
fog in Canada or frequency of fog incidence in urban areas were
identified to be able to support an assumption that Canadian
biota are being exposed to formaldehyde under such conditions
as those used in the experiment. Also, the study did not seem to
take into consideration potential exposure to gas-phase
formaldehyde in between exposures to formaldehyde in fog. A
study of long-term exposure to formaldehyde in gas phase in air
may be more realistic.
For the conservative analysis of the exposure of terrestrial

organisms to formaldehyde in air, the CTV is 78 g/m3, based on
the lowest average concentration in air that caused a slight imbal-
ance in the growth of shoots and roots in the common bean
(Phaseolus vulgaris) exposed for 7 h/day, 3 days/week, for 4 weeks
in air (day: 25 C, 40% humidity; night: 14 C, 60% humidity)
(Mutters et al., 1993). This value was selected as the most
sensitive end-point from a moderate data set composed of acute
and chronic toxicity studies conducted on at least 18 species of
terrestrial plants, microorganisms, invertebrates, and mammals
exposed to air and/or fog water.
The 28-day intermittent exposure of the bean plant can be

considered as long-term exposure (covering a significant portion
of a life stage of the organism). Dividing the CTV by a factor of 10
to account for the uncertainty surrounding the conversion of the
effect concentration to a no-effect value, the extrapolation from
laboratory to field conditions, and interspecies and intraspecies
variations in sensitivity, the resulting ENEV is 7.8 g/m3.
In considering a weight-of-evidence approach, other data

similarly do not indicate the likelihood of high risks associated
with atmospheric exposure. It is uncertain what the potential
65
FORMALDEHYDE 0275
October 2000
CAS No: 50-00-0 Methanal
RTECS No: LP8925000 Methyl aldehyde
Methylene oxide
(cylinder)
H2CO
Molecular mass: 30.0
TYPES OF
HAZARD/ ACUTE HAZARDS/SYMPTOMS PREVENTION FIRST AID/FIRE FIGHTING
EXPOSURE
FIRE Extremely flammable. NO open flames, NO sparks, and Shut off supply; if not possible and
NO smoking. no risk to surroundings, let the fire
burn itself out; in other cases
extinguish with powder, carbon
dioxide.
EXPLOSION Gas/air mixtures are explosive. Closed system, ventilation, In case of fire: keep cylinder cool by
explosion-proof electrical equipment spraying with water.
and lighting.
EXPOSURE AVOID ALL CONTACT! IN ALL CASES CONSULT A

DOCTOR!
Inhalation Burning sensation. Cough. Ventilation, local exhaust, or Fresh air, rest. Half-upright position.
Headache. Nausea. Shortness of breathing protection. Artificial respiration if indicated.
breath. Refer for medical attention.
Skin Cold-insulating gloves. Remove contaminated clothes.

Rinse skin with plenty of water or
shower. Refer for medical attention.
Eyes Lacrymation. Safety goggles, or eye protection in First rinse with plenty of water for
Redness. Pain. Blurred vision. combination with breathing several minutes (remove contact
protection. lenses if easily possible), then take
to a doctor.
Ingestion Do not eat, drink, or smoke during

work.
SPILLAGE DISPOSAL PACKAGING & LABELLING
Evacuate danger area! Consult an expert!

Ventilation. Remove all ignition sources. Remove
gas with fine water spray. Do NOT wash away into
sewer. (Extra personal protection: complete
protective clothing including self-contained
breathing apparatus).
EMERGENCY RESPONSE STORAGE
Fireproof. Cool.
Prepared in the context of cooperation between the International

IPCS Programme on Chemical Safety and the European Commission
International IPCS 2000
Programme on
Chemical Safety SEE IMPORTANT INFORMATION ON THE BACK.
0275 FORMALDEHYDE
IMPORTANT DATA
Physical State; Appearance Routes of exposure
GAS, WITH CHARACTERISTIC ODOUR. The substance can be absorbed into the body by inhalation.
Physical dangers Inhalation risk

The gas mixes well with air, explosive mixtures are formed On loss of containment, a harmful concentration of this gas in
easily. the air will be reached very quickly.
Chemical dangers Effects of short-term exposure

The substance polymerizes due to warming. Reacts with The substance is severely irritating to the eyes and is irritating
oxidants. to the respiratory tract. Inhalation of may cause lung oedema
(see Notes).
Occupational exposure limits
TLV: 0.3 ppm; (ceiling values) (ACGIH 2000). Effects of long-term or repeated exposure
MAK: 0.5 ppm; 0.6 mg/m 3; (ceiling values), skin, group 3 (1999) This substance is possibly carcinogenic to humans.
PHYSICAL PROPERTIES
Boiling point: -20C Relative vapour density (air = 1): 1.08
Melting point: -92C Flash point: Flammable Gas
Relative density (water = 1): 0.8 Auto-ignition temperature: 430C
Solubility in water: very good Explosive limits, vol% in air: 7-73
ENVIRONMENTAL DATA
NOTES
The symptoms of lung oedema often do not become manifest until a few hours have passed and they are aggravated by physical
effort. Rest and medical observation is therefore essential.
Immediate administration of an appropriate spray, by a doctor or a person authorized by him/her, should be considered.
ADDITIONAL INFORMATION
Neither the EC nor the IPCS nor any person acting on behalf of the EC or the IPCS is responsible
LEGAL NOTICE for the use which might be made of this information
IPCS 2000
RSUM DORIENTATION par le Programme international sur la scurit chimique

(IPCS, 2000), est galement reproduite dans le prsent
document.
Ce CICAD relatif au formaldhyde a t prpar
conjointement par la Direction de lHygine du Milieu de Le formaldhyde (No CAS 50-0-0) se prsente sous
Sant Canada et la Direction de lEvaluation des produits la forme dun gaz incolore et trs inflammable qui est
chimiques commerciaux dEnvironnement Canada partir vendu dans le commerce en solutions aqueuses 30-50 %
dune documentation rdige simultanment dans le cadre en poids. Il peut pntrer dans lenvironnement partir de
du programme sur les substances prioritaires prvu par la sources naturelles (notamment les feux de fort), de
Loi canadienne sur la protection de lenvironnement diverses sources de combustion anthropogniques
(LCPE). Les tudes sur les substances prioritaires comme par exemple les moteurs combustion interne ou
prescrites par la LCPE ont pour objectif dvaluer les encore la faveur de son utilisation sur certains sites
effets potentiels sur la sant humaine dune exposition industriels. Il peut galement se former par oxydation des
indirecte celles de ces substances qui sont prsentes composs organiques naturels ou artificiels prsents dans
dans lenvironnement ainsi que leurs effets sur latmosphre. Les concentrations les plus leves
lenvironnement lui-mme. Le CICAD contient galement mesures dans lenvironnement se rencontrent au
des donnes sur lexposition professionnelle. La prsente voisinage des sources anthropogniques; ce sont elles
mise au point prend en compte les donnes publies qui constituent le principal sujet de proccupation en ce
jusqu fin dcembre 1999 en ce qui concerne les effets qui concerne lexposition de lHomme et des autres tres
sur lenvironnement et jusqu janvier 1999 en ce qui vivants. Dans le pays qui a servi de modle pour
concerne les effets sanitaires.1 Dautres mises au point ltablissement de ce CICAD (le Canada), la principale
ont t galement consultes, savoir celles du CIRC source anthropognique directe de formaldhyde est
(1981, 1995), de lIPCS (1989), du RIVM (1992), de BIBRA constitue par les vhicules moteur. Les missions
Toxicology International (1994) et de lATSDR (1999). Des provenant doprations industrielles sont beaucoup
renseignements sur la nature de lexamen par des pairs et moins importantes. Le formaldhyde est utilis dans
la disponibilit du document de base ainsi que les sources lindustrie, entre autres pour la production de rsines et
utilises pour sa prparation (Environnement Canada & dengrais.
Sant Canada, 2001) sont donns lappendice 1. Il est
noter, comme indiqu dans le document, que le modle Lorsque du formaldhyde est libr dans latmos-
biologique spcifique utilis pour lanalyse des relation phre ou quil y prend naissance, il se dcompose en
exposition-rponse dans le cas du cancer a t mis au majeure partie et une infime quantit passe dans leau.
point conjointement par lEnvironmental Protection Libr dans leau, le formaldhyde ne passe pas dans
Agency des Etats-Unis (EPA), Sant Canada, le Chemical dautres milieux avant de stre dcompos. Il ne persiste
Industry Institute of Toxicology (CIIT) et dautres pas dans lenvironnement, mais comme il y est libr ou
organismes. Le rsultat de cet effort commun remplace sy forme en permanence, il constitue une source dexpo-
lavant-projet de CICAD qui avait t prpar sition chronique proximit des sites o il est mis ou
antrieurement par lOffice of Pollution Prevention and form.
Toxics de lEPA, sur la base des donnes toxicologiques
publies avant 1992. Les informations concernant Lvaluation du risque pour la sant humaine est
lexamen par des pairs du prsent CICAD figurent centre sur lexposition atmosphrique, principalement du
lappendice 2. Ce CICAD a t approuv en tant fait que lon manque de donnes reprsentatives sur les
quvaluation internationale lors dune runion du Comit concentrations prsentes dans dautres milieux que lair et
dvaluation finale qui sest tenue Genve (Suisse), du 8 que les donnes relatives aux effets dune ingestion
au 12 janvier 2001. La liste des participants cette runion restent limites.
se trouve lappendice 3. La fiche internationale sur la
scurit chimique du formaldhyde (ICSC 0275), prpare On dispose dun grand nombre de donnes rcentes
sur la concentration du formaldhyde dans lair au
voisinage de sites industriels, urbains, suburbains, ruraux
ou carts du pays qui a servi ltablissement du CICAD
1
Les nouvelles donnes notes par les auteurs et
(le Canada, comme on la vu plus haut). Les donnes
obtenues par un dpouillement de la littrature effectu
relatives la concentration dans lair intrieur (plus
avant la runion du Comit dvaluation finale ont t
leve) sont moins nombreuses mais nanmoins trs
examines compte tenu de leur influence probable sur les
abondantes. Celles qui concernent la concentration dans
conclusions essentielles de la prsente valuation, le but
leau sont plus limites. Bien que le formaldhyde soit un
tant avant tout dtablir si leur prise en compte serait
constituant naturel de diverses denres alimentaires, la
prioritaire lors dune prochaine mise jour. Les auteurs
surveillance est gnralement sporadique et axes sur les
ayant estim quelles apportaient des lments
sources. Les donnes disponibles rvlent que cest dans
dinformation supplmentaires, on a ajout des donnes
certains fruits et dans certains poissons de mer que la
plus rcentes encore que non essentielles pour la
concentration du formaldhyde dorigine naturelle est la
caractrisation des dangers ou lanalyse des relations
plus leve. Les produits alimentaires peuvent en contenir
dose-rponse.
68
Formaldehyde
par suite de son utilisation comme bactriostatique lors de ment exposs peuvent sinterprter comme un ensemble
la production et de son adjonction la nourriture pour de ractions gnotoxiques positives mais faibles, avec de
animaux afin den faciliter la manutention. Le bonnes indications dune action au point de contact (par
formaldhyde et ses drivs sont galement ajouts aux ex. prsence de micronoyaux dans les cellules de la
produits de consommation les plus divers afin den viter muqueuse buccale et nasale). Les donnes relatives aux
la dtrioration microbienne. La population gnrale est effets produits en distalit du point de contact (cest--
expose lors de la combustion de diverses matires (par dire systmiques) sont ambigus. Globalement, si on
ex. lorsque lon fume une cigarette ou que lon cuisine) ou prend en considration les tudes sur lHomme et lanimal,
en raison de lmission de formaldhyde par certains le formaldhyde apparat comme faiblement gnotoxique,
matriaux de construction comme le contreplaqu. avec de bonnes indications deffets aux points de contact,
mais sans preuves convaincantes dune action en distalit
Comme le formaldhyde (qui est galement un de ces points. Dans lensemble, les tudes
produit du mtabolisme intermdiaire) est soluble dans pidmiologiques ne fournissent pas darguments solides
leau, quil ragit nergiquement sur les macromolcules en faveur dun rapport de cause effet entre lexposition
biologiques et quil est rapidement mtabolis, les effets au formaldhyde et le cancer chez lHomme, encore que
nocifs de lexposition sobservent surtout au niveau des lon ne puisse, sur la base des donnes disponibles,
organes ou des tissus avec lesquels il entre en premier en exclure la possibilit dun risque accru de cancers des
contact (par exemple, les voies respiratoires et aro- voies respiratoires, notamment des voies ariennes
digestives suprieures, et notamment les muqueuses suprieures. Dans ces conditions et en sappuyant
buccale et gastrointestinale, respectivement aprs principalement sur les tudes en laboratoire, on estime
inhalation ou ingestion). que linhalation de formaldhyde dans des circonstances
propres induire une cytotoxicit et une prolifration
Les tudes cliniques et pidmiologiques mettent rgnrative soutenue, prsente un risque de
rgulirement en vidence une sensation dirritation des cancrognicit pour lHomme.
yeux et des voies respiratoires sur les lieux de travail
comme dans les zones rsidentielles. Aux concentrations Dans sa majorit, la population gnrale est expose
qui produisent gnralement une sensation dirritation, le des concentrations de formaldhyde infrieures celles
formaldhyde peut aussi exercer des effets tnus et qui provoquent une sensation dirritation (cest--dire
rversibles sur la fonction pulmonaire. 0,083 ppm ou 0,1 mg/m3). Il peut cependant arriver que
dans certains locaux, la concentration de formaldhyde
En ce qui concerne la population gnrale, une soit proche de celle qui provoque une sensation
exposition cutane au formaldhyde en solution environ dirritation oculaire et respiratoire chez lHomme. Le risque
1-2 % (10 000 - 20 000 mg/litre) est probablement de cancer estim sur la base dun modle biologique
susceptible de provoquer une irritation de lpiderme; spcifique en utilisant la valeur calcule de lexposition de
cependant, chez les sujets hypersensibles, il peut se la population gnrale au formaldhyde dans le pays
produire une dermatite de contact des concentrations de dorigine (le Canada) daprs le scnario type retenu se
formaldhyde ne dpassant pas 0,003 % ou 30 mg/litre. En rvle tre excessivement faible. La mthode utilise
Amrique du Nord, moins de 10 % des malades qui comporte une modlisation biphasique de la croissance
consultent pour une dermatite de contact pourraient tre clonale qui sappuie sur des calculs de dose partir dun
immunologiquement hypersensibles au formaldhyde. modle hydrodynamique informatis du flux de
Selon certains rapports mdicaux, lasthme produit par formaldhyde dans les diverses rgions des fosses
une exposition au formaldhyde serait d des nasales, la modlisation ne prenant en compte quun seul
mcanismes immunologiques, mais cette hypothse na parcours dans le cas des voies respiratoires infrieures.
pu tre clairement dmontre. Dun autre ct,
lexprimentation animale montre que le formaldhyde On dispose de donnes cotoxicologiques con-
peut augmenter la sensibilisation des allergnes inhals. cernant des organismes terrestres et aquatiques trs
divers. En sappuyant sur les concentrations maximales
Aprs inhalation, le formaldhyde entrane des mesures dans lair, les eaux superficielles ou souterraines
effets dgnratifs non noplasiques chez le singe et la et les effluents dans le pays dorigine et selon le scnario
souris et des tumeurs des fosses nasales chez le rat. In type retenu pour lexposition, ainsi que sur la valeur des
vitro, il forme des ponts ADN-protines, provoque la concentrations effet nul tires des donnes
rupture dun des brins de lADN, des aberrations chromo- exprimentales relatives aux organismes terrestres et
somiques, des changes entre chromatides-soeurs et des aquatiques, on peut dire que le formaldhyde na
mutations gniques dans les cellules humaines et les vraisemblablement aucun effet nocif sur les organismes
cellules de rongeur. Du formaldhyde administr par terrestres ou aquatiques.
gavage ou inhalation des rats a provoqu des aberra-
tions chromosomiques dans les cellules pulmonaires et la
formation de micronoyaux dans la muqueuse des voies
digestives. Les rsultats des tudes pidmiologiques
effectues sur des populations de sujets professionnelle-
69
Formaldehyde
RESUMEN DE ORIENTACIN las Sustancias Qumicas (IPCS, 2000), tambin se

reproduce en este documento.
Este CICAD sobre el formaldehdo, preparado El formaldehdo (CAS N 50-0-0) es un gas incoloro
conjuntamente por la Direccin de Higiene del Medio del muy inflamable que se vende comercialmente como
Ministerio de Sanidad del Canad y la Divisin de soluciones acuosas del 30%-50% (en peso). El
Evaluacin de Productos Qumicos Comerciales del formaldehdo pasa al medio ambiente a partir de fuentes
Ministerio de Medio Ambiente del Canad, se bas en la naturales (incluidos los incendios forestales) y de fuentes
documentacin preparada al mismo tiempo como parte del humanas directas, como la combustin de carburantes de
Programa de Sustancias Prioritarias en el marco de la Ley los automviles y de otros tipos y los usos industriales in
Canadiense de Proteccin del Medio Ambiente (CEPA). situ. Hay tambin una formacin secundaria por la oxi-
Las evaluaciones de sustancias prioritarias previstas en la dacin de compuestos orgnicos naturales y de origen
CEPA tienen por objeto valorar los efectos potenciales humano presentes en el aire. Las concentraciones ms
para la salud humana de la exposicin indirecta en el altas en el medio ambiente se han medido cerca de fuentes
medio ambiente general, as como los efectos ecolgicos. humanas; stas son motivo de preocupacin primordial
Este CICAD incluye adems informacin sobre la para la exposicin de las personas y de otra biota. Los
exposicin en el lugar de trabajo. En este examen se vehculos de motor son la principal fuente directa de
analizaron los datos identificados hasta el final de origen humano de formaldehdo en el medio ambiente en
diciembre de 1999 (efectos ecolgicos) y enero de 1999 el pas de origen (Canad). Las emisiones procedentes de
(efectos en la salud humana).1 Tambin se consultaron procesos industriales son considerablemente menores.
otros exmenes, entre ellos los del CIIC (1981, 1995), IPCS Entre los usos industriales del formaldehdo cabe
(1989), RIVM (1992), BIBRA Toxicology International mencionar la produccin de resinas y de fertilizantes.
(1994) y ATSDR (1999). La informacin relativa al carcter
del examen colegiado y la disponibilidad del documento La mayor parte del formaldehdo que se libera o se
original (Ministerios de Medio Ambiente y de Sanidad del forma en el aire se degrada y una cantidad muy pequea
Canad, 2001) y su documentacin justificativa figura en se desplaza hacia el agua. Cuando se libera formaldehdo
el apndice 1. Hay que sealar, como se indica all, que el en el agua, no se desplaza hacia ningn otro medio, sino
modelo especfico de casos con una base biolgica para el que se degrada. El formaldehdo no persiste en el medio
anlisis de la exposicin-respuesta en relacin con el ambiente, pero su emisin y formacin continuadas dan
cncer incluido en este CICAD fue el resultado de una lugar a una exposicin crnica cerca de las fuentes de
labor conjunta que cont con la participacin de la emisin y formacin.
Agencia para la Proteccin del Medio Ambiente (EPA) de
los Estados Unidos, el Ministerio de Sanidad del Canad, La evaluacin con respecto a la salud humana se
el Instituto de Toxicologa de la Industria Qumica (CIIT) y concentra sobre todo en la exposicin al formaldehdo
otros. El producto de esta labor de colaboracin rebasaba suspendido en el aire, debido fundamentalmente a la falta
el contenido de un proyecto de CICAD sobre el formalde- de datos representativos sobre las concentraciones en
hdo preparado previamente por la Oficina de Prevencin otros medios distintos del aire y a la escasez de
de la Contaminacin y de Sustancias Txicas de la EPA de informacin sobre los efectos tras la ingestin.
los Estados Unidos, tomando como base informacin
toxicolgica sobre la salud publicada antes de 1992. La Hay datos recientes abundantes sobre las concen-
informacin sobre el examen colegiado de este CICAD traciones de formaldehdo en el aire de zonas industriales,
aparece en el apndice 2. Este CICAD se aprob como urbanas, suburbanas, rurales y remotas en el pas de
evaluacin internacional en una reunin de la Junta de origen (Canad). Los datos son ms escasos, aunque
Evaluacin Final celebrada en Ginebra (Suiza) del 8 al 12 siguen siendo todava considerables, sobre las concentra-
de enero de 2001. La lista de participantes en esta reunin ciones en el aire de espacios cerrados, que son superi-
figura en el apndice 3. La Ficha internacional de ores. Los datos sobre las concentraciones en el agua son
seguridad qumica (ICSC 0275) para el formaldehdo, ms limitados. Aunque el formaldehdo es un componente
preparada por el Programa Internacional de Seguridad de natural de diversos productos alimenticios, su vigilancia
generalmente ha sido irregular y se ha concentrado en el
origen. Sobre la base de los datos disponibles, las
concentraciones ms altas de formaldehdo de origen
1
Se ha incluido nueva informacin destacada por los
natural en los alimentos se observan en algunas frutas y
examinadores y obtenida en una bsqueda bibliogrfica
peces marinos. El formaldehdo puede estar presente
realizada antes de la reunin de la Junta de Evaluacin
tambin en los alimentos debido a su uso como agente
Final para sealar sus probables repercusiones en las
bacteriosttico en la produccin y su incorporacin a los
conclusiones esenciales de esta evaluacin,
piensos para mejorar sus caractersticas de manipulacin.
principalmente con objeto de establecer la prioridad para
Tambin se encuentran formaldehdo y sus derivados en
su examen en una actualizacin. Se ha aadido infor-
una amplia variedad de productos de consumo para
macin ms reciente, no esencial para la caracterizacin
protegerlos del deterioro que provoca la contaminacin
del peligro o el anlisis de la exposicin-respuesta, que a
microbiana. La poblacin general est expuesta tambin al
juicio de los examinadores aumentaba el valor informativo.
71
que se libera en la combustin (por ejemplo, de los efecto en el lugar de contacto, pero menos claras en
cigarrillos y el cocinado) y de algunos materiales de los lugares distales. Los estudios epidemiolgicos
edificios, como los productos de madera prensada. considerados en conjunto no proporcionan pruebas
contundentes de una asociacin causal entre la
Debido a que el formaldehdo (que tambin es un exposicin al formaldehdo y el cncer humano, aunque a
producto de metabolismo intermedio) es soluble en agua, la vista de los datos disponibles no se puede excluir la
muy reactivo con macromolculas biolgicas y se posibilidad de un mayor riesgo de cncer de las vas
metaboliza con rapidez, se observan efectos adversos respiratorias, en particular de las superiores. Por consigui-
derivados de la exposicin principalmente en los tejidos u ente, tomando como base fundamentalmente los datos
rganos con los cuales entra primero en contacto (es obtenidos en estudios de laboratorio, se considera que la
decir, las vas respiratorias y el tracto aerodigestivo, en inhalacin de formaldehdo en condiciones que inducen
particular la mucosa oral y gastrointestinal, tras la citotoxicidad y proliferacin regenerativa sostenida
inhalacin o la ingestin, respectivamente). representa un peligro carcinognico para las personas.
En estudios clnicos y encuestas epidemiolgicas La mayor parte de la poblacin general est expu-
realizados en entornos laborales y residenciales se ha esta a concentraciones de formaldehdo suspendido en el
observado de manera constante irritacin sensorial de los aire inferiores a las asociadas con la irritacin sensorial (es
ojos y las vas respiratorias. A concentraciones superi- decir, 0,083 ppm [0,1 mg/m3]). Sin embargo, en algunos
ores a las generalmente relacionadas con la irritacin recintos cerrados las concentraciones pueden acercarse a
sensorial, el formaldehdo puede contribuir asimismo a la las asociadas con la irritacin sensorial de los ojos y las
induccin de efectos generalmente pequeos y rever- vas respiratorias en las personas. Los riesgos de cncer
sibles en la funcin pulmonar. estimados a partir de un modelo especfico de casos con
una base biolgica para el clculo de la exposicin de la
Para la poblacin general, la exposicin cutnea a poblacin general al formaldehdo en el aire basndose en
concentraciones de formaldehdo en solucin en torno al el modelo de exposicin de muestra para el pas de origen
1%-2% (10 000-20 000 mg/l) es probable que provoque (Canad) son sumamente bajos. Este sistema incorpora la
irritacin cutnea; sin embargo, en personas hipersen- elaboracin de modelos de crecimiento clonal en dos
sibles puede producirse dermatitis por contacto tras la fases y est respaldado por los clculos de dosimetra
exposicin a concentraciones de formaldehdo de slo el obtenidos a partir de modelos informticos de dinmica de
0,003% (30 mg/l). En Amrica del Norte, pueden ser fluidos para el flujo del formaldehdo en diversas regiones
inmunolgicamente hipersensibles al formaldehdo menos de la nariz y de modelos de va nica para las vas
del 10% de los pacientes con dermatitis por contacto. respiratorias inferiores.
Aunque en los informes de casos se ha indicado que para
algunas personas el asma inducido por el formaldehdo Hay datos relativos a la toxicidad en el medio ambi-
era atribuible a mecanismos inmunitarios, no hay pruebas ente para una gran variedad de organismos terrestres y
convincentes de ello. Sin embargo, en estudios con acuticos. A la vista de las concentraciones mximas
animales de laboratorio el formaldehdo ha aumentado su medidas en el aire, las aguas superficiales, los efluentes y
sensibilizacin a los alergenos inhalados. las aguas freticas en el modelo de exposicin de muestra
del pas de origen y de los valores sin efectos estimados
Tras su inhalacin por los animales de laboratorio, el obtenidos de datos experimentales para la biota terrestre y
formaldehdo provoca efectos degenerativos no neo- acutica, no es probable que el formaldehdo provoque
plsicos en ratones y monos y tumores nasales en ratas. efectos adversos en los organismos terrestres.
In vitro, el formaldehdo indujo la formacin de enlaces
cruzados ADN-protenas, fragmentacin de las cadenas
sencillas de ADN, aberraciones cromosmicas, inter-
cambio de cromtides hermanas y mutaciones genticas
en clulas humanas y de roedores. El formaldehdo
administrado por inhalacin o mediante sonda a ratas in
vivo indujo anomalas cromosmicas en las clulas pul-
monares y la formacin de microncleos en la mucosa
gastrointestinal. Los resultados de estudios epidemio-
lgicos en poblaciones expuestas en el lugar de trabajo
son compatibles con un modelo de respuesta positiva
dbil para la genotoxicidad, con pruebas claras de efectos
en el lugar de contacto (por ejemplo, presencia de
microncleos en las clulas de la mucosa bucal o nasal).
Las pruebas para los efectos distales (es decir, sistmicos)
son contradictorias. En conjunto, basndose en estudios
tanto en animales como en personas, el formaldehdo es
dbilmente genotxico, con pruebas convincentes de un
72
THE CONCISE INTERNATIONAL CHEMICAL ASSESSMENT DOCUMENT SERIES
Acrylonitrile (No. 39, 2002)

Azodicarbonamide (No. 16, 1999)
Barium and barium compounds (No. 33, 2001)
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Beryllium and beryllium compounds (No. 32, 2001)
Biphenyl (No. 6, 1999)
1,3-Butadiene: Human health aspects (No. 30, 2001)
2-Butoxyethanol (No. 10, 1998)
Chloral hydrate (No. 25, 2000)
Chlorinated naphthalenes (No. 34, 2001)
Chlorine dioxide (No. 37, 2002)
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3,3'-Dichlorobenzidine (No. 2, 1998)
1,2-Dichloroethane (No. 1, 1998)
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Diphenylmethane diisocyanate (MDI) (No. 27, 2000)
Ethylenediamine (No. 15, 1999)
Ethylene glycol: environmental aspects (No. 22, 2000)
2-Furaldehyde (No. 21, 2000)
HCFC-123 (No. 23, 2000)
Limonene (No. 5, 1998)
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Mononitrophenols (No. 20, 2000)
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Phenylhydrazine (No. 19, 2000)
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1,1,2,2-Tetrachloroethane (No. 3, 1998)
1,1,1,2-Tetrafluoroethane (No. 11, 1998)
o-Toluidine (No. 7, 1998)
Tributyltin oxide (No. 14, 1999)
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Triphenyltin compounds (No. 13, 1999)
Vanadium pentoxide and other inorganic vanadium compounds (No. 29, 2001)
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This report contains the collective views of an international group of experts and does not

Concise International Chemical Assessment Document 40

First draft prepared by

World Health Organization

WHO Library Cataloguing-in-Publication Data

(Concise international chemical assessment document ; 40)

1.Formaldehyde - adverse effects 2.Risk assessment 3.Environmental

ISBN 92 4 153040 5 (NLM Classification: QV 225)

World Health Organization 2002

Printed by Wissenschaftliche Verlagsgesellschaft mbH, D-70009 Stuttgart 10

2. IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

4. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

4.1 Natural sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

5. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION . . . . . . . . . . . . . . . . . . . . . 10

6. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

6.1 Environmental levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

7. COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS AND

8. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS . . . . . . . . . . . . . . . . . . . . . . . . . . 20

8.1 Single exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

9.1 Case reports and clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

10. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

10.1 Aquatic environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

11. EFFECTS EVALUATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

11.1 Evaluation of health effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48

APPENDIX 1 SOURCE DOCUMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61

APPENDIX 2 CICAD PEER REVIEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62

APPENDIX 3 CICAD FINAL REVIEW BOARD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

APPENDIX 4 BIOLOGICALLY MOTIVATED CASE-SPECIFIC MODEL FOR CANCER . . . . . . . . . . . . . . 64

APPENDIX 5 ESTIMATION OF TUMORIGENIC CONCENTRATION05 (TC05) . . . . . . . . . . . . . . . . . . . . . 67

APPENDIX 6 ADDITIONAL INFORMATION ON ENVIRONMENTAL RISK CHARACTERIZATION . 67

INTERNATIONAL CHEMICAL SAFETY CARD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69

FOREWORD provided as guidance only. The reader is referred to EHC

CICAD PREPARATION FLOW CHART

SELECTION OF PRIORITY CHEMICAL

SELECTION OF HIGH QUALITY

PRIMARY REVIEW BY IPCS

REVIEW BY IPCS CONTACT POINTS/

FINAL REVIEW BOARD 2

APPROVAL BY DIRECTOR, IPCS

1 Taking into account the comments from reviewers.

is submitted to a Final Review Board together with the

The CICAD Final Review Board has several

to ensure that each CICAD has been subjected to

Board members serve in their personal capacity, not as

Board members, authors, reviewers, consultants,

Values reported for the physical and chemical

Conversion factor 1 ppm = 1.2 mg/m 3

Table 2: Methods for the analysis of formaldehyde in air and food.a,b

Sample matrix/preparation Assay procedure Limit of detection Reference

Distil sample; add 1,8-dihydroxynaphthalene-3,6- Chromotropic acid NR Helrich, 1990

Large-scale chamber tests. 0.083 ppm European Commission, 1989;

a From IARC (1995).

4.1 Natural sources Other anthropogenic combustion sources

4.4 Production and use USAc 2185 2517 3048

Former Yugoslavia 108 99 88

related to fertilizer production, while 2% of the formalde- 5. ENVIRONMENTAL TRANSPORT,

Formaldehyde is often added to cosmetics, in 5.1 Air

The nighttime destruction of formaldehyde is