Glyoxal

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Glyoxal

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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 57

GLYOXAL

Please note that the layout and pagination of this pdf file are not identical to the
version in press

First draft prepared by Drs J. Kielhorn, C. Pohlenz-Michel, S. Schmidt, and I. Mangelsdorf,


Fraunhofer Institute for Toxicology and Experimental Medicine, Hanover, Germany

Published under the joint sponsorship of the United Nations Environment Programme, the
International Labour Organization, and the World Health Organization, and produced within the
framework of the Inter-Organization Programme for the Sound Management of Chemicals.

World Health Organization


Geneva, 2004
The International Programme on Chemical Safety (IPCS), established in 1980, is a joint venture of
the United Nations Environment Programme (UNEP), the International Labour Organization (ILO), and the
World Health Organization (WHO). The overall objectives of the IPCS are to establish the scientific basis
for assessment of the risk to human health and the environment from exposure to chemicals, through
international peer review processes, as a prerequisite for the promotion of chemical safety, and to provide
technical assistance in strengthening national capacities for the sound management of chemicals.
The Inter-Organization Programme for the Sound Management of Chemicals (IOMC) was
established in 1995 by UNEP, ILO, the Food and Agriculture Organization of the United Nations, WHO, the
United Nations Industrial Development Organization, the United Nations Institute for Training and
Research, and the Organisation for Economic Co-operation and Development (Participating Organizations),
following recommendations made by the 1992 UN Conference on Environment and Development to
strengthen cooperation and increase coordination in the field of chemical safety. The 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

Glyoxal.

(Concise international chemical assessment document ; 57)

1.Glyoxal - toxicity 2.Risk assessment 3.Environmental exposure 4. Food contamination


I.International Programme on Chemical Safety II.Series

ISBN 92 4 153057 X (LC/NLM Classification: QD 305.A6)


ISSN 1020-6167

©World Health Organization 2004

All rights reserved. Publications of the World Health Organization can be obtained from Marketing and
Dissemination, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel: +41 22
791 2476; fax: +41 22 791 4857; email: bookorders@who.int). Requests for permission to reproduce or
translate WHO publications — whether for sale or for noncommercial distribution — should be addressed to
Publications, at the above address (fax: +41 22 791 4806; email: permissions@who.int).
The designations employed and the presentation of the material in this publication do not imply the
expression of any opinion whatsoever on the part of the World Health Organization concerning the legal
status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers
or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full
agreement.
The mention of specific companies or of certain manufacturers’ products does not imply that they are
endorsed or recommended by the World Health Organization in preference to others of a similar nature that
are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by
initial capital letters.
The World Health Organization does not warrant that the information contained in this publication is
complete and correct and shall not be liable for any damages incurred as a result of its use.
Risk assessment activities of the International Programme on Chemical Safety, including the production
of Concise International Chemical Assessment Documents, are supported financially by the Department of
Health and Department for Environment, Food & Rural Affairs, UK, Environmental Protection Agency,
Food and Drug Administration, and National Institute of Environmental Health Sciences, USA, European
Commission, German Federal Ministry of Environment, Nature Conservation and Nuclear Safety, Health
Canada, Japanese Ministry of Health, Labour and Welfare, and the Swiss Agency for Environment, Forests
and Landscape.

Technically and linguistically edited by Marla Sheffer, Ottawa, Canada, and printed by Wissenchaftliche
Verlagsgesellschaft mbH, Stuttgart, Germany
TABLE OF CONTENTS

FOREWORD ......................................................................................................................................................1

1. EXECUTIVE SUMMARY ................................................................................................................................4

2. IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES ............................................................................6

3. ANALYTICAL METHODS ..............................................................................................................................6

3.1 Air ............................................................................................................................................................6


3.2 Water........................................................................................................................................................7
3.3 Solid materials .........................................................................................................................................7
3.4 Human blood and plasma ........................................................................................................................7

4. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE ................................................................8

4.1 Natural sources ........................................................................................................................................8


4.2 Estimated production ...............................................................................................................................8
4.3 Uses ..........................................................................................................................................................8
4.4 Emissions .................................................................................................................................................8

5. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION .................................8

5.1 Environmental transport and distribution................................................................................................8


5.2 Abiotic transformation.............................................................................................................................9
5.3 Biotransformation and biodegradation....................................................................................................9

6. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE .........................................................................9

6.1 Environmental levels ...............................................................................................................................9


6.1.1 Atmosphere ...................................................................................................................................9
6.1.2 Hydrosphere ..................................................................................................................................9
6.1.3 Sediment......................................................................................................................................10
6.1.4 Food.............................................................................................................................................10
6.2 Human exposure ....................................................................................................................................10
6.2.1 General population......................................................................................................................10
6.2.2 Occupational exposure................................................................................................................11
6.2.3 Human plasma and urine ............................................................................................................11

7. COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS AND


HUMANS .........................................................................................................................................................11

7.1 Endogenous glyoxal...............................................................................................................................11


7.2 Absorption, distribution, and excretion.................................................................................................13
7.3 Biotransformation ..................................................................................................................................13
7.4 Covalent binding....................................................................................................................................13

8. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS ......................................14

8.1 Single exposure......................................................................................................................................14


8.2 Short-term exposure...............................................................................................................................15
8.3 Medium-term exposure..........................................................................................................................15
8.4 Long-term exposure and carcinogenicity..............................................................................................16
8.5 Genotoxicity and related end-points......................................................................................................17
8.6 Reproductive toxicity.............................................................................................................................18
8.6.1 Effects on fertility .......................................................................................................................18
8.6.2 Developmental toxicity...............................................................................................................18
iii
Concise International Chemical Assessment Document 57

8.7 Irritation and sensitization .....................................................................................................................19


8.7.1 Skin irritation ..............................................................................................................................19
8.7.2 Eye irritation ...............................................................................................................................19
8.7.3 Sensitization ................................................................................................................................19
8.8 Mode of action .......................................................................................................................................19

9. EFFECTS ON HUMANS ................................................................................................................................20

10. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD ..........................................21

10.1 Aquatic environment..............................................................................................................................21


10.2 Terrestrial environment .........................................................................................................................22

11. EFFECTS EVALUATION...............................................................................................................................22

11.1 Evaluation of health effects ...................................................................................................................22


11.1.1 Hazard identification and dose–response assessment ..............................................................22
11.1.2 Criteria for setting tolerable intakes/concentrations.................................................................23
11.1.3 Sample risk characterization.....................................................................................................23
11.1.4 Uncertainties in the evaluation of health risks and in the sample risk characterization..........23
11.2 Evaluation of environmental effects......................................................................................................24
11.2.1 Aquatic environment.................................................................................................................24
11.2.2 Terrestrial environment.............................................................................................................24
11.2.3 Uncertainties in the evaluation of environmental effects.........................................................24

12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES .................................................................25

REFERENCES.........................................................................................................................................................25

APPENDIX 1 — SOURCE DOCUMENT.............................................................................................................32

APPENDIX 2 — CICAD PEER REVIEW.............................................................................................................33

APPENDIX 3 — CICAD FINAL REVIEW BOARD ...........................................................................................33

APPENDIX 4 — ABBREVIATIONS AND ACRONYMS ..................................................................................34

APPENDIX 5 — AEROSOL EXPOSURE MODEL.............................................................................................35

INTERNATIONAL CHEMICAL SAFETY CARD ..............................................................................................36

RÉSUMÉ D’ORIENTATION.................................................................................................................................38

RESUMEN DE ORIENTACIÓN............................................................................................................................41

iv
Glyoxal

FOREWORD possible exposure situations, but are provided as


guidance only. The reader is referred to EHC 170.1
Concise International Chemical Assessment
Documents (CICADs) are the latest in a family of While every effort is made to ensure that CICADs
publications from the International Programme on represent the current status of knowledge, new informa-
Chemical Safety (IPCS) — a cooperative programme of tion is being developed constantly. Unless otherwise
the World Health Organization (WHO), the International stated, CICADs are based on a search of the scientific
Labour Organization (ILO), and the United Nations literature to the date shown in the executive summary. In
Environment Programme (UNEP). CICADs join the the event that a reader becomes aware of new informa-
Environmental Health Criteria documents (EHCs) as tion that would change the conclusions drawn in a
authoritative documents on the risk assessment of CICAD, the reader is requested to contact IPCS to
chemicals. inform it of the new information.

International Chemical Safety Cards on the relevant Procedures


chemical(s) are attached at the end of the CICAD, to
provide the reader with concise information on the The flow chart on page 2 shows the procedures
protection of human health and on emergency action. followed to produce a CICAD. These procedures are
They are produced in a separate peer-reviewed designed to take advantage of the expertise that exists
procedure at IPCS. They may be complemented by around the world — expertise that is required to produce
information from IPCS Poison Information Monographs the high-quality evaluations of toxicological, exposure,
(PIM), similarly produced separately from the CICAD and other data that are necessary for assessing risks to
process. human health and/or the environment. The IPCS Risk
Assessment Steering Group advises the Coordinator,
CICADs are concise documents that provide sum- IPCS, on the selection of chemicals for an IPCS risk
maries of the relevant scientific information concerning assessment based on the following criteria:
the potential effects of chemicals upon human health
and/or the environment. They are usually based on • there is the probability of exposure; and/or
selected national or regional evaluation documents or on • there is significant toxicity/ecotoxicity.
existing EHCs. Before acceptance for publication as
CICADs by IPCS, these documents undergo extensive Thus, it is typical of a priority chemical that
peer review by internationally selected experts to ensure
their completeness, accuracy in the way in which the • it is of transboundary concern;
original data are represented, and the validity of the • it is of concern to a range of countries (developed,
conclusions drawn. developing, and those with economies in transition)
for possible risk management;
The primary objective of CICADs is characteri- • there is significant international trade;
zation of hazard and dose–response from exposure to a • it has high production volume;
chemical. CICADs are not a summary of all available • it has dispersive use.
data on a particular chemical; rather, they include only
that information considered critical for characterization The Steering Group will also advise IPCS on the appro-
of the risk posed by the chemical. The critical studies priate form of the document (i.e., a standard CICAD or a
are, however, presented in sufficient detail to support the de novo CICAD) and which institution bears the respon-
conclusions drawn. For additional information, the sibility of the document production, as well as on the
reader should consult the identified source documents type and extent of the international peer review.
upon which the CICAD has been based.
The first draft is usually based on an existing
Risks to human health and the environment will national, regional, or international review. When no
vary considerably depending upon the type and extent of appropriate source document is available, a CICAD may
exposure. Responsible authorities are strongly encour- be produced de novo. Authors of the first draft are
aged to characterize risk on the basis of locally measured usually, but not necessarily, from the institution that
or predicted exposure scenarios. To assist the reader, developed the original review. A standard outline has
examples of exposure estimation and risk characteriza- been developed to encourage consistency in form. The
tion are provided in CICADs, whenever possible. These
examples cannot be considered as representing all
1
International Programme on Chemical Safety (1994)
Assessing human health risks of chemicals: derivation of
guidance values for health-based exposure limits. Geneva,
World Health Organization (Environmental Health Criteria
170) (also available at http://www.who.int/pcs/).
1
Concise International Chemical Assessment Document 57

CICAD PREPARATION FLOW CHART

Selection of priority Advice from Risk Assessment


chemical, author
Steering Group
institution, and agreement
on CICAD format
Criteria of priority:

Preparation of first draft • there is the probability of exposure; and/or


• there is significant toxicity/ecotoxicity.

Primary acceptance Thus, it is typical of a priority chemical that


review by IPCS and
revisions as necessary
• it is of transboundary concern;
• it is of concern to a range of countries
(developed, developing, and those with
economies in transition) for possible risk
Selection of review
management;
process
• there is significant international trade;
• the production volume is high;
• the use is dispersive.
Peer review
Special emphasis is placed on avoiding
duplication of effort by WHO and other
international organizations.
Review of the comments
and revision of the
document A usual prerequisite of the production of a
CICAD is the availability of a recent high-
quality national/regional risk assessment
document = source document. The source
Final Review Board: document and the CICAD may be produced in
Verification of revisions parallel. If the source document does not
due to peer review contain an environmental section, this may be
comments, revision, and produced de novo, provided it is not
approval of the document controversial. If no source document is
available, IPCS may produce a de novo risk
assessment document if the cost is justified.
Editing
Approval by Coordinator, Depending on the complexity and extent of
IPCS controversy of the issues involved, the steering
group may advise on different levels of peer
review:
• standard IPCS Contact Points
Publication of CICAD on • above + specialized experts
web and as printed text • above + consultative group

2
Glyoxal

first draft undergoes primary review by IPCS to ensure


that it meets the specified criteria for CICADs.

The second stage involves international peer review


by scientists known for their particular expertise and by
scientists selected from an international roster compiled
by IPCS through recommendations from IPCS national
Contact Points and from IPCS Participating Institutions.
Adequate time is allowed for the selected experts to
undertake a thorough review. Authors are required to
take reviewers’ comments into account and revise their
draft, if necessary. The resulting second draft is
submitted to a Final Review Board together with the
reviewers’ comments. At any stage in the international
review process, a consultative group may be necessary
to address specific areas of the science. When a CICAD
is prepared de novo, a consultative group is normally
convened.

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 repre-
sentation.

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
Concise International Chemical Assessment Document 57

1. EXECUTIVE SUMMARY Glyoxal released into the environment is rapidly


converted by abiotic processes, such as transformation
by photochemically produced hydroxyl radicals. Due to
This CICAD on glyoxal was prepared by the the low soil sorption coefficient (Koc) reported for this
Fraunhofer Institute for Toxicology and Experimental compound, it may leach from soil into groundwater.
Medicine, Hanover, Germany. It is based on reports However, it is readily biodegraded and quickly trans-
compiled by the German Advisory Committee on formed enzymatically by bacteria and fungi. Its low log
Existing Chemicals of Environmental Relevance (BUA, octanol/water partition coefficient (Kow) indicates that
1997). A comprehensive literature search of relevant glyoxal is unlikely to bioaccumulate.
databases was conducted up to February 2003 to identify
any relevant references published subsequent to those The main routes of occupational exposure to glyoxal
incorporated in these reports. Information on the during use as a disinfectant are via inhalation of aerosol
preparation and peer review of the source document is and dermal absorption. The general population is
presented in Appendix 1. Information on the peer review exposed mainly through ingestion of glyoxal-containing
of this CICAD is presented in Appendix 2. This CICAD food, but could be exposed through polluted air in urban
was considered and approved as an international assess- regions and through traces of glyoxal in drinking-water.
ment at a meeting of the Final Review Board, held in
Varna, Bulgaria, on 8–11 September 2003. Participants Glyoxal is endogenously produced during normal
at the Final Review Board meeting are presented in cellular metabolism by a multitude of enzyme-
Appendix 3. The International Chemical Safety Card for independent pathways. Glyoxal is also a product of the
glyoxal (ICSC 1162), produced by the International metabolism and microsomal oxidation of other com-
Programme on Chemical Safety (IPCS, 2002), has also pounds, such as glycolaldehyde, ethylene glycol, and β-
been reproduced in this document. hydroxy-substituted N-nitrosamines. The concentration
of glyoxal in human blood plasma has been reported to
Anhydrous glyoxal (CAS No. 107-22-2) has a be 0.1–1 µmol/litre, with higher levels reported for
melting point of about 15 °C. However, it is generally patients with diabetes or renal failure. In biological
available as an aqueous solution (typically containing materials, less than 10% of the glyoxal present is in
30–50% glyoxal) in which hydrated oligomers are unbound forms in aqueous solution (free glyoxal and
present. Glyoxal is used as a chemical intermediate in hydrates), as most of the reactive carbonyl groups are
the production of pharmaceuticals and dyestuffs, as a reversibly bound to cysteinyl, lysyl, and arginyl residues
cross-linking agent in the production of a range of of proteins.
different polymers, as a biocide, and as a disinfecting
agent. Releases to the environment are primarily Glyoxal, which attacks amino groups of proteins,
emissions to ambient air and water. nucleotides, and lipids, is considered an important inter-
mediate in the formation of advanced glycation end-
The predominant target compartments for glyoxal in products (AGEs). AGE modification alters protein func-
the environment are the hydrosphere and soil (at about tion and inactivates enzymes, resulting in disturbance of
46% and 54%, respectively) and, to a lesser extent, air cellular metabolism, impaired proteolysis, and inhibition
(<1%). Reported concentrations of glyoxal in ambient of cell proliferation and protein synthesis. The deleteri-
air in the USA, Europe, and Asia are in the range of ous effects of the highly reactive glyoxal are counter-
about 0.1 µg/m3 up to 10 µg/m3. In European rivers and acted by a ubiquitous glutathione (GSH)-dependent
groundwater, concentrations up to 12 µg/litre are glyoxalase system, which converts glyoxal to the less
reported. Glyoxal is a by-product of ozone disinfection reactive glycolate.
and has been detected at low µg/litre concentrations in
drinking-water. The acute toxicity of glyoxal in experimental
animals is low to moderate, depending on the actual
Due to microbial activity as well as non-enzymatic concentration of glyoxal in the tested product. In rats, for
autoxidation of oil or browning reactions of saccharides, 40% glyoxal, the LC50 for a single 4-h inhalation of
glyoxal is frequently detected in fermented food and aerosol is 2440 mg/m3, the oral LD50 value ranges from
beverages. It was found in different brands of beer, wine, 3000 to 9000 mg/kg body weight (with higher sensitivity
and other beverages such as tea at concentrations rang- in females), and dermal LD50 values are >2000 mg/kg
ing from about 20 µg/litre (black tea) up to 1556 µg/litre body weight. After inhalation exposure, local irritations
(sherry wine). In addition, it was detected in a range of of the eyes and respiratory organs as well as hyperaemia
fermented products such as soybean paste and yoghurt and foamy secretion in the lungs predominate. After oral
(0.63–4.2 mg/kg), bakery products such as bread (0.07– exposure to glyoxal, macroscopic observations include
1.6 mg/kg), different plant materials (3–14 mg/kg), and irritations of the gastrointestinal tract and congestion in
edible oils (up to 6.5 mg/kg). the gastrointestinal tract, lung, kidney, and adrenal
glands. In the prominent target organs, pancreas and

4
Glyoxal

kidney, the toxic action of glyoxal leads to severe mucosa of rats by demonstration of unscheduled DNA
degenerative changes resembling those induced during synthesis and DNA single strand breaks. After oral
diabetes. application, DNA strand breaks were further observed in
rat liver. There are no carcinogenesis bioassays with
Studies into short-term (29-day) inhalation exposure inhalation exposure to glyoxal. Glyoxal showed tumour-
of rats to glyoxal showed a no-observed-effect level promoting activity in a two-stage glandular stomach
(NOEL) of 0.6 mg/m3 (nominal concentration was carcinogenesis model in male Wistar rats, whereas it was
0.4 mg/m3) for local effects in the larynx and a NOEL of inactive in a short-term liver foci assay. In an assay for
>8.9 mg/m3 (nominal concentration was 10 mg/m3) for tumour-initiating activity of glyoxal in skin and in cell
systemic effects (examination of body weight, haematol- transformation assays, glyoxal yielded negative test
ogical and biochemical parameters, urine analysis, results.
macroscopic and histological examination). A 28-day
study in which glyoxal was administered to rats in Taking the 29-day inhalation study in rats exposed
drinking-water resulted in a no-observed-adverse-effect to glyoxal, which showed a NOEL of 0.6 mg/m3 for
level (NOAEL) of 100 mg glyoxal/kg body weight per local effects in the larynx, and using uncertainty factors
day. The 90-day feeding of glyoxal to rats resulted in a of 10 for interspecies differences and 10 for inter-
NOAEL of 125 mg/kg body weight per day (dosage individual differences, a tolerable concentration of
corresponding to 100% glyoxal). Effects stated at higher 6 µg/m3 for local effects in the larynx for short-term
dosages in these two latter studies were reduced water exposure was estimated.
and food intake (first study only) and retardation of body
weight gain (both studies). In a study examining more In a sample risk assessment for the general popu-
sensitive end-points (serum clinical biochemistry), the lation, an exposure scenario has been compiled as a
lowest tested dosage of 107 mg/kg body weight per day hypothesized worst case. Using the daily intake of,
(99% glyoxal) corresponded to the lowest-observed- maximally, 10 mg glyoxal via food, an estimated intake
adverse-effect level (LOAEL) for a 90-day exposure of of 0.16 mg glyoxal/kg body weight per day can be cal-
rats via drinking-water. A 90-day feeding study in dogs culated. This is similar to the tolerable intake of about
failed to reveal any substance-related changes at the top 0.2 mg/kg body weight per day for lifetime oral expo-
dose of 115 mg/kg body weight per day (dose corres- sure to glyoxal.
ponding to 100% glyoxal).
In a second sample risk assessment, for a nurse or
In animal studies, 30% and 40% aqueous glyoxal hospital cleaner or consumer using disinfectant, a typical
caused slight to definite skin irritations, depending on brand of disinfectant (7.5 g in 100 g = 7.5% glyoxal) is
the application time. Glyoxal is irritating to mucous used at a dilution of 1% for disinfection and cleaning of
membranes and acts as a skin sensitizing agent in surfaces (i.e., 0.075% glyoxal). Using a rounded-up
humans and experimental animals. 0.1% glyoxal solution and a calculation derived from a
model gives an uptake of about 4 µg/kg body weight per
Fetotoxic effects occurred only with doses of day, assuming a body weight of 64 kg. This is much
glyoxal that induced maternal toxicity. In developmental (50 times) less than the tolerable intake of about
toxicity studies with rats, a NOEL for embryotoxicity 0.2 mg/kg body weight per day for lifetime oral expo-
was ≥300 mg glyoxal dihydrate/kg body weight per day sure. However, using a worst-case exposure to 4%
(corresponding to ≥185 mg glyoxal/kg body weight per glyoxal and the same assumptions as above would give
day), whereas a lowest-observed-effect level (LOEL) an uptake of about 0.15 mg/kg body weight, which is
(decreased body weight gain) for maternal toxicity was approximately the same as the tolerable intake of about
200 mg glyoxal dihydrate/kg body weight per day 0.2 mg/kg body weight per day for lifetime oral expo-
(corresponding to 123 mg glyoxal/kg body weight per sure.
day). Developmental toxicity range-finding studies in
rabbits yielded a NOEL of 200 mg glyoxal dihydrate/kg In the final sample risk assessment, a farmer using a
body weight per day (corresponding to 123 mg glyoxal/ spray application of biocidal products containing glyoxal
kg body weight per day) for both maternal toxicity and to disinfect a stable was used as an example. The model
embryotoxicity. calculation using the given assumptions predicts a short-
term exposure concentration of 24 µg glyoxal/m3 for a 6-
Glyoxal is directly genotoxic in vitro in bacterial min exposure and 32 µg glyoxal/m3 for a 15-min expo-
and mammalian cells, inducing, for example, DNA sure. This can be compared with the estimated tolerable
adducts, mutations, chromosomal aberrations, DNA concentration of 6 µg/m3 for local effects in the larynx
repair, sister chromatid exchanges, and DNA single for a short-term exposure. There is a perceived risk of
strand breaks. In vivo, a genotoxic activity of glyoxal local laryngeal effects and irritation to the skin from this
was established at the site of application in the pyloric spray application of glyoxal.

5
Concise International Chemical Assessment Document 57

Exposure to glyoxal has been shown to inhibit the Some of the most important hydrated derivatives of
activities of aerobic as well as anaerobic bacteria, green glyoxal formed by nucleophilic addition in aqueous
algae (96-h EC50 value of about 149 mg/litre for Pseudo- solution are shown below (Whipple, 1970; Chastrette et
kirchneriella subcapitata [formerly Selenastrum capri- al., 1983). These include the monomer ethane-1,1,2,2-
cornutum]), and an invertebrate species. In four fish tetraol (I), the dimer 2-dihydroxymethyl-(1,3)dioxolane-
species tested, the lowest reported 96-h LC50 value was 4,5-trans-diol (II), and the trimer bis(dioxolane) (i.e.,
215 mg/litre (Pimephales promelas). 2,2'-bi-1,3-dioxolanyl-4,4',5,5'-tetraol) (III) — both cis
and trans configurations. However, the proportion of the
A sample risk characterization for the aquatic different structures varies with concentration and pH.
environment was performed by calculating the ratio OH
OH OH O
between a local predicted environmental concentration O
HO HO HO O
(PEC), based on recently measured data, and a corres- OH OH O OH
O O
ponding predicted no-effect concentration (PNEC). A OH
HO HO
PNEC of 149 µg/litre for surface water was estimated
I II III
from the lowest EC50 value of 149 mg/litre by applying
an uncertainty factor of 1000. Using the highest recently Some studies (developmental toxicity) have used
measured concentration of glyoxal in surface water glyoxal trimeric dihydrate (CAS No. 4405-13-4).
(1.9 µg/litre), a PEC/PNEC quotient of 0.013 was
obtained. As this is less than 1, no further information, The environmentally relevant physicochemical
testing, or risk reduction measures are required. properties of glyoxal and of the commercially employed
40% aqueous solution of this compound are summarized
A no-observed-effect concentration (NOEC) of in Table 1. Additional physical and chemical properties
68 mg/litre was determined for the inhibition of the are presented in the International Chemical Safety Card
proliferation of rhizome fragments of Helianthus reproduced in this document.
tuberosus, with a corresponding EC30 value of
136 mg/litre, in the only study available. As no addi- The conversion factors1 for glyoxal in air (at 20 °C
tional data characterizing the toxic effects exhibited by and 101.3 kPa) are as follows:
glyoxal upon terrestrial microorganisms or invertebrates
are available, it was not possible to perform a reliable 1 ppm in air = 2.41 mg/m3
quantitative risk characterization. 1 mg/m3 = 0.414 ppm

2. IDENTITY AND PHYSICAL/CHEMICAL 3. ANALYTICAL METHODS


PROPERTIES

Accepted methods for the detection and quantifica-


Glyoxal (CAS No. 107-22-2; C2H2O2) is also known tion of glyoxal in different matrices are given below.
as ethanedial, diformyl, ethanedione, biformal, and oxal. Additional and more detailed information is available in
At room temperature, anhydrous glyoxal is a liquid, with BUA (1997) and references cited therein.
a melting point of about 15 °C. It crystallizes in its
monomeric form to yield yellow, irregular to prism-like 3.1 Air
crystals. However, it is generally employed as an
aqueous solution (typically containing 30–50% glyoxal), Determination of glyoxal in air usually involves
in which hydrated oligomers are present due to nucleo- concentration of the α-dicarbonyl onto a solid sorbent
philic addition (Chastrette et al., 1983; Hoechst AG, coated with an appropriate derivatization agent followed
1984a). by solvent desorption prior to high-performance liquid
Glyoxal can undertake rotational isomerization
1
between the planar cis and trans conformations, with In keeping with WHO policy, which is to provide measure-
trans-glyoxal being the more stable isomer (Bulat & ments in SI units, all concentrations of gaseous chemicals in air
Toro-Labbé, 2002): will be given in SI units in the CICAD series. Where the
original study or source document has provided concentrations
O O O in SI units, these will be cited here. Where the original study or
source document has provided concentrations in volumetric
units, conversions will be done using the conversion factors
O given here, assuming a temperature of 20 °C and a pressure of
trans-glyoxal cis-glyoxal 101.3 kPa. Conversions are to no more than two significant
digits.

6
Glyoxal

chromatographic (HPLC) detection. Zhou & Mopper array detection at 360 nm. They reported a detection
(1990) reported a detection limit of about 0.05 µg/m3 for limit of 295 ng/litre. Glaze et al. (1989) employed
a 100-litre air sample using 2,4-dinitrophenylhydrazine aqueous-phase PFBHA derivatization, yielding the
(DNPH)-coated C18 cartridges, elution with carbon corresponding pentafluorobenzyl oxime, followed by n-
tetrachloride, and subsequent HPLC detection. As an hexane extraction and detection by GC/electron capture
alternative approach, Ho & Yu (2002) employed detection (ECD) or GC/MS. A minimum detection limit
pentafluorobenzyl hydroxylamine (PFBHA)-coated of 5.1 µg/litre was obtained using GC/ECD, whereas
sorbent sampling followed by thermal desorption and GC/MS detection gave a minimum detection limit of
gas chromatography/mass spectrometry (GC/MS) 7.7 µg/litre. Method 556.1 of the US Environmental
detection of formed oximes and reported a minimum Protection Agency (US EPA, 1999) suggests a similar
detection limit of 0.24 µg/m3 for a sample volume of procedure (aqueous-phase PFBHA derivatization
4.8 litres. followed by hexane extraction and fast GC/ECD
detection), leading to method detection limits in the
range of 0.13–0.39 µg/litre. Steinberg & Kaplan (1984)
Table 1: Physicochemical properties of glyoxal and its used both HPLC and GC/MS as well as direct insertion
commercially employed aqueous solution (40%).
probe/MS to detect and quantify glyoxal after 2,4-DNPH
derivatization followed by dichloromethane extraction in
Property Value Reference
fog and mist samples. As a viable alternative, derivatiza-
Glyoxal
tion using o-phenylenediamine to give the corresponding
Relative molecular 58.04 quinoxaline prior to HPLC/ultraviolet (UV) detection
mass
has been described (Barros et al., 1999).
3
Density (g/cm ) 1.14 (20 °C) Lide (1995)
Refractive index 1.3826 (20 °C) Lide (1995) 3.3 Solid materials
Melting point (°C) 15 Brabec (1993)
Boiling point (°C) 50.4 (101.3 kPa) Lide (1995) As described for gaseous and liquid samples,
Vapour pressure 29.33 (~20 °C) Brabec (1993)
glyoxal is usually derivatized either directly in sus-
(kPa) pended samples or after extraction by using o-phenyl-
n-Octanol/water –1.65 (calculated) This report
a enediamine with subsequent GC/ECD detection or 2,4-
partition coefficient DNPH with HPLC/UV detection. Kawata et al. (1980)
–0.85 (measured) BASF AG (1988)
(log Kow) found a detection limit of 0.02 mg/kg analysing sedi-
Water solubility 600 (25 °C) Hoechst AG ment samples for the presence of glyoxal. No specific
(g/litre) (1994) method for the analysis of soil is available (BUA, 1997).
Henry’s law constant Betterton &
3
(Pa·m /mol) –4 Hoffmann (1988) 3.4 Human blood and plasma
≤3.38 × 10
(25 °C,
measured) The concentration of glyoxal in whole-blood
–7
(dimensionless) ≤1.36 × 10 samples was determined by derivatization with 1,2-
40% aqueous solution of glyoxal diamino-4,5-dimethoxybenzene, solid-phase extraction,
Vapour pressure 2.03 (20 °C) BASF AG
and HPLC of the resulting quinoxaline adduct with
(kPa) (personal fluorometric detection (Thornalley et al., 1996). The
communication, interbatch coefficient of variation was 20%, the limit of
2003) detection 40 pmol, and the recovery 99%. Odani et al.
3
Density (g/cm ) 1.27 (20 °C) Hoechst AG (1999) employed a similar method for plasma, using
(1993) quantitative derivatization of glyoxal present in plasma
Viscosity (mPa·s) 5–10 (23 °C) BASF AG (1991) with 2,3-diaminonaphthalene prior to organic extraction
Setting point (°C) ~ –10 Hoechst AG followed by subsequent analysis employing HPLC
(1993) resolution and detection by electrospray ionization/MS.
pH of aqueous 2.1–2.7 Lundberg (1995) Lapolla et al. (2003) quantified glyoxal in plasma using
solution GC/MS after derivatization with O-(2,3,4,5,6-penta-
a
Using KowWin v.1.66. fluorobenzyl)hydroxylamine hydrochloride.

3.2 Water

Edelkraut & Brockmann (1990) detected and


quantified glyoxal in water samples by using the typical
2,4-DNPH derivatization followed by HPLC with diode

7
Concise International Chemical Assessment Document 57

4. SOURCES OF HUMAN AND disinfecting agent and is present in many products, such
ENVIRONMENTAL EXPOSURE as cleansers used for the disinfection of surfaces (BPI,
1993; OECD, 2002; BASF AG, personal communica-
tion, 2003).
4.1 Natural sources
4.4 Emissions
There are several natural sources of glyoxal. Thus,
glyoxal can be produced biologically as a useful by- Generally, glyoxal might be released during its
product (i.e., for the generation of hydrogen peroxide manufacture or its application (BUA, 1997; see also
required by manganese-dependent peroxidase enzymes; section 4.3). A well recognized source of glyoxal is
Kersten, 1990) or non-enzymatically by autoxidation of automotive emissions and the subsequently formed
lipids (Hirayama et al., 1984). Furthermore, it can be photochemical smog, which gives rise to the formation
produced from a range of abiotic reactions with aromatic of this compound (California State Air Resources Board,
compounds in the presence of ozone and/or hydroxyl 1984; Jing et al., 2001). In addition, emissions from
radicals. Accordingly, Mopper & Stahovec (1986) cigarettes have been shown to contain trace amounts of
detected the formation of glyoxal from humic acids by glyoxal (Moree-Testa & Saint-Jalm, 1981). Another
photochemical reactions in seawater. Mopper et al. potential source of glyoxal is domestic and residential
(1991) estimated the photochemical glyoxal formation log fires (Kleindienst et al., 1986; McDonald et al.,
rates in Sargasso seawater (0–4000 m) to be in the range 2000). Using an irradiated smog chamber, Kleindienst et
of 0.4–1.1 nmol carbon/h. In addition, one can safely al. (1986) and McDonald et al. (2000) detected glyoxal
assume that natural fires — in analogy with results concentrations of up to about 110 µg/m3. Interestingly,
reported for domestic and residential log fires (Klein- glyoxal was detected as a minor species in turbulent
dienst et al., 1986; McDonald et al., 2000) — will flames of acetylene and ethylene under atmospheric
release glyoxal in addition to other aldehydes. Ozone pressure (Tichy et al., 1998).
can — for example, when applied as a water disinfectant
— catalyse the formation of glyoxal from organic carbon
present in water (Glaze et al., 1989; Le Lacheur et al.,
1991; Lopez et al., 1999). 5. ENVIRONMENTAL TRANSPORT,
DISTRIBUTION, AND TRANSFORMATION
4.2 Estimated production

Two well established processes employed for the 5.1 Environmental transport and
production of glyoxal are the gas-phase oxidation of distribution
ethylene glycol with air in the presence of copper or
silver catalysts at elevated temperature (about 300 °C) The predominant target compartments for glyoxal in
and the liquid-phase oxidation of acetaldehyde with the environment are the hydrosphere and soil (about
nitric acid (Chumbhale & Awasarkar, 2001). In Ger- 46% and 54%, respectively) and, to a lesser extent, air
many, less than 10 000 tonnes of glyoxal (40%) were (<1%; Level III fugacity calculation, using EPI v.3.1).
produced in 1992 (BUA, 1997). However, in 2002, According to Thomas (1982), the reported Henry’s law
BASF started up a new production plant with an annual constant of ≤3.38 × 10–4 Pa·m3/mol (Betterton & Hoff-
capacity of about 60 000 tonnes (BASF AG, personal mann, 1988) indicates that glyoxal is essentially non-
communication, 2003). The Japanese production figure volatile with regard to the aqueous phase. Therefore, a
for glyoxal was 13 000 tonnes in 1999 (J. Sekizawa, noteworthy transfer of glyoxal from the aqueous to the
personal communication, 2001). The world production gas phase is not expected. This is supported by the find-
volume of glyoxal is about 120–170 kilotonnes (OECD, ings of Harke & Höffler (1984), who used Hela cells as
2002). an indicator for the presence of inhibitory compounds
(i.e., a range of biocides) in the gas phase. Their results
4.3 Uses clearly indicated that glyoxal — as opposed to other
biocides tested, such as formaldehyde — was not trans-
Glyoxal is used as a chemical intermediate in the ferred from solution to the gas phase. However, glyoxal
production of pharmaceuticals and dyestuffs. It is also has to be regarded as a highly mobile compound in soil
used in the industrial production of α-hydroxyalkylureas due to the low log Koc value (<1) reported (BUA, 1997).
(the addition of glyoxal to urea) and is industrially Due to its excellent solubility in water and its low log
employed as a cross-linking agent in the production of a Kow, it is not expected to bioaccumulate.
range of different polymers, such as textiles (e.g., per-
manent press fabrics) (Hoechst AG, 1984a; Choi et al.,
1998, 1999; Choi, 2002), paper (Xu et al., 2002), and
proteins (Marquié, 2001). It is used as a biocide and as a

8
Glyoxal

5.2 Abiotic transformation aldehyde dehydrogenases with sufficient activity for 2-


oxoaldehydes should yield glyoxylate.
Atkinson (2000) calculated a lifetime of 1.1 days for
glyoxal in the presence of hydroxyl radicals (assuming Even under physiological conditions, glyoxal reacts
an average 12-h daytime concentration of 2 × 106 mole- quickly with arginine, leading to the formation of 1-(4-
cules/cm3). With respect to photolytic transformation amino-4-carboxybutyl)-2-imino-5-oxo-imidazolidine
(overhead sun), a lifetime of 5 h was calculated by the (Schwarzenbolz et al., 1997). Thus, arginine residues
same author. Li & Schlegel (2001) showed that the present in proteins can act as scavengers for glyoxal.
photofragmentation of glyoxal proceeded — under Further, glyoxal is able to oxidize an amino acid such as
collision-free conditions — by internal conversion to a phenylalanine to a plethora of products, such as Strecker
vibrationally excited state, which dissociates to yield H2 aldehydes and O- and N-heterocycles (Adamiec et al.,
+ CO + CO (28%), H2CO (formaldehyde) + CO (65%), 2001), and can produce amides from amino acids such as
and HCOH (hydroxycarbene) + CO (7%). Hence, lysine (Glomb & Pfahler, 2001) and arginine (Glomb &
glyoxal released into the atmosphere will undergo a Lang, 2001).
rapid degradation in this environmental compartment.
According to Yadav & Gupta (2000), the hydrolysis of
glyoxal with sodium hydroxide as catalyst proceeded
with a second-order rate constant of 9.3 × 10–6 cm3/mol·s 6. ENVIRONMENTAL LEVELS AND
at 25 °C to yield glycolic acid. Brunet et al. (1984) HUMAN EXPOSURE
showed the transformation of glyoxal to oxalic acid via
glyoxylic acid in the presence of ozone.
6.1 Environmental levels
5.3 Biotransformation and biodegradation
6.1.1 Atmosphere
In biodegradation tests corresponding to Organi-
sation for Economic Co-operation and Development Residential wood combustion was reported to
(OECD) guideline 301C, glyoxal was readily biodegrad- release up to about 600 mg glyoxal/kg hardwood used in
able (65% biochemical oxygen demand [BOD] of the fireplace (McDonald et al., 2000). Borrego et al.
theoretical oxygen demand [ThOD], incubation for (2000) detected glyoxal in ambient air sampled in the
14 days; MITI, 1992). Similar results were obtained by Giesta area (a rural location 20 km south-east of Aveiro,
applying the method of Zahn Wellens, yielding an Portugal) and reported an average level of 3.7 µg/m3.
elimination of >70% of dissolved organic carbon in Kawamura et al. (2000) showed the presence of glyoxal
7 days (Hoechst AG, 1991a). Conway et al. (1983) in all ambient air samples taken at four different loca-
observed a significant bio-oxidation of glyoxal by tions (modest to high degree of urbanization and traffic)
sewage inocula (76% of ThOD after 20 days), while in the Los Angeles region (USA) and found glyoxal at
Gerike & Gode (1990) showed that glyoxal was bio- concentrations ranging from about 0.096 to 2.3 µg/m3.
degradable (i.e., 90% of ThOD within 28 days) by More recently, Ho & Yu (2002) analysed the ambient air
employing the OECD 301D closed bottle test. Further- at a roadside location near a bus stop (Clear Water Bay,
more, using both the oxygen consumption inhibition test Kowloon) in Hong Kong for 24 h and showed that the
and the OECD confirmatory test, they established an lowest levels of glyoxal (about 1.2 µg/m3) were present
inhibition limit of 500 mg/litre. Hence, water or sewage in the early hours (01:00–05:00), whereas the maximum
treatment plants should be impacted detrimentally only levels (about 9.9 µg/m3) were obviously correlated with
at high influent concentrations. In fact, a large number of increasing traffic (09:00–13:00). Jing et al. (2001) found
microbial enzymes catalyse the transformation of gly- glyoxal present in urban air samples taken in Las Vegas
oxal to common intermediates in microbial catabolism. (USA) in both summer (range 0.29–0.99 µg/m3) and
Thus, Sakai et al. (2001) reported the efficient transfor- winter (range 0.22–0.51 µg/m3).
mation of glyoxal to glycolaldehyde by glyoxal reduc-
tase from Bacillus subtilis. Furthermore, glyoxal can be 6.1.2 Hydrosphere
effectively oxidized by enzymes such as the fungal
glyoxal oxidase (Kersten, 1990) and its bacterial coun- Steinberg & Kaplan (1984) detected glyoxal in fog
terpart (Whittaker et al., 1999) to yield glyoxylic acid, samples collected near Los Angeles (Topanga Canyon),
which, in turn, is a common intermediate of many USA, at concentrations up to about 1.9 mg/litre.
metabolic sequences (i.e., glyoxylate cycle) present in
microorganisms. Finally, the microbial glyoxalase The presence of glyoxal was reported at 4–12 µg/li-
system (Cooper, 1984) should yield glycolate in analogy tre in water of the river Elbe sampled near Brunsbüttel,
to the reaction with methylglyoxal, whereas microbial Germany (Edelkraut & Brockmann, 1990), and in sam-
ples from the Sargasso Sea (Mopper et al., 1991; no

9
Concise International Chemical Assessment Document 57

values given). Le Lacheur et al. (1991) detected glyoxal 3 mg/kg; malt — about 7 mg/kg) might contain glyoxal
at low µg/litre concentrations in raw drinking-water as well (Palamand et al., 1970). Yamaguchi et al. (1994)
sampled in Fort Dix, USA. More recently, Nawrocki et detected glyoxal in fermented food such as yoghurt
al. (1996) detected glyoxal in distilled (0.9 µg/litre) and (about 0.63–0.92 mg/kg). Due to heat-induced autoxida-
double-distilled (0.1 µg/litre) reagent water. The same tion, edible oils might contain glyoxal, as was shown for
authors (Dabrowska et al., 2003) demonstrated the sardine oil, containing up to 6.5 mg/kg (Hirayama et al.,
presence of glyoxal at concentrations up to 1.9 µg/litre 1984).
in groundwater (Mosina water intake serving Poznañ)
and surface water samples (river Bogdanka) from 6.2 Human exposure
Poland. These levels did not significantly increase upon
chlorine dioxide treatment of the raw water samples. 6.2.1 General population
IPCS (2000) reported the median concentration of
glyoxal in ozone-treated drinking-water to be 9 µg/litre. The main route of exposure of the general popula-
tion to glyoxal is probably via intake of water and food
6.1.3 Sediment containing glyoxal. Glyoxal is present in a broad range
of different food products. However, due to the lack of
Kawata et al. (1980) reported the presence of quantitative data on the presence of glyoxal in food
glyoxal in sediment samples from Japanese rivers at up products such as meat, dairy products, or fish, an exact
to 13 mg/kg dry weight. value cannot be given. The general population might
also be exposed to glyoxal via cigarette or residential log
6.1.4 Food fire smoke or vehicle exhaust containing glyoxal.

Glyoxal is a substance frequently detected in An exposure scenario has been compiled as a


fermented food and beverages. This is mainly due to hypothesized worst case. A food/drink intake of
microbial activity as well as non-enzymatic browning 10 mg/day has been calculated from foods with a known
reactions such as caramelization and Maillard reactions glyoxal content (see section 6.1.4). About three cups of
of saccharides (Hollnagel & Kroh, 1998; Glomb & brewed coffee per day (>400 µg glyoxal), toast (>50 µg
Tschirnich, 2001; Hollnagel & Kroh, 2002). Accord- glyoxal), a stir-fried meal containing rice (>4 mg
ingly, Barros et al. (1999) found glyoxal present in glyoxal), oil (>500 µg glyoxal), soy sauce (>200 µg
different brands of beer and wine on sale in Portugal. glyoxal), a pint of beer (500 µg glyoxal), one yoghurt
Sampling three different brands of white wine, they (>130 µg glyoxal), and one glass of sherry (>30 µg
detected glyoxal at concentrations of 6.2, 8.7, and glyoxal) leads to an intake of about 6 mg/day. A further
26 µmol/litre (about 360, 464, and 1509 µg/litre). De intake of 3–4 mg glyoxal/day might come from other
Revel & Bertrand (1993) evaluated a range of French fermented products (dairy products or vegetables), from
wines and detected glyoxal in one white wine (mean of other popular roasted or fried products (meat, fish,
125 µg/litre), red wines (151–368 µg/litre), and five mushrooms, sausages), or from additional bakery
sherry wines (lowest level of glyoxal in a Seco with products.
435 µg/litre and highest level in an Olorosso with
1556 µg/litre). Palamand et al. (1970) detected glyoxal Assuming a daily intake of 20 m3 air containing
levels ranging from about 230 to 1000 µg/litre in eight about 4 µg glyoxal/m3 (Borrego et al., 2000), a daily
different beers. Nagao et al. (1986) detected glyoxal in consumption of 2 litres of water containing 9 µg
Bourbon whiskey (390 µg/litre), wine (970 µg/litre), glyoxal/litre (median for ozone-treated drinking-water;
and apple brandy (33 µg/litre), as well as in black tea IPCS, 2000), and an estimated daily intake of 10 mg
(20 µg/litre) and instant (340 µg/litre) and brewed coffee glyoxal via food, an intake of about 160 µg of glyoxal
(870 µg/litre). Yamaguchi et al. (1994) detected glyoxal per kg body weight (using 64 kg as the value for body
in beverages such as beer (20–40 µg/litre) as well as weight) per day can be calculated. This intake is almost
white (510 µg/litre) and red wine (740 µg/litre). totally from food.

Nagao et al. (1986) found glyoxal in soybean paste Modifying this calculation by including a 2-h daily
(4.2 mg/kg), soy sauce (4.9 mg/litre), toast (0.5 mg/kg), exposure to traffic exhaust containing glyoxal (at
and bread (0.3 mg/kg). Markianova et al. (1971) 9.9 µg/m3 — from Ho & Yu (2002) — instead of
reported glyoxal levels in bread ranging from 0.07 to 4 µg/m3) while still using the other values as stated
0.31 mg/kg, depending on the yeast type employed. above (water, food) does not yield a significantly higher
However, Roiter & Borovikova (1972) showed that value.
using amylase in the baking process led to glyoxal levels
of up to 1.4 mg/kg in the bread crust and of up to Glyoxal has been reported as being present in some
1.6 mg/kg in the bread crumbs. Plant materials used for household cleaners up to a concentration of 4% (product
brewing (rice — about 14 mg/kg; barley — about databanks, Switzerland, Denmark, and Germany; R.

10
Glyoxal

Hertel, personal communication, 2003). People can section 7.1). The urine of patients without these diseases
therefore be exposed to glyoxal during its use as a contained glyoxal at about 132 µmol/litre (Espinosa-
household cleaner. Mansilla et al., 1998). This value is in apparent conflict
with the low levels found in tissues and body fluids and
6.2.2 Occupational exposure with the assumed efficient glyoxalase activities in these
patients.
Glyoxal does not appear to evaporate from solution
(Harke & Höffler, 1984). Further, the reported Henry’s
law constant of ≤3.38 × 10–4 Pa·m3/mol (Betterton &
Hoffmann, 1988) indicates that glyoxal is essentially 7. COMPARATIVE KINETICS AND
non-volatile with regard to the aqueous phase. There- METABOLISM IN LABORATORY ANIMALS
fore, occupational exposure by inhalation will probably AND HUMANS
take place only in situations where aerosols containing
glyoxal are released. Such an exposure situation might
be the spray application of biocidal products containing 7.1 Endogenous glyoxal
glyoxal.
Glyoxal is endogenously produced during normal
A model calculation has been made using an aerosol cellular metabolism by a multitude of enzyme-
droplet simulation programme for a worst-case exposure independent pathways, such as the spontaneous reaction
via inhalation of aerosol droplets — for example, of a of amino groups in proteins with reducing sugars
farmer disinfecting his stable by spray application of a (Maillard reaction), sugar autoxidation, DNA oxidation,
commercial product (see Appendix 5 for details). The peroxidation of polyunsaturated fatty acids, and UV
model calculation using the given assumptions predicts photodamage, and in conditions of oxidative stress and
an exposure concentration of 24 µg glyoxal/m3 for a 6- depletion of GSH (Loidl-Stahlhofen & Spiteller, 1994;
min exposure and 32 µg glyoxal/m3 for 15 min. Shibamoto, 1994; Murata-Kamiya et al., 1995, 1997a;
Wells-Knecht et al., 1995; Fu et al., 1996; Mlakar &
Exposure via skin (i.e., unprotected use of disinfec- Spiteller, 1996; Abordo et al., 1999; Miyata & Kuro-
tant solution) may be estimated using DermWin v.1.43 kawa, 1999; Thornalley et al., 1999; Kasper & Funk,
(US EPA, 2000). A typical brand of disinfectant (7.5 g 2001; Ulrich & Cerami, 2001; Kasai, 2002; Thornalley,
in 100 g = 7.5% glyoxal) recommends a dilution of 1% 2002; Wondrak et al., 2002a) (see Figure 1). Further-
for disinfection and cleaning of surfaces (i.e., 0.075% more, glyoxal is a product of the metabolism and
glyoxal). Using a rounded-up figure of 0.1% glyoxal microsomal oxidation of compounds such as glycol-
solution and a Kp value (estimated from the following aldehyde, ethylene glycol, and β-hydroxy-substituted N-
equation: log Kp = –2.72 + 0.71 log Kow – 0.0061 MW) nitrosamines and possibly contributes to the toxic,
of 5.63 × 10–5 cm/h (given in DermWin v.1.43 taken genotoxic, and tumorigenic action of these substances
from US EPA, 2000; where Kp is the permeability (Loeppky & Goelzer, 2002; Loeppky et al., 2002).
coefficient from water and MW is molecular weight) for
glyoxal, the dermally absorbed dose per event (assuming In biological materials, less than 10% of the glyoxal
a final concentration of glyoxal in the aqueous solution present is in unbound forms in aqueous solution (free
used for cleaning surfaces of 1 mg/cm3 [0.1%] and an glyoxal and hydrates), as most of the reactive carbonyl
event duration of 30 min) yields a potential uptake of groups are reversibly bound to cysteinyl, lysyl, and
2.8 × 10–2 µg/cm2 per event (using Fick’s first law) with arginyl residues of proteins (Thornalley, 1995).
regard to exposed, unprotected skin. Taking a worst case
of 10 events/day, a surface area of hands of 840 cm2 (US The endogenous concentrations of glyoxal in human
EPA, 1997), and assuming 100% uptake through the tissues and body fluids, as with other α-oxoaldehydes,
skin, this would mean 235 µg glyoxal/day, which equals are limited by the high catalytic efficiency of the glyox-
3.7 µg/kg body weight, assuming a body weight of alase system (Thornalley, 1995) as well as by the rapid
64 kg. reaction of glyoxal with proteins (Sady et al., 2000).
6.2.3 Human plasma and urine
During certain pathological conditions (e.g., dia-
betes mellitus, uraemia), raised concentrations of glyoxal
Glyoxal is produced endogenously and is commonly
have been measured. The concentration of glyoxal in
present in blood plasma of healthy subjects, with one
blood samples from normal human subjects (n = 19) was
study giving values of about 67 ng/ml (corresponding to
0.21 ± 0.14 µmol/kg (Thornalley et al., 1996). For blood
about 1.16 µmol/litre; Odani et al., 1999) and other
plasma, a value of approximately 0.1 µmol/litre was
studies reporting 0.23 µmol/litre (Agalou et al., 2002)
estimated for normal healthy subjects, which can double
and 0.3 µmol/litre (Lapolla et al., 2003). Higher levels
in diabetics (Thornalley, 1998; Thornalley et al., 2000).
are found in patients with diabetes or renal diseases (see

11
Concise International Chemical Assessment Document 57

Endogenous Formation

oxidative
stress
HOCH2 O
HO sugar
OH
autoxidation
HO + Protein
OH UV - DNA
photo oxidation
Glucose damage

Maillard
reaction lipid peroxidation

+ DNA
O
DNA adducts
dC-Glyoxal O
Glyoxal
dG-Glyoxal
via Glyoxalase I and II
+ Protein + GSH
Schiff base

Glycolate
R
NH Amadori product

Detoxification
O OH

CML
Nε-(carboxymethyl)lysine

Advanced Glycated Products


Fig. 1: Scheme of formation, detoxification, and protein and DNA adduct formation of glyoxal

The concentration of glyoxal in blood plasma was 0.23 ± higher levels of glyoxal in plasma (n = 15–20 subjects):
0.13 µmol/litre in controls (n = 6), 0.4 ± 0.16 µmol/litre 67 µg/litre in normal control subjects and 78 µg/litre in
in patients with mild/moderate uraemia (n = 10), and patients with non-insulin-dependent diabetes, corres-
0.76 ± 0.21 µmol/litre in patients with end-stage renal ponding to approximately 1 µmol/litre. Chronic renal
disease on haemodialysis (n = 5) (Agalou et al., 2002). failure resulted in accumulation of glyoxal, with a mean
Similar levels in plasma samples were reported by plasma level of 221 µg/litre (about 4 µmol/litre), which
Lapolla et al. (2003) (n = 3 persons/group): a mean of was possibly caused by accelerated autoxidation of
17.3 µg/litre (0.3 µmol/litre) for healthy subjects, 26.4 glucose in uraemic patients (Odani et al., 1999). A
µg/litre (0.45 µmol/litre) for badly controlled diabetics, possible higher non-physiological production of glyoxal
and 27.2 µg/litre (0.47 µmol/litre) for those affected by leading to local accumulation was assumed in patients
chronic renal failure. Another working group reported

12
Glyoxal

with hyperglycaemia associated with diabetes (Akhand approximately proportional to the cytosolic concentra-
et al., 2001). tion of GSH. When GSH is severely depleted (e.g.,
under conditions of oxidative stress), however, 2-oxo-
In porcine ischaemic heart tissue, glyoxal levels in aldehyde dehydrogenase and aldose reductase may also
the lipid fraction (determination of “free glyoxal”) metabolize glyoxal. Imbalances in intracellular redox
increased 4-fold after up to 4 h of ischaemia and 24-fold systems may impair these detoxification mechanisms,
after 6 h of ischaemia (0.2 µg/g lipid) in comparison resulting in higher levels of glyoxal (Thornalley, 1995,
with extraischaemic heart tissue (Dudda et al., 1996). 1998; Abordo et al., 1999; Miyata et al., 1999, 2001). A
further GSH-independent route of detoxification via
In cultures of P388D1 cells (murine macrophage cell glyoxalase III exists. Glyoxalase III is reported to be the
line), the intracellular background concentration was most abundant glyoxalase in Escherichia coli (MacLean
31.2 pmol glyoxal/106 viable cells (sum of free glyoxal et al., 1998; Okada-Matsumoto & Fridovich, 2000).
and glyoxal reversibly bound to proteins). Intracellularly
produced glyoxal readily crosses cell membranes, The glyoxalase I concentration in human tissues and
possibly by passive diffusion. Despite reversible binding blood cells was about 0.2 µg/g protein. In human tissues,
to cellular peptides and proteins, accumulation of the specific activity was highest in pancreas, lung, kid-
glyoxal in the extracellular medium could be demon- ney, and brain and lowest in adipose tissue and liver.
strated, with concentrations in the culture medium rising Specific activities in fetal tissues were about 3 times
from below the detection limit to 61 nmol/litre (P < higher than in corresponding adult tissues. Human
0.01) during a 3-h culture period (Abordo et al., 1999). glyoxalase I was found to exhibit genetic polymorphism,
with three phenotypes resulting from a diallelic gene.
7.2 Absorption, distribution, and excretion The frequency of the GLO1 allele in various populations
on average ranges from 0.046 to 0.853 (Thornalley,
There are limited qualitative and no quantitative 1993).
data on the absorption and distribution of glyoxal in
humans and experimental animals. Acute and subacute Exposure to glyoxal induced the activity of glyox-
inhalation exposure resulted in local effects on eyes and alase I in Salmonella typhimurium strains TA 100 and
respiratory organs, the extent of systemic absorption TA 104 (0.1 mg glyoxal/ml) (Ueno et al., 1991b) as well
being unclear. After acute and chronic oral administra- as in erythrocytes, liver, and kidney of male Sprague-
tion, there is evidence of systemic absorption, with Dawley rats (4000 or 6000 mg glyoxal/litre drinking-
distribution to erythrocytes, liver, lung, kidney, pan- water for 30 days, no increased activity for longer
creas, and adrenal glands (BUA, 1997; see also section exposure periods; for details, see section 8.3) (Ueno et
8; e.g., Ueno et al., 1991a). There is some qualitative al., 1991a).
evidence that glyoxal is absorbed after dermal exposure.
Granular and vacuole degeneration in liver, kidney, and 7.4 Covalent binding
pancreas have been observed along with a distinct
increase in blood glucose levels following dermal appli- Glyoxal attacks the amino groups of proteins,
cation (Ito, 1963). Further, data on skin sensitization (see nucleotides, and lipids with its highly reactive carbonyl
sections 8.7 and 9) provide supportive qualitative evi- groups. A sequence of non-enzymatic reactions, called
dence that glyoxal is absorbed across the skin. glycation, yields stable AGEs with a background extent
of 0.1–1% of lysine and arginine residues in proteins and
In normal human urine, a glyoxal concentration of 1 in 107 nucleotides in DNA.
132 µmol/litre was found by HPLC analysis (Espinosa-
Mansilla et al., 1998). However, this could either be AGEs originating from the reaction of glyoxal with
produced endogenously or stem from an exogenous lysine and arginine residues of proteins identified so far
source, such as food intake. are Nε-(carboxymethyl)lysine (CML), imidazolium
cross-links as glyoxal–lysine dimer and imidazolysine,
7.3 Biotransformation arginine-derived imidazolium products, and arginine–
lysine cross-links. Cyclic imidazolidones may be formed
The cytosolic GSH-dependent glyoxalase system is on reaction with arginine residues.
the major pathway for the detoxification of glyoxal (see
Figure 1). Glyoxal reacts non-enzymatically with GSH Glyoxal forms stable adducts with guanosine by
with formation of a hemithioacetal, which is subse- reaction with the N-1 as well as with the exocyclic
quently converted to S-glycolylglutathione by glyoxalase nitrogen of guanine. The rate of glyoxal–guanine adduct
I. Glyoxalase II catalyses the hydrolysis of S-glycolyl- formation is rapid under physiological conditions
glutathione to glycolate, re-forming the GSH from the (Loeppky et al., 1999). A stable tricyclic glyoxal–DNA
first reaction. The activity of glyoxalase I in situ is adduct is formed by covalent binding to two nitrogens of

13
Concise International Chemical Assessment Document 57

guanine under physiological conditions in vitro (for (Mellon Institute, 1958, 1965) or 40% glyoxal (Hoechst
details, see BUA, 1997). Besides 8-hydroxy-deoxy- AG, 1984d,e). After inhalative uptake, observations
guanosine, the glyoxal–deoxyguanosine (dG) adduct is reported included local irritations of the eyes and
one of the major deoxyguanosine oxidation products, respiratory organs as well as hyperaemia and foamy
being formed by oxygen radicals, lipid peroxidation secretion in the lungs. No macroscopic organ changes
systems, various types of oxidative stress, and UV were reported in those rats surviving the 14-day post-
irradiation and after in vivo exposure to β-hydroxy- observation period (Hoechst AG, 1984d,e).
substituted N-nitrosamines (Murata-Kamiya et al.,
1997a,b; Loeppky et al., 1999; Mistry et al., 1999; After oral administration to rats, LD50 values rang-
Cooke et al., 2000; Kasai, 2002). ing from 2960 mg/kg body weight (lowest value in
females) to 8979 mg/kg body weight (highest value in
Reaction of glyoxal with deoxycytidine (dC) yields males) were reported in several studies using products
5-hydroxyacetyl-deoxycytidine or, by deamination, containing 40% glyoxal, demonstrating a higher sensi-
deoxyuridine. Deamination of 5-methyl-deoxycytidine is tivity of female rats. In mice (sex not given), the LD50 of
also possible, forming deoxythymidine. The analysis of 40% glyoxal was 4064 mg/kg body weight. For a prepar-
DNA bases involved in DNA cross-links formed in vitro ation containing 80% glyoxal, oral LD50 values of 2000
showed cross-linking by deoxyguanosine–glyoxal– mg/kg body weight in rats and 900 mg/kg body weight
deoxycytidine adducts and deoxyguanosine–glyoxal– in guinea-pigs were found. Macroscopic observations
deoxyadenine adducts (Kasai et al., 1998). reported after oral uptake include irritations of the gas-
trointestinal tract and congestions in the gastrointestinal
Incubation of rat retinal organ culture with glyoxal tract, lung, kidney, and adrenal glands (BUA, 1997).
(<300 µmol/litre for 9 h) increased apoptotic events in
all layers. After 800 µmol glyoxal/litre, approximately After dermal administration of 40% glyoxal, the
50% of the cells in all layers of the retina were apoptotic. LD50 values were >2000 mg/kg body weight for the rat,
The glyoxal-induced rapid formation of CML showed 12 700 mg/kg body weight for the rabbit, and >5000 mg/
the ability of the retina model to simulate AGE-related kg body weight for the guinea-pig (for details, see BUA,
events in vitro. The neurotoxicity of glyoxal-induced 1997).
AGE formation was shown by the significantly
increased rate of cell death in the retina (Reber et al., In the 1940s to 1960s, histopathological findings in
2003). studies with acute application of glyoxal pointed to a
connection between effects induced by glyoxal and those
induced in the course of diabetes; this has been con-
firmed by recent intensive studies on the mechanism of
8. EFFECTS ON LABORATORY MAMMALS action of endogenous glyoxal and its involvement in the
AND IN VITRO TEST SYSTEMS development of diabetic complications (see section 8.8).

Pancreas and kidney were identified as the promi-


8.1 Single exposure nent target organs of the toxic action of glyoxal; severe
degenerative changes in these organs were attributed to
The acute toxicity of glyoxal in experimental an inhibition of glyoxalase activity in these tissues.
animals is low to moderate, depending on the actual Changes in the pancreas were dominated by the observa-
concentration of glyoxal in the tested product. However, tion of necrotic areas containing B-cells of the Langer-
from the documentation in the study reports, it is not hans islets in rabbits (105 mg glyoxal/kg body weight
always clear if the values given for the LC50 or LD50 intracardial or two administrations of 320 mg/kg body
refer to the tested product with its specified concentra- weight subcutaneous) and in cats (227 mg/kg body
tion or if the values were converted to a concentration of weight, application not specified). A simultaneous
100% glyoxal. A detailed compilation of acute toxicity increase of blood glucose levels was demonstrated in
data is given in the source document (BUA, 1997). rabbits and cats, comparable to alloxan-induced diabetes
(Doerr et al., 1948). The pancreas is a prominent target
An LC50 value of 2440 mg/m3 (2410 mg/m3 for organ of alloxan toxicity, too, which is mediated by free
females, 2470 mg/m3 for males) was calculated from radicals (Younes, 1997). Rats responded to intravenous
single 4-h inhalation exposures of rats to aerosols of injection of 100–200 mg glyoxal/kg body weight with a
40% glyoxal (Hoechst AG, 1984b). All 10 rats exposed dose-dependent, reversible, and reproducible reduction
by inhalation to an atmosphere containing dust of 80% of the blood glucose level, which was attributed to a
glyoxal in the highest technically feasible concentration glyoxal-stimulated secretion of insulin secondary to
of 1300 mg/m3 survived (Hoechst AG, 1984c). All rats oedematous changes of the pancreas. At higher dosage
survived 7- and 8-h exposures to concentrated atmos- (175 mg/kg body weight intravenous), more severe
pheres (concentration not further specified) of 30% changes, such as irreversible necroses and degranulation

14
Glyoxal

of B-cells, were observed in connection with visible were adjusted to water intake). Changes in mid- and
changes in other organs. However, the B-cells of the high-dose groups, such as increased erythrocyte number
pancreas showed the highest sensitivity to the toxic and reduced urine volume, were attributed to reduced
action of glyoxal (Helge, 1959). The nephrotoxic action water intake; changes of various organ weights in the
of glyoxal is characterized by vacuole degeneration in high-dose group were attributed to reduced body weight.
the kidney (460 mg glyoxal per cat subcutaneous) No changes were found at macroscopic and histological
(Doerr, 1957a,b). Acute effects noted in the pancreas in examination. The NOAEL for this study is 100 mg
several studies all seemed to arise when glyoxal was glyoxal/kg body weight per day (Société Française
administered parenterally, compared with other routes. Hoechst, 1987). (More details were not available to the
This may be due to toxicokinetic reasons. authors of this CICAD. It is not known whether these
concentrations are adjusted to 100% glyoxal. If not, the
A further study in rabbits described histopatholog- NOAEL would be about 40 mg/kg body weight adjusted
ical changes in liver, kidney, and pancreas 40 days after to 100% glyoxal.)
a single dermal application of a 40% glyoxal solution
(leading to severe necrotic dermatitis at application site; 8.3 Medium-term exposure
dose not specified). Granular and vacuole degeneration
in liver, kidney, and pancreas and atrophy and fibrous In a 90-day feeding study, Wistar rats (10 males and
change of Langerhans islets were assessed to show a 10 females per dose group) were exposed to glyoxal
close resemblance to changes in these tissues in the (40% preparation). The study gives the dosages con-
course of diabetes. In glucose tolerance tests performed verted to 100% glyoxal content as corresponding to
5 and 10 days after dermal application of glyoxal, a about 32, 63, 125, and 250 mg/kg body weight per day
distinct increase of blood glucose levels was observed in for male and female rats. Males of the high-dose group
comparison with a constant level in control rabbits (Ito, showed a reversible significant retardation of body
1963). weight gain during the first 2 weeks of exposure without
a concomitant reduction of food intake. Significant
8.2 Short-term exposure increases of liver and kidney weights were observed in
the high-dose group (these are the only organ weights
In an inhalation study conducted according to examined). No relevant macroscopic or micropathologi-
OECD guideline 412, groups of five male and five cal changes were observed in thoracic and abdominal
female Wistar rats inhaled aerosols containing glyoxal organs (pancreas not examined). Haematological and
(40% in water) at 0, 0.4, 2.0, or 10 mg/m3 (analytical biochemical parameters were not analysed. From these
concentrations 0, 0.6, 2.3, and 8.9 mg/m3; mass median investigations, a NOAEL of 125 mg (corresponding to
aerodynamic diameter 0.8–1.2 µm) for a period of 100% glyoxal)/kg body weight per day was estimated
29 days (nose only, 6 h/day, 5 days/week). Exposure was (Mellon Institute, 1966).
tolerated by all dose groups without any systemic effects
(examination of body weight, haematological and Beagle dogs (three per dose group) were also
biochemical parameters, urine analysis, macroscopic and exposed to the same preparation of glyoxal by feeding
histological examination). The only local effect found in dosages of 31, 65, or 115 mg/kg body weight per day
the larynx was a minimal squamous metaplasia of the (dosages corresponding to 100% glyoxal). Up to the
epiglottal epithelium accompanied by a minimal sub- high dosage, no substance-related changes of body
mucosal infiltration of lymphocytes in the mid- and weight, food consumption, liver or kidney weight, or
high-dose groups. Consequently, for local effects, a haematological or serum clinical chemistry parameters
NOEL of 0.6 mg/m3 (nominal concentration 0.4 mg/m3) and no macroscopic or histopathological changes were
resulted for subacute inhalation exposure of rats to observed in thoracic and abdominal organs (pancreas not
glyoxal (Hoechst AG, 1995). examined). The NOEL for 90-day feeding of glyoxal to
dogs was >115 mg/kg body weight per day (dosage
In a 28-day oral toxicity study conducted according corresponding to 100% glyoxal) (Mellon Institute,
to OECD guideline 407, six male and six female 1966).
Sprague-Dawley rats per dose group were exposed to
glyoxal (40% in water) at dosages of 0, 100, 300, or Five male Sprague-Dawley rats per group were
1000 mg/kg body weight per day via the drinking-water. treated with glyoxal (98.7% purity) in drinking-water at
A dose-dependent retardation of body weight gain in the concentrations of 2000, 4000, or 6000 mg/litre for
mid-dose group (slight effect) and the high-dose group periods of 30, 60, or 90 days (Phase I study) (Ueno et al.,
(significant effect) was accompanied by reduced food 1991a). Due to a decrease in food intake, the actual
intake. A dose-dependent reduction of water intake was dosages decreased with increasing time of exposure (30,
observed in male rats at the lowest dose and in female 60, and 90 days) and corresponded to 188, 135, and
rats at the mid- and high doses (glyoxal concentrations 107 mg/kg body weight per day for the low-dose groups,

15
Concise International Chemical Assessment Document 57

407, 239, and 234 mg/kg body weight per day for the systemic toxicity of glyoxal. Significant decreases of
mid-dose groups, and 451, 344, and 315 mg/kg body absolute weights and significant increases of relative
weight per day for the high-dose groups, respectively. weights of liver, kidneys, and heart were observed in
The study design included observations of clinical signs, glyoxal-exposed rats (Ueno et al., 1991a).
body weights, major organ weights (liver, kidneys,
spleen, heart, testes, brain), serum clinical chemistry, Fischer 344 rats (10 per dose group and sex) were
and biochemical examinations of glyoxalase activity and exposed daily to drinking-water containing 0, 1000,
extent of lipid peroxidation (content of GSH and 2-thio- 2000, 4000, 8000, or 16 000 mg glyoxal/litre for 90 days
barbituric acid-reactive substances) in liver, kidneys, and to establish dose ranges for a chronic study. All animals
erythrocytes. of the highest dose group were sacrificed prematurely on
day 12 in a moribund state. Decreased dose-related body
There was a dose-dependent retardation of body and organ weights as well as decreased food and water
weight gain, which was significant for the mid- and consumptions were observed at the lowest dosage. For
high-dose groups, and also a dose-dependent decrease of chronic exposure, the maximum tolerated dose for rats
food and water intake. From Phase II of this study (see was estimated in the range of 500–2000 mg/litre for
below), it was concluded that body weight reduction did males as the more sensitive sex (decrease of water
not correspond to decreased food intake but was a consumption up to 28%) and 1000–4000 mg/litre for
reflection of the systemic effects of glyoxal. Absolute females (decrease of water consumption up to 46%)
weight of liver, kidneys, spleen, and heart significantly (NTP, 1991a).
decreased in all dosed groups at all time points. A signi-
ficant increase of relative kidney weight in the high-dose In a similar study in B6C3F1 mice (10 per sex per
group resulted after 90 days. There was no indication of dose group) exposed daily to drinking-water containing
increased lipid peroxidation. the same doses (0, 1000, 2000, 4000, 8000, or
16 000 mg glyoxal/litre for 90 days), all animals sur-
Glyoxalase I activity was significantly increased in vived. The salient features observed were decreased
liver and erythrocytes at the mid- and high doses and in body weight (decrease of 7–30% from 4000 to
the kidneys at the high dose at the 30-day termination, 16 000 mg/litre) and selected organ weights, decreased
but not for longer exposure periods. In contrast, the food and water consumption, and, in the male mice of all
serum clinical parameters aspartate aminotransferase, dose groups, possible chemical-related salivary gland
alanine aminotransferase, lactate dehydrogenase, albu- changes (secretory depletion of submandibular gland). It
min, and total protein were significantly reduced by the was felt that the decreased water consumption (dose-
mid- and/or high-dose exposures for all examination dependently about 10–50%) was due to unsatisfactory
time points. In the low-dose group, alanine aminotrans- palatability of the dosed water, subsequently leading to
ferase and total protein were significantly decreased, so lower daily dosages and decreased feed consumption (up
that it was not possible to derive a NOAEL for this to 24%). From this preliminary study, recommended
study. Consequently, a dosage of 107 mg/kg body doses for further studies with long-term exposure were
weight per day (99% glyoxal) corresponds to the estimated to be in the range of 500–2000 mg/litre for
LOAEL for a 90-day exposure of rats (Ueno et al., males as the more sensitive sex (decrease of water
1991a). The decrease of serum protein levels was consumption up to 12%) and 1000–4000 mg/litre for
attributed to a decrease of protein synthesis, which was females (decrease of water consumption up to 27%)
demonstrable after acute exposure to glyoxal (Ueno et (NTP, 1991b).
al., 1991a) and is explainable by the mode of action of
glyoxal (see section 8.8). 8.4 Long-term exposure and
carcinogenicity
In Phase II of the study, five rats received 6000 mg
glyoxal/litre drinking-water (highest test concentration No studies with long-term exposure to glyoxal by
from Phase I) for 90 or 180 days. One control group inhalation or oral routes were available.
received food ad libitum, whereas a second diet-limited
control group received the same amount of food as con- After the exposure of Sprague-Dawley rats to
sumed by the dosed animals. Dosages were 315 and dosages of 6000 mg glyoxal/litre drinking-water for up
298 mg/kg body weight per day (glyoxal 98.7% purity) to 180 days (for details, see section 8.3), there were no
for the 90- and 180-day exposure, respectively. The neoplastic changes found at the gross and histopatho-
extent of examinations was comparable to that in Phase I logical examination of liver, kidneys, spleen, stomach,
and was further supplemented by gross and histopatho- thymus, and mesenteric lymph nodes (Ueno et al.,
logical examinations of liver, kidneys, spleen, stomach, 1991a).
thymus, and mesenteric lymph nodes. Terminal body
weight was significantly lower than in the pair-fed Glyoxal showed tumour-promoting activity in a
control, so that weight reduction is reflective of the two-stage glandular stomach carcinogenesis model in

16
Glyoxal

male Wistar rats after an 8-week initiation treatment 8.5 Genotoxicity and related end-points
with N-methyl-N'-nitro-N-nitrosoguanidine in the
drinking-water (100 mg/litre) along with a 10% sodium Glyoxal is directly genotoxic in vitro in bacterial
chloride dietary supplement. Subsequent promotion by and mammalian cells. In vivo tests show various
exposure to glyoxal (0.5% in drinking-water from week findings. A detailed overview of genotoxicity tests in
8 to week 40) induced significantly increased incidences bacterial test systems is published in the source
of adenocarcinoma and hyperplasia in the pylorus of the document (BUA, 1997).
glandular stomach in comparison with rats with initia-
tion treatment only. Glyoxal treatment alone induced In the Salmonella microsomal assay, glyoxal (test
neither neoplastic nor hyperplastic changes in the substance 30–40% glyoxal) was a direct mutagen in
pylorus (Takahashi et al., 1989). However, genotoxic strains TA 100, TA 102, TA 104, and TA 2638, with a
activity (induction of unscheduled DNA synthesis and weaker response in the presence of a metabolic activa-
strand breaks) was demonstrated in the pyloric mucosa tion system (BUA, 1997). A direct genotoxic activity of
of the rat stomach (see section 8.5; Furihata et al., 1985, glyoxal was further evident in the L-arabinose resistance
1989; Furihata & Matsushima, 1989). A tumour- assay with S. typhimurium BA9 and BA13 (Ruiz-Rubio
promoting potential was also derived from dose- et al., 1985; Ariza et al., 1988) and in the SOS chromo-
dependent induction of ornithine decarboxylase and test with E. coli PQ37 (von der Hude et al., 1988).
replicative DNA synthesis in the pyloric mucosa after a
single application of 150–400 mg glyoxal/kg body Furthermore, DNA repair tests yielded positive
weight (Furihata et al., 1985; Furihata & Matsushima, responses in both the presence and absence of metabolic
1989, 1995). activation systems, as in the SOS umu-test with S.
typhimurium TA 1535/pSK 1002 (Ono et al., 1991a,b),
In contrast, no tumour-promoting activity was found in the rec-assay with Bacillus subtilis (also with
in a short-term liver foci assay with a 6-week glyoxal metabolic activation; Matsui et al., 1989), and in the
exposure via drinking-water (different concentrations of differential DNA repair test with E. coli K-12/343/636
5000 and 2000 mg/litre given in the publications) after uvrB+/recA+ and K-12/343/591 uvrB–/recA– (Hellmér &
initiation with diethylnitrosamine (single intraperitoneal Bolcsfoldi, 1992a). When the latter test was performed
dose of 200 mg/kg body weight, start of glyoxal expo- as a host-mediated assay in mice, with oral application
sure after 2-week recovery period, partial hepatectomy at of 570 or 1700 mg glyoxal/kg body weight and intra-
week 3). Relative to the initiator-treated control group, venous application of the bacteria, a genotoxic effect
number and area of glutathione-S-transferase placental was not demonstrable in bacteria isolated from blood,
form (GST-P) positive foci in the liver, as well as body liver, lungs, kidneys, or testicles (Hellmér & Bolcsfoldi,
weight, absolute liver weight, and water consumption, 1992b), which may be explained by the high reactivity
were significantly decreased in glyoxal-treated F344 rats of glyoxal — for example, with proteins (see section
(Hasegawa & Ito, 1992; Hasegawa et al., 1995). 8.8). In Saccharomyces cerevisiae D61.M, induction of
mitotic recombinations pointed to reaction of glyoxal
No increase of skin tumours was observed after with DNA, whereas modification of proteins was
lifetime application of 3 µl glyoxal (two commercial indicated by chromosome losses (in the presence of
products, 12.5% in water) 3 times a week to the skin of propionitrile, which is a strong inducer of chromosomal
C3H/HeJ mice. Survival rates of glyoxal-treated rats malsegregation), suggesting interference of glyoxal with
were higher than those of controls. Some treated rats microtubular function (Zimmermann & Mohr, 1992).
showed skin irritation with necrotic areas (Bushy Run,
1982). With E. coli WP2 uvrA, in both the absence and
presence of metabolic activation, negative test results
In an assay for tumour-initiating activity, the dermal were found in the standard plate incorporation assay
application of glyoxal alone (total initiating dose 30 mg (Hoechst AG, 1984f), whereas an insufficiently docu-
glyoxal/mouse, 37–43% in water applied 2 times weekly mented preincubation assay reported positive test results
for 5 weeks) induced no skin tumours in CD-1 mice (Kato et al., 1989). Ueno et al. (1991b) investigated the
within 53 weeks. After promotion by 12-O-tetra- characteristics of mutagenicity by glyoxal (particularly a
decanoyl-phorbol-13-acetate treatment for 47 weeks, possible role of active oxygen species) in S. typhimurium
2 of 10 animals had a total of four skin papillomas, TA 100 and TA 104. The scavengers of singlet oxygen
showing no significant tumour-initiating activity of almost completely suppressed the mutagenic action of
glyoxal by this route (Miyakawa et al., 1991). glyoxal.

A direct genotoxic action of glyoxal was established


in a variety of tests with mammalian cells without meta-
bolic activation (see BUA, 1997): in a mutagenicity test

17
Concise International Chemical Assessment Document 57

with mouse lymphoma cells (TK assay) (Wangenheim & Glyoxal was demonstrated to be genotoxic at the
Bolcsfoldi, 1988), in chromosomal aberration tests with site of application after administration by gastric
Chinese hamster ovary (CHO) cells (NOTOX, 1986) and intubation. In the pyloric mucosa of male Fischer 344
V79 cells (Nishi et al., 1989), and in tests for the induc- rats, both significantly increased unscheduled DNA
tion of unscheduled DNA synthesis in TC-SV40 cells of synthesis and DNA single strand breaks were induced at
Syrian hamster (Cornago et al., 1989), for the induction dosages of 400–500 mg/kg body weight within 2 h.
of sister chromatid exchanges in CHO cells and human Cytotoxicity was not reported (Furihata et al., 1985,
lymphocytes, for the induction of endoreduplication in 1988, 1989; Furihata & Matsushima, 1989). In contrast,
CHO cells (Tucker et al., 1989), and for the induction of in rat hepatocytes, a test for unscheduled DNA synthesis
DNA strand breaks in mouse lymphoma cells (Garberg was negative (CCR, 1992). Glyoxal has also been shown
et al., 1988). In primary rat hepatocytes, glyoxal induced to cause DNA strand breaks in rat hepatocytes 2–9 h
DNA single strand breaks but no DNA cross-links (Ueno after a single oral exposure to 200–1000 mg glyoxal/kg
et al., 1991c). body weight (Ueno et al., 1991b). Single strand breaks
were also detected in livers of rats within 2 h following a
DNA damage was further demonstrated in the single oral exposure at 200–1000 mg glyoxal/kg body
comet assay with TK6 human lymphoblastoid cells by weight. The frequency of breaks reached a maximum
the induction of concentration-dependent increases of after 9 h of exposure. Hardly any DNA lesions were
tail moment and tail length (Henderson et al., 1998). detected in other tissues following exposure to 1000 mg
Primary rat hepatocytes exposed to glyoxal at higher glyoxal/kg body weight. Glyoxal causes DNA single
concentrations (0.5–10 mg/ml) produced different strand breaks in rat hepatocytes following in vitro and in
concentration-dependent types of DNA damage. Tail vivo exposure (Ueno et al., 1991c).
moment and the formation of comets with head and tail
(indicative of DNA strand breakage) decreased with Cell transformation assays in C3H/10T½ cells with
increasing glyoxal concentration, whereas circular DNA three different commercial products of glyoxal (test
spots with highly condensed areas increasingly appeared concentrations from 0.0013 to 0.195 µl/ml) yielded
at the mid- and high concentrations. Among 100 tested negative test results (Mason 1980a,b,c).
substances, this damage was shown to be specific for
certain aldehydes and was attributed to their DNA cross- 8.6 Reproductive toxicity
linking activity (Kuchenmeister et al., 1998). In cultures
of human umbilical vein endothelial cells, addition of 8.6.1 Effects on fertility
100 µg glyoxal/ml caused a significant increase of
formamidopyrimidine N-glycosylase (FPG)-sensitive There were no studies available on the effects of
sites (measured by the comet assay) in the absence of glyoxal on fertility.
increased intracellular levels of hydroperoxides. FPG
repairs oxidative DNA damage and abasic sites and 8.6.2 Developmental toxicity
further was supposed to repair guanine–glyoxal adducts
(Shimoi et al., 2001). In developmental toxicity studies with Sprague-
Dawley rats, glyoxal trimeric dihydrate was adminis-
A significantly increased rate of sex-linked reces- tered by gavage on gestation days 6–15 at doses of 0,
sive lethals reported in Drosophila melanogaster in 200, 800, 1200, 1600, or 2000 mg/kg body weight per
preliminary experiments (Mazar Barnett & Muñoz, day in the preliminary study and 50, 150, or 300 mg/kg
1969) was not confirmed in later assays, showing the body weight per day in the main study (NTP, 1991c,
absence of any genotoxic effect in assays for sex-linked 1994a,b). In the initial range-finding study, maternal
recessive lethals in mature sperm and in the earlier toxicity (decreased weight gain) was observed at 200 mg
stages of spermatogenesis, as well as in assays for glyoxal dihydrate/kg body weight per day (correspond-
clastogenic activity in mature sperm (reciprocal ing to 123 mg glyoxal/kg body weight per day), with
translocation, dominant lethal, and chromosome loss). clinical signs of toxicity and decreased gravid uterine
However, from the increase of radiation-induced weight at 800 mg glyoxal dihydrate/kg body weight per
clastogenic effects after pretreatment with glyoxal, it day and maternal deaths at 1200 mg/kg body weight per
was concluded that glyoxal came in contact with the day and above (NTP, 1991c). No maternal toxicity was
target cells. The possibility of detoxifying mechanisms observed, however, in the second study at the top dose
for glyoxal or of an efficient repair of glyoxal-induced of 300 mg/kg body weight per day (corresponding to
damage in Drosophila was discussed (Mazar Barnett & 185 mg glyoxal/kg body weight per day). No embryo-
Muñoz, 1989). toxicity was observed at 200 mg glyoxal dihydrate/kg
body weight per day in the preliminary study or at the
No clastogenic activity was found in a micronucleus highest dose in the main study.
assay in mouse bone marrow (Société Française
Hoechst, 1986; no further data available).

18
Glyoxal

In a study conducted according to OECD guideline 8.7 Irritation and sensitization


414, 40% glyoxal was administered to 19–24 female
Wistar rats as a solution in water at doses of 0, 5, 25, or 8.7.1 Skin irritation
125 mg/kg body weight per day (related to 100%
glyoxal) on days 6 through 19 post-coitum. Maternal After a 4-h exposure patch test on rabbits (OECD
toxicity (significantly reduced food consumption and guideline 404), glyoxal (40%) caused no irritation.
significantly lower corrected body weight gain) was However, in earlier studies (e.g., patch test on the shaven
observed at 125 mg/kg body weight per day. No back skin of white rabbits using 30% or 40% glyoxal),
substance-related effects were observed on gestational slight to pronounced irritation could be seen, depending
parameters or fetuses. NOAELs of 25 mg/kg body on the application period (1 min, 5 min, 15 min, and
weight per day for maternal toxicity and 125 mg/kg 20 h). A single dermal administration (occlusive) of 40%
body weight per day for embryotoxicity were established glyoxal to the shaven skin (dorsal, dorsolateral) of five
(BASF & Clariant, 2000). Wistar rats per sex for 24 h caused erythemas in all
animals (BUA, 1997).
Developmental toxicity range-finding studies in
New Zealand White rabbits administered glyoxal by A 40% glyoxal solution was applied to the shaven
gavage yielded a NOEL of 200 mg glyoxal trimeric back skin of white rabbits (no details of the time of
dihydrate/kg body weight per day, corresponding to administration). From the 3rd day, a strong reddened
123 mg glyoxal/kg body weight per day (NTP, 1991d), inflammation was observed, followed by a necrosis with
and a LOEL of 400 mg glyoxal dihydrate/kg body tissue demarcation. Histopathological examination
weight per day, corresponding to 247 mg glyoxal/kg showed severe necrotic skin changes on the 4th day and
body weight per day (NTP, 1992), for both maternal a regeneration of the epidermis on the 18th day (Ito,
toxicity and embryotoxicity. Maternal signs of systemic 1963).
toxicity and decreases of weight parameters were
accompanied by reduced fetal weight (NTP, 1992). The Therefore, taking into account studies where the
application of doses in the range of 200 mg glyoxal duration of exposure was longer, glyoxal is clearly
dihydrate/kg body weight per day was discussed as irritating to the skin (see details in BUA, 1997).
problematic due to the corrosive nature of the substance,
leading to damage of gastric mucosa of pregnant rabbits 8.7.2 Eye irritation
(unpublished observations cited in NTP, 1993). In a
subsequent study with a single dose level of 50 mg In a study conducted according to OECD guideline
glyoxal dihydrate/kg body weight per day, correspond- 405, glyoxal (40%) led to a reversible reddening and
ing to 31 mg glyoxal/kg body weight per day, there was chemosis of the conjunctiva within 8 days and thus
no maternal mortality or persistent signs of toxicity, showed an irritating effect. This confirmed older studies
although minimal reductions in body weight gain and reporting that glyoxal caused irritations and even
food consumption were noted. Glyoxal exposure did not necrotic changes in the rabbit eye (see details in BUA,
significantly alter post-implantation loss and had no 1997).
effect on fetal body weight or the incidence of external,
visceral, or skeletal malformations. The authors gave a 8.7.3 Sensitization
NOAEL for developmental toxicity for rabbits of 50 mg
glyoxal dihydrate/kg body weight per day, correspond- Two studies using the Magnusson and Kligman test
ing to 31 mg glyoxal/kg body weight per day (NTP, and one study using the Buhler test on guinea-pigs gave
1993). positive results. Glyoxal can be considered as a sensitiz-
ing substance (see details in BUA, 1997).
In an investigation on the effects of ethylene glycol
and its metabolites, glyoxal was tested in a whole rat Glyoxal has been shown to be sensitizing in humans
embryo culture test system (head-fold rat embryos, (see section 9).
which lack biotransforming enzyme activities, such as
alcohol dehydrogenase or acetaldehyde dehydrogenase) 8.8 Mode of action
(Klug et al., 2001). At glyoxal concentrations of 3 mmol/
litre, the rate of dysmorphogenic embryos was within Glyoxal, which attacks amino groups of proteins,
historical controls; at 6 mmol/litre, however, a general nucleotides, and lipids, is considered an important inter-
embryotoxic effect of glyoxal was noted, with a steep mediate in the formation of AGEs. AGE modification
concentration–response relationship. At 10 mmol/litre, alters protein function and inactivates enzymes, resulting
no growth or differentiation of the embryo could be in disturbance of cellular metabolism, impaired prote-
determined. The relevance of this test for the in vivo olysis, and inhibition of cell proliferation and protein
toxicity of glyoxal is unclear. synthesis (Gan & Ansari, 1986; Ueno et al., 1991a,b;
Kasper et al., 1999; Witowski et al., 2000; Bulteau et al.,

19
Concise International Chemical Assessment Document 57

2001; Kasper & Funk, 2001; Murata-Kamiya & Kamiya, mainly on the lower arms and fingers. Patch tests with a
2001). The extent of AGE modification increases with 20% glyoxal solution produced a positive reaction in 7
the increasing life span of proteins. Consequently, AGEs of 9 workers (Ito, 1963).
are especially associated with long-lived proteins, such
as collagens, lens crystallins, and neurofilaments, but In a German multicentre study of dermal sensitivity,
also have been identified in shorter-lived proteins, the records of 31 849 health care workers from 24
including haemoglobin, plasma proteins, lipoproteins, allergy departments between 1992 and 1995 were
and intracellular proteins. AGEs have a role in the evaluated; 4.2% of the 774 female patients working in
pathogenesis or progression of many pathological the medical profession were found to show positive
conditions — e.g., diabetes, Alzheimer’s disease and reactions to glyoxal patch testing, whereas only 1.4% of
other neurodegenerative diseases, chronic inflammatory the control group (1895 persons not in the medical
diseases, arthritis, atherosclerosis, vascular damage, profession) were found to be positive (Schnuch et al.,
cataract formation and skin changes during ageing, 1998).
pulmonary fibrosis, and renal failure — as well as in
peritoneal dialysis complications (Miyata et al., 1999, In a continuation of this multicentre study, between
2000; Thornalley et al., 1999; Cerami & Ulrich, 2001; 1997 and 1999, 2689 patients were reported to have been
Ulrich & Cerami, 2001; Thornalley, 2002). Although patch tested with glyoxal (trimer; 1% in petrolatum).
glyoxal is known to be an intermediate in the formation Positive (allergic) reactions were observed in 1.6% of
of AGEs, these effects have not specifically been shown the patients, whereas irritant (0.3%) and questionable
for glyoxal. (0.6%) (i.e., non-allergic) reactions were observed less
frequently. Even prior to diagnostic patch testing,
Inhibition studies in bacterial mutagenicity tests disinfectants had been suspected to be causative for
demonstrated the production of the reactive oxygen dermatitis in 23 and cleaning agents in 10 of the 44
species superoxide, hydrogen peroxide, and singlet patients sensitized to glyoxal. Occupations included
oxygen from glyoxal. The mutagenic activity of glyoxal nursing (n = 15), room cleaning (n = 12), dental nursing
is related to singlet oxygen, as well as to the intracellular (n = 5), geriatric nursing (n = 3), and some other medical
GSH level (Suwa et al., 1982; Garst et al., 1983; Yama- associated professions (n = 5), with very few other non-
guchi & Nakagawa, 1983; Ueno et al., 1991b). The medical occupations (n = 4) (Uter et al., 2001).
hydroxyl radical plays a prominent role in glyoxal-
induced DNA cleavage (Roberts et al., 2003). In a retrospective descriptive analysis of records
from an occupational dermatitis clinic in Osnabrück,
The sensitizing potential of glyoxal is attributed to Germany, 189 patients with occupational dermatitis
the electron-deficient α,β-dicarbonyl structure with its were patch tested with glyoxal (15 in water or, as trimer,
high electrophilic reactivity. Glyoxal easily forms Schiff 1% in petrolatum) between 1993 and 1999. Of the 11
bases with lysine or arginine units and so becomes cases with positive reactions to glyoxal, 9 were consid-
bound to skin proteins (Roberts et al., 1999). ered as being occupationally relevant — those with
nursing and room cleaning jobs (Uter et al., 2001).

In another study of 280 health care workers in


9. EFFECTS ON HUMANS Poland, the frequency of allergy to aldehydes (1%
formaldehyde, glutaraldehyde, or glyoxal) with allergic
dermatitis was 22.8%. The majority were sensitive to
Only limited information on the effects of glyoxal in only one aldehyde, indicating lack of cross-reaction;
humans has been identified. glutaraldehyde was positive in 12.4% and glyoxal in
1.9% (Kieć-Świerczyńska et al., 1998). In a further study
The oral ingestion of 50–300 ml of a disinfectant of the causes of occupational dermatosis in 27 dental
containing 7.5% (w/w) glyoxal, 9.5% glutaral, and 9.6% nurses during the years 1995–1999, contact sensitization
didecyldimethylammoniumchloride in suicidal intention by glyoxal was found in 3 cases (Kieć-Świerczyńska &
caused severe coagulative necrosis of the mucous mem- Kręcisz, 2000).
branes in the upper gastrointestinal tract and whole
respiratory tract in a 31-year-old female. Despite the In a maximization test, all 24 patients tested gave a
severe effects, no perforation occurred, probably because positive reaction with 10% glyoxal solution (induction),
mucous membranes were denatured and fixed through 2% solution (challenge) showing a very strong skin
the carbonyl groups of the aldehydes, so that the sub- sensitizing potential (Kligman, 1966).
stances did not penetrate deeply (Menzner et al., 1998).

Of 14 workers who had contact with 40% glyoxal,


9 exhibited a contact dermatitis with localizations

20
Glyoxal

Table 2: Aquatic and terrestrial toxicity of glyoxal.

Species tested End-point Concentration


(reported test method) (effect) (mg/litre) Reference
Bacteria
Pseudomonas putida 16-h EC10 46 Hoechst AG (1989)
(inhibition of cell multiplication) 16-h EC50 134
16-h EC100 389
Pseudomonas putida EC0 500 Gerike & Gode (1990)
(inhibition of respiration)
Photobacterium phosphoreum 5-min EC50 755 ± 55 Chou & Que Hee
(inhibition of bioluminescence) 15-min EC50 554 ± 34 (1992)

25-min EC50 429 ± 26


Anaerobes (not characterized) 24-h EC0 200 Hoechst AG (1984f)
(inhibition of gas formation) 24-h EC50 625
Algae
Pseudokirchneriella subcapitata (formerly Selenastrum 96-h EC50 149 Bollman et al. (1990)
capricornutum)
(inhibition of growth)
Invertebrates
Daphnia magna (water flea) 24-h EC50 430 OECD (1992)
(no details given)
Vertebrates
Brachydanio rerio (zebra danio) 24-h LC50 1200 Hoechst AG (1991b)
(no details given) 48-h LC50 760
Leuciscus idus melanotus (orfe) 48-h LC50 >680 BUA (1997)
(no details given) 96-h LC50 460–680
Pimephales promelas (fathead minnow) 24-h LC50 550 Conway et al. (1983)
(mortality) 48-h LC50 230
96-h LC50 215
Rhombus maximus (turbot) 48-h EC50 >500 Hoechst AG (1990)
(mortality, abnormal behaviour) 96-h EC50 >500
Plants
Helianthus tuberosus (Jerusalem artichoke) EC30 136 BUA (1997)
(inhibition of rhizome fragment proliferation) NOEC 68

10. EFFECTS ON OTHER ORGANISMS IN putida, anaerobic bacteria, and Photobacterium phos-
THE LABORATORY AND FIELD phoreum showed that P. putida (end-point = inhibition
of cell proliferation, 16 h) exhibited the lowest EC50
value of 134 mg/litre (Hoechst AG, 1989).
10.1 Aquatic environment
The only algal species tested was Pseudokirchner-
Glyoxal may enter the hydrosphere due to its iella subcapitata (formerly Selenastrum capricornutum),
production, use, and application and can be formed, in with a 96-h EC50 value of 149 mg/litre (Bollman et al.,
addition, by natural processes. 1990).

A limited number of acute tests have been per- For the only invertebrate species tested, Daphnia
formed to establish the toxicity of glyoxal for aquatic magna, a 24-h EC50 value of 430 mg/litre was reported
organisms representing different trophic levels (data are (OECD, 1992).
summarized in Table 2; see BUA, 1997, for more
detailed information). Assays performed by employing Acute toxicity studies conducted with four different
aerobic heterotrophic bacteria such as Pseudomonas fish species established the lowest LC50 value (96-h

21
Concise International Chemical Assessment Document 57

incubation) as 215 mg glyoxal/litre using Pimephales There are almost no data on other toxicity end-
promelas (Conway et al., 1983). points in humans.

10.2 Terrestrial environment Because of the limited nature of data in humans,


hazard identification and dose–response analysis for
Data concerning the toxicity of glyoxal for soil- glyoxal are based primarily on studies in animals.
bound microbial activity, terrestrial invertebrates, or
vertebrates or effects upon terrestrial ecosystems are not The acute toxicity of glyoxal in experimental
available. For the terrestrial compartment, the only animals is low to moderate. After exposure by inhala-
available toxicity study reported the inhibition of tion, local irritations of the eyes and respiratory organs
rhizome fragment proliferation of Helianthus tuberosus predominate. After oral uptake of glyoxal, macroscopic
by glyoxal, with a NOEC value of 68 mg/litre and a observations include irritation of the gastrointestinal
corresponding EC30 value of 136 mg/litre (BUA, 1997). tract and congestion in the gastrointestinal tract, lung,
kidney, and adrenal glands. In the pancreas and kidney,
the toxic action of glyoxal leads to severe degenerative
changes resembling those induced during diabetes.
11. EFFECTS EVALUATION
A 29-day nose-only inhalation exposure study in
rats using 40% glyoxal showed a NOEL of 0.6 mg/m3
11.1 Evaluation of health effects (nominal concentration was 0.4 mg/m3) for local effects
in the larynx and a NOEL of >8.9 mg/m3 (nominal
Glyoxal is endogenously produced during normal concentration was 10 mg/m3) for systemic effects
cellular metabolism by several enzyme-independent (Hoechst AG, 1995).
pathways. The cytosolic GSH-dependent glyoxalase
system is the major pathway for the detoxification of The 90-day feeding study in rats resulted in a
glyoxal. When GSH is severely depleted, 2-oxoaldehyde NOAEL of 125 mg/kg body weight per day (dose
dehydrogenase and aldose reductase also metabolize corresponding to 100% glyoxal). A 28-day drinking-
glyoxal. water study of 40% glyoxal in rats resulted in a NOAEL
of 100 mg glyoxal/kg body weight per day (Société
Due to its highly reactive carbonyl groups, glyoxal Française Hoechst, 1987). Effects at higher doses were
attacks proteins, nucleotides, and lipids, followed by reduced water and food intake and retardation of body
further reactions leading to the formation of AGEs. weight gain (Mellon Institute, 1966). A 90-day feeding
These adducts can interfere with normal cellular study in dogs failed to reveal any substance-related
function, inducing carbonyl stress and oxidative stress changes at the top dose of 115 mg/kg body weight per
and affecting protein function and signal transduction day (dose corresponding to 100% glyoxal) (Mellon
pathways of the cells; these result in a range of patho- Institute, 1966).
logical changes, cell proliferation, genotoxicity, or
programmed cell death. In a 90-day drinking-water study in rats examining
more sensitive end-points, the lowest tested dosage of
During certain pathological conditions (e.g., 107 mg/kg body weight per day (99% glyoxal) was
diabetes mellitus, uraemia), raised concentrations of given as the LOAEL for serum clinical parameters
glyoxal have been measured in the plasma. (Ueno et al., 1991a).

It is not known if acute environmental exposure to There are no data available on the effects of glyoxal
glyoxal also leads to raised concentrations in the blood on fertility. Fetotoxic and developmental effects occur
or whether the high catalytic efficiency of the glyoxalase only with doses of glyoxal that induce maternal toxicity.
system is able to detoxify it.
Glyoxal is directly genotoxic in vitro in bacterial
11.1.1 Hazard identification and dose–response and mammalian cells. In vivo, a genotoxic activity of
assessment glyoxal was established at the site of application in the
pyloric mucosa of rats by demonstration of unscheduled
Studies in patients and volunteers have confirmed DNA synthesis and DNA single strand breaks. After oral
the sensitizing potential of glyoxal. This has been application, DNA strand breaks were further observed in
substantiated by animal studies. Glyoxal is irritating to rat liver. Glyoxal forms stable adducts with proteins and
mucous membranes. In animal studies, 30% and 40% DNA bases.
aqueous glyoxal cause slight to definite skin irritations,
depending on the application time. No carcinogenicity studies were available for expo-
sure by inhalation. Glyoxal showed tumour-promoting

22
Glyoxal

activity in a two-stage glandular stomach carcinogenesis calculated. This is slightly less than the tolerable intake
model in male Wistar rats (Takahashi et al., 1989), of about 0.2 mg/kg body weight per day for lifetime oral
whereas it was inactive in a short-term liver foci assay exposure to glyoxal (see section 11.1.2).
(Hasegawa & Ito, 1992; Hasegawa et al., 1995). In a
skin painting study for tumour-initiating activity and in Example 2 — A nurse or hospital cleaner or con-
cell transformation assays, glyoxal yielded negative test sumer using disinfectant: A typical brand of disinfectant
results. A lifetime skin painting study showed no (7.5 g in 100 g = 7.5% glyoxal) is used at a dilution of
increase of tumours, but some treated rats showed skin 1% for disinfection and cleaning of surfaces (i.e.,
irritation with necrotic areas. 0.075% glyoxal). Using a rounded-up 0.1% glyoxal
solution and a calculation derived from a model gives an
11.1.2 Criteria for setting tolerable intakes/ uptake of about 4 µg/kg body weight per day, assuming
concentrations a body weight of 64 kg (see section 6.2.2).

Due to lack of data, it is not possible to determine This is much (50 times) less than the tolerable
whether glyoxal has a carcinogenic potential. It is, intake of about 0.2 mg/kg body weight per day for
however, genotoxic in vitro in bacterial and mammalian lifetime oral exposure (see section 11.1.2).
cells, and there is some evidence that this may be so in
vivo. It readily forms DNA adducts, generating potential However, it should be noted that other substances
carcinogens such as glyoxalated deoxyguanosine and (e.g., glutaral or formaldehyde) may also be present in
deoxycytidine. the product.

Exposure to exogenous glyoxal causes local effects, An exposure scenario has been compiled as a
probably due to formation of AGEs. Occupational expo- hypothesized worst case. Assuming exposure to 4%
sure would be mainly due to the use of glyoxal in dis- glyoxal given in section 6.2.1 and using the same
infectants and adhesives and would be via inhalation of assumptions as above would give an uptake of about
aerosols or dermal routes, causing irritant or sensitizing 0.15 mg/kg body weight, which is slightly less than the
effects. tolerable intake of about 0.2 mg/kg body weight per day
for lifetime oral exposure (see section 11.1.2).
A 29-day inhalation study in rats exposed to glyoxal
showed a NOEL of 0.6 mg/m3 for local effects in the However, it should be noted that dermal contact to
larynx. Use of uncertainty factors of 10 for interspecies glyoxal may cause sensitization.
differences and 10 for interindividual differences gives a
tolerable concentration of 6 µg/m3 for local effects in the Example 3 — A farmer using a spray application of
larynx for short-term exposure. biocidal products containing glyoxal to disinfect a stable
(see section 6 and Appendix 5): The model calculation
From studies on oral exposure, the NOAEL seems using the given assumptions predicts a short-term expo-
to be about 100 mg/kg body weight per day (adjusted to sure concentration of 24 µg glyoxal/m3 for a 6-min
100% glyoxal). Using uncertainty factors of 10 for inter- exposure and 32 µg glyoxal/m3 for 15 min. This can be
species differences and 10 for interindividual differences compared with the estimated tolerable concentration of
and a factor of 5 for less-than-lifetime exposure, this 6 µg/m3 for local effects in the larynx for a short-term
results in a tolerable intake of about 0.2 mg/kg body exposure (see section 11.1.2). There is a perceived risk
weight per day for lifetime oral exposure to glyoxal. The of local laryngeal effects and irritation to the skin from
short- and medium-term studies seem to have similar this spray application of glyoxal.
outcomes, with no evidence of systemic effects, suggest-
ing that exogenous glyoxal is efficiently detoxified and 11.1.4 Uncertainties in the evaluation of health
does not accumulate in the body. The use of the lifetime risks and in the sample risk
extrapolation uncertainty factor (factor of 5) is also justi- characterization
fied on the basis of the 125 mg/kg body weight LOAEL
with wide dose spacing to a NOAEL of 25 mg/kg body Glyoxal is produced endogenously during normal
weight (BASF & Clariant, 2000). cellular metabolism. Glyoxal attacks proteins, nucleo-
tides, and lipids, followed by further reactions leading to
11.1.3 Sample risk characterization the formation of AGEs. It is uncertain as to the effects of
exogenously administered glyoxal. It is possible that the
Example 1 — General population: An exposure detoxification mechanisms (e.g., cytosolic GSH-
scenario has been compiled as a hypothesized worst dependent glyoxalase system) are sufficient to counter-
case. Using the daily intake of, maximally, 10 mg act this. There are, however, no data available to confirm
glyoxal via food given in section 6.2.1, an estimated this.
intake of 0.16 mg glyoxal/kg body weight per day can be

23
Concise International Chemical Assessment Document 57

There are no data on the effects of glyoxal in region. The highest reported value for surface water
humans, except for sensitization effects. samples of the river Bogdanka of 1.9 µg/litre can be
employed as a local PEC. A corresponding PNEC for
There is a lack of data on the carcinogenicity of surface water can be predicted from the lowest 96-h
glyoxal, in particular via inhalation and oral routes. EC50 value obtained for Pseudokirchneriella subcapitata
growth inhibition (149 mg/litre) using an uncertainty
There is little known about the toxicokinetics of factor of 1000 (EC, 1996). Thus, PNEC = 149 mg/litre /
glyoxal. 1000 = 0.149 mg/litre.

There is little known about the ability of stable Employing the highest recently measured concen-
protein adducts to accumulate in long-life cells (e.g., tration of glyoxal in surface water, the PEC/PNEC ratio
retinal neurons), even at normal plasma and tissue (1.9 µg/litre / 149 µg/litre) gives a risk quotient of 0.013.
concentrations. As this value is clearly smaller than 1, no further infor-
mation, testing, or risk reduction measures are required.
There is no information on occupational exposure in Further, using the maximum but older value measured in
the glyoxal production industry. surface water, 12 µg/litre in the river Elbe, the risk
quotient PEC/PNEC is still less than 1.
There are no dermal exposure data for, for example,
hospital staff frequently in contact with this chemical. 11.2.2 Terrestrial environment

There are uncertainties with regard to model calcu- Glyoxal will preferably partition into soil and water
lations. (about 54% and 46%, respectively; Level III fugacity
calculation) and only to a lesser extent into air.
Glyoxal is present in products together with other
chemicals. Therefore, the risk assessment given here is For the terrestrial compartment, the only available
for glyoxal, but not for the product itself. toxicity study measured the inhibition of rhizome
fragment proliferation of Helianthus tuberosus by
11.2 Evaluation of environmental effects glyoxal (NOEC = 68 mg/litre).

11.2.1 Aquatic environment The reported log Koc values indicate a high mobility
in soil and point to a potential to leach into groundwater.
The main environmental target compartments of However, the ready biodegradability, rapid abiotic trans-
glyoxal are soil and water. Glyoxal is quickly trans- formation, and negligible bioaccumulation potential
formed by abiotic reactions and readily biodegraded. At indicate a low tendency of glyoxal to pose a risk to the
present, a reliable quantification of glyoxal currently terrestrial compartment. As there is a lack of valid data
released from all sources is impossible with the data concerning the ecotoxicity of this simple dialdehyde for
available. relevant soil indicator organisms, a risk characterization
is not possible.
The reported low log Kow values along with the high
solubility in water indicate a negligible bioaccumulation 11.2.3 Uncertainties in the evaluation of
potential for glyoxal. environmental effects

The biocidal activity of the dialdehyde glyoxal is The acute toxicity of glyoxal was tested using
related to the availability of the carbonyl group. How- several aquatic species from different trophic levels.
ever, due to the hydration of glyoxal in the presence of However, the amount of data is still limited; in parti-
water (by means of a nucleophilic addition), this activity cular, long-term toxicity studies with invertebrates or
is apparently reduced, as indicated by inhibition studies vertebrates are not available.
with bacteria (Eggensperger, 1977).
No toxicity studies are available for sediment-
A sample risk characterization may be performed dwelling organisms.
for glyoxal present in the hydrosphere, according to EC
(1996), by calculating the ratio between a PEC (based on For the terrestrial compartment, the only available
measured data) and a corresponding PNEC. toxicity study measuring the inhibition of rhizome frag-
ment proliferation of Helianthus tuberosus by glyoxal
Due to the limited data available, a reliable quanti- appears not to be sufficient to support a quantitative risk
fication of glyoxal released into the environment is not characterization.
possible. However, up-to-date monitoring data from
Poland may be regarded as pertinent for an industrialized

24
Glyoxal

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31
Concise International Chemical Assessment Document 57

Younes M (1997) Freie Radikale und Sauerstoffspezies. In: APPENDIX 1 — SOURCE DOCUMENT
Marquardt H, Schäfer SG, eds. Lehrbuch der Toxikologie.
Heidelberg, Spektrum Akademischer Verlag.

Zhou X, Mopper K (1990) Measurement of sub-parts-per-billion BUA (1997) [Glyoxal.] German Chemical Society
levels of carbonyl compounds in marine air by a simple cartridge (GDCh) Advisory Committee on Existing
trapping procedure followed by liquid chromatography. Environ-
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Stuttgart, S. Hirzel, Wissenschaftliche
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urethane, methyl carbamate, 2,3-butanedione, 2,3-hexanedione, German)
ethyl acrylate, dibromoacetonitrile and 2-hydroxypropionitrile
induce chromosome loss in Saccharomyces cerevisiae.
Mutation Research, 270:151–166. The objective of BUA assessments is to serve as a basis
for the instigation of administrative measures when there are
indications of risks of a chemical to health or to the environment.

For the BUA review process, the company that is in charge


of writing the report (usually the largest manufacturer in
Germany) prepares a draft report using literature from an
extensive literature search as well as internal company studies.
This draft is subject to a peer review in several readings of a
working group consisting of representatives from government
agencies, the scientific community, and industry.

The toxicological sections of this BUA report were prepared


by Berufsgenossenschaft der Chemischen Industrie (BG
Chemie, Toxicological Evaluations No. 177, 1996). The English
version of the BUA report was published in 1998.

32
Glyoxal

APPENDIX 2 — CICAD PEER REVIEW APPENDIX 3 — CICAD FINAL REVIEW


BOARD
The draft CICAD on glyoxal was sent for review to IPCS
national Contact Points and Participating Institutions, as well as Varna, Bulgaria
to identified experts. Comments were received from: 8–11 September 2003
R. Benson, Drinking Water Program, US Environmental
Protection Agency, Denver, CO, USA
Members
H.S. Chan, National Institute for Occupational Safety and
Health, Cincinnati, OH, USA Dr I. Benchev, Sofia, Bulgaria

R.S. Chhabra, National Institute of Environmental Health Dr R. Chhabra, National Institute of Environmental Health
Sciences, Research Triangle Park, NC, USA Sciences, Research Triangle Park, NC, USA

C. Cooke, Health and Safety Executive, Bootle, Dr C. De Rosa, Agency for Toxic Substances and Disease
Merseyside, United Kingdom Registry, Centers for Disease Control and Prevention, Atlanta,
GA, USA
P. Copestake, Toxicology Advice & Consulting Ltd, Sutton,
United Kingdom Dr S. Dobson, Centre for Ecology and Hydrology, Monks Wood,
Abbots Ripton, Huntingdon, Cambridgeshire, United Kingdom
I. Desi, Department of Public Health, University of Szeged,
Szeged, Hungary Dr G. Dura, National Institute of Environment, József Fodor
Public Health Centre, Budapest, Hungary
J. Donohue, Office of Water, US Environmental Protection
Agency, Washington, DC, USA Dr L. Fishbein, Fairfax, VA, USA

C. Elliot-Minty, Health and Safety Executive, Bootle, Dr H. Gibb, National Center for Environmental Assessment, US
Merseyside, United Kingdom Environmental Protection Agency, Washington, DC, USA

L. Fishbein, Private consultant, Fairfax, VA, USA Dr R.F. Hertel, Federal Institute for Risk Assessment, Berlin,
Germany
E. Frantik, National Institute of Public Health, Prague,
Czech Republic Mr P. Howe, Centre for Ecology and Hydrology, Monks Wood,
Abbots Ripton, Huntingdon, Cambridgeshire, United Kingdom
R. Gatehouse, Environment Australia, Canberra, Australia
Dr S. Ishimitsu, Division of Safety Information on Drug, Food
T. Gebhart, BASF Aktiengesellschaft, Jockgrim, Germany and Chemicals, National Institute of Hygienic Sciences, Tokyo,
Japan
P. Harvey, Department of Health and Ageing, Sydney,
Australia Dr D. Kanungo, Central Insecticides Board, Directorate of Plant
Protection, Quarantine & Storage, Ministry of Agriculture,
R.F. Hertel, Federal Institute for Risk Assessment, Berlin, Haryana, India
Germany
Dr J. Kielhorn, Fraunhofer Institute for Toxicology and
P. Joseph, National Institute for Occupational Safety and Experimental Medicine, Hanover, Germany
Health, Morgantown, WV, USA
Ms B. Meek, Environmental Health Directorate, Health Canada,
R. Morgenstern, Karolinska Institute, Stockholm, Sweden Ottawa, Ontario, Canada

T.-M. Ong, National Institute for Occupational Safety and Dr T. Morita, Division of Safety Information on Drug, Food and
Health, Morgantown, WV, USA Chemicals, National Institute of Hygienic Sciences, Tokyo,
Japan
V. Riihimäki, Finnish Institute of Occupational Health,
Helsinki, Finland Mr F.K. Muchiri, Directorate of Occupational Health and Safety
Services, Nairobi, Kenya
J.L. Stauber, CSIRO Energy Technology, Bangor, NSW,
Australia Dr L. Olsen, Biological Monitoring & Health Assessment Branch,
Division of Applied Research & Technology, National Institute
K. Ziegler-Skylakakis, European Commission, Luxembourg for Occupational Safety and Health, Cincinnati, OH, USA

Dr N. Rizov, National Center of Hygiene, Medical Ecology and


Nutrition, Sofia, Bulgaria

Dr P. Schulte, Education and Information Division, National


Institute for Occupational Safety and Health, Cincinnati, OH,
USA

Dr J. Sekizawa, Faculty of Integrated Arts and Sciences,


Tokushima University, Tokushima, Japan

33
Concise International Chemical Assessment Document 57

APPENDIX 4 — ABBREVIATIONS AND


Dr F. Petrova Simeonova, Sofia, Bulgaria
ACRONYMS
Dr S. Soliman, Faculty of Agriculture, Alexandria University, El
Shatby, Alexandria, Egypt
AGE advanced glycation end-product
Dr J. Stauber, CSIRO Energy Technology, Centre for Advanced
Analytical Chemistry, Bangor, NSW, Australia BOD biochemical oxygen demand
CAS Chemical Abstracts Service
Mr P. Watts, Toxicology Advice & Consulting Ltd, Surrey, United
Kingdom CHO Chinese hamster ovary
CICAD Concise International Chemical Assessment
Ms D. Willcocks, National Industrial Chemicals Notification and Document
Assessment Scheme, Sydney, NSW, Australia ε
CML N -(carboxymethyl)lysine
Dr K. Ziegler-Skylakakis, European Commission, Luxembourg dC deoxycytidine
dG deoxyguanosine
DNA deoxyribonucleic acid
Observers
DNPH dinitrophenylhydrazine
Dr S. Jacobi, Degussa AG, Fine Chemicals, Hanau-Wolfgang, EC50 median effective concentration
Germany
ECD electron capture detection
Mr M. Southern, Shell International Petroleum Company Ltd, EHC Environmental Health Criteria
London, United Kingdom FPG formamidopyrimidine N-glycosylase
Dr W. ten Berge, DSM, Heerlen, The Netherlands GC gas chromatography
GSH glutathione
GST-P glutathione-S-transferase placental form
Secretariat HPLC high-performance liquid chromatography
Dr A. Aitio, International Programme on Chemical Safety, World ICSC International Chemical Safety Card
Health Organization, Geneva, Switzerland ILO International Labour Organization

Mr T. Ehara, International Programme on Chemical Safety, IPCS International Programme on Chemical Safety
World Health Organization, Geneva, Switzerland Koc soil sorption coefficient
Kow octanol/water partition coefficient
Kp permeability coefficient from water
LC50 median lethal concentration
LD50 median lethal dose
LOAEL lowest-observed-adverse-effect level
LOEL lowest-observed-effect level
MS mass spectrometry
MW molecular weight
NOAEL no-observed-adverse-effect level
NOEC no-observed-effect concentration
NOEL no-observed-effect level
OECD Organisation for Economic Co-operation and
Development
PEC predicted environmental concentration
PFBHA pentafluorobenzyl hydroxylamine
PIM Poison Information Monograph
PNEC predicted no-effect concentration
SI International System of Units (Système
international d’unités)
ThOD theoretical oxygen demand
UNEP United Nations Environment Programme
USA United States of America
UV ultraviolet
WHO World Health Organization

34
Glyoxal

APPENDIX 5 — AEROSOL EXPOSURE


MODEL

In section 6.2.2, the exposure to a glyoxal-containing


aerosol disinfectant was estimated for the scenario of a stable.
The deterministic model for predicting aerosol exposure and
inhalation during the spray application of biocidal products,
which was developed by Prof. W. Koch, Fraunhofer Institute for
Toxicology and Experimental Medicine, Hanover, was employed
for the calculation. This model (Droplet Simulation Model) is
mentioned in the 2002 version of Technical Notes for Guidance.
Human Exposure to Biocidal Products. Guidance on Exposure
Estimation. Final June 2002 (CA-Jul02-Doc.7.2-Part 2, Chapter
3.4, p. 225; for European Commission, DG Environment).

Assumptions for the model calculation


performed

Type of Type of Spraying Aerosol


a
Sprayer sprayer nozzle conditions diameter
Frowein air large, 2000 hPa; 304 µm (d50)
“Spray cushion fan- 980 ml/min 89 µm (d5)
Boss” sprayer shaped 569 µm (d90)
nozzle

a
For droplet distribution, dx means that x percentile have given
aerosol diameter.

• A commercial product as typically employed for stable


spray disinfection, containing 3.6% (w/w) glyoxal as
biocidal ingredient, which is employed as a 2% (v/v)
solution
• Size of stable: 10 × 20 m
• Height of stable: 3 m
• Volume of 6 litres of the final disinfectant solution sprayed
at a release height of 1 m
• Respiration rate: 10 litres/min
• Exposure time: approximately 6 min and 15 min
• No ventilation of the stable
• Additional release from surfaces is not accounted for

Exposure concentrations and doses

Mean exposure concentration (mg/m³)


Exposure time
Aerosol characteristics 6 min 15 min
Able to pass into the alveolar space 0.012 0.016
(<4.5 µm)
Able to pass into the thorax (<10 µm) 0.023 0.031
Total inhalable 0.024 0.032

Mean inhaled dose (mg)


Exposure time
Aerosol characteristics 6 min 15 min
Able to pass into the alveolar space 0.0008 0.0025
(<4.5 µm)
Able to pass into the thorax (<10 µm) 0.0015 0.0045
Total inhalable 0.0016 0.0048

35
GLYOXAL (stabilized) 1162
March 1998
CAS No: 107-22-2 1,2-Ethanedione
RTECS No: MD2625000 Biformyl
UN No: Ethanedial
EC No: 605-016-00-7 Oxalaldehyde
C2H2O2 / OHCCHO
Molecular mass: 58.0

TYPES OF
HAZARD/ ACUTE HAZARDS/SYMPTOMS PREVENTION FIRST AID/FIRE FIGHTING
EXPOSURE

FIRE Combustible. NO open flames. Powder, carbon dioxide.

EXPLOSION Finely dispersed particles form Prevent deposition of dust; closed In case of fire: cool drums, etc., by
explosive mixtures in air. Risk of system, dust explosion-proof spraying with water but avoid
fire and explosion as a result of electrical equipment and lighting. contact of the substance with water.
polymerization reactions.

EXPOSURE STRICT HYGIENE!

Inhalation Burning sensation. Cough. Sore Local exhaust or breathing Fresh air, rest. Refer for medical
throat. protection. attention.

Skin Redness. Protective gloves. Protective Remove contaminated clothes.


clothing. Rinse skin with plenty of water or
shower.

Eyes Redness. Pain. Safety goggles, or eye protection in First rinse with plenty of water for
combination with breathing several minutes (remove contact
protection. lenses if easily possible), then take
to a doctor.

Ingestion Abdominal pain. Nausea. Sore Do not eat, drink, or smoke during Rinse mouth. Refer for medical
throat. Vomiting. work. attention.

SPILLAGE DISPOSAL PACKAGING & LABELLING

Collect leaking and spilled liquid in sealable Xi Symbol Airtight.


containers as far as possible. Sweep spilled R: 36/38
substance into containers. Do NOT absorb in S: (2-)26-28
saw-dust or other combustible absorbents (extra Note: B
personal protection: A/P2 filter respirator for organic
vapour and harmful dust).

EMERGENCY RESPONSE STORAGE

Separated from strong oxidants, bases. Cool. Dry. Store only if stabilized.

Prepared in the context of cooperation between the International


IPCS Programme on Chemical Safety and the European Commission
International © IPCS 1999
Programme on
Chemical Safety SEE IMPORTANT INFORMATION ON THE BACK.
1162 GLYOXAL (stabilized)

IMPORTANT DATA
Physical State; Appearance Routes of Exposure
PALE YELLOW LIQUID OR YELLOW CRYSTALS. The substance can be absorbed into the body by inhalation of
its vapour or its aerosol, and by ingestion.
Physical Dangers
The vapour is heavier than air. Dust explosion possible if in Inhalation Risk
powder or granular form, mixed with air. A harmful contamination of the air can be reached very quickly
on evaporation of this substance at 20C.
Chemical Dangers
The substance may polymerize quickly on standing or under Effects of Short-term Exposure
the influence of water, base(s) and temperatures above 50C The substance irritates the eyes, the skin and the respiratory
with fire or explosion hazard. The substance is a strong tract.
reducing agent and reacts violently with oxidants. The solution
in water is a weak acid. Effects of Long-term or Repeated Exposure
Repeated or prolonged contact may cause skin sensitization.
Occupational Exposure Limits May cause genetic damage in humans.
TLV not established. MAK not established.

PHYSICAL PROPERTIES
Boiling point: 51C Relative vapour density (air = 1): 2.0
Melting point: 15C Relative density of the vapour/air-mixture at 20C (air = 1): 1.3
Relative density (water = 1): 1.3 (40% solution) Flash point: 220C
Density: 1.14 g/cm3 (solid) Auto-ignition temperature: 285C
Solubility in water, g/100 ml at 20C: 60 Octanol/water partition coefficient as log Pow: -2.54 (calc.)
Vapour pressure, kPa at 20C: 29

ENVIRONMENTAL DATA

NOTES
The substance is commercially available as a crystalline dihydrate (80% glyoxal), or as a 40% aqueous solution which may
contain polymerization inhibitors. An added stabilizer or inhibitor can influence the toxicological properties of this substance,
consult an expert. Daicel GY 60, Glyfix CS 50, Gohsezal P, Permafresh 114 are trade names.

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 1999
Concise International Chemical Assessment Document 57

RÉSUMÉ D’ORIENTATION bière et dans des vins de divers crus, de même que dans
d’autres boissons comme le thé, on en a décelé la pré-
sence à des concentrations allant de d’environ 20 µg/litre
Le présent CICAD consacré au glyoxal a été (thé noir) à 1556 µg/litre (vin de Xérès). Par ailleurs, on
préparé par l’Institut Fraunhofer de toxicologie et en a trouvé dans plusieurs produits alimentaires comme
médecine expérimentale de Hanovre (Allemagne). Il la pâte de soja et le yoghourt (0,63 à 4,2 mg/kg), dans
s’inspire de rapports établis par le Comité consultatif des produits de boulangerie comme le pain (0,07 à
allemand sur les substances chimiques d’importance 1,6 mg/kg) et divers produits végétaux (3-14 mg/kg)
écologique (BUA, 1997). Il a été procédé à un ou huiles comestibles (jusqu’à 6,5 mg/kg).
dépouillement bibliographique exhaustif des bases de
données correspondantes jusqu’en février 2003, afin de Le glyoxal libéré dans l’environnement subit une
rechercher toute référence intéressante à des publications transformation rapide sous l’effet de processus abiot-
postérieures à celles qui sont prises en compte dans les iques, dans lesquels interviennent notamment des
rapports en question. Des informations sur la préparation radicaux hydroxyles produits par voie photochimique.
et l’examen par des pairs des sources documentaires En raison de son faible coefficient de sorption aux
utilisées sont données à l’appendice 1. L’appendice 2 particules du sol (Koc), le composé est susceptible de
fournit des renseignements sur l’examen par des pairs du passer par lessivage du sol aux eaux souterraines. Il est
présent CICAD. Ce CICAD a été examiné et approuvé toutefois rapidement biodégradé et les enzymes bactéri-
en tant qu’évaluation internationale lors d’une réunion ennes ou fongiques le transforment en peu de temps.
du Comité d’évaluation finale qui s’est tenue à Varna Comme son coefficient de partage entre l’octanol et
(Bulgarie) du 8 au 11 septembre 2003. La liste des l’eau (Kow) est peu élevé, il n’a vraisemblablement guère
participants à cette réunion figure à l’appendice 3. La tendance à subir une bioaccumulation.
fiche internationale sur la sécurité chimique du glyoxal
(ICSC 1162), établie par le Programme international sur Les principales voies d’exposition professionnelle
la sécurité chimique (IPCS, 2002), est également au glyoxal lors de son utilisation comme désinfectant
reproduite dans le présent document. consistent dans l’inhalation d’aérosols ou dans l’absorp-
tion transcutanée du produit. L’exposition de la popula-
Le glyoxal anhydre (No CAS 107-22-2) a un point tion dans son ensemble est principalement due à la
de fusion d’environ 15 °C. Il se présente toutefois consommation de denrées alimentaires contenant du
généralement sous la forme d’une solution aqueuse glyoxal, mais elle peut également résulter d’une forte
contenant habituellement 30 à 50 % de glyoxal et dans pollution atmosphérique ou de la présence de traces de
laquelle sont présents des oligomères hydratés. Le glyoxal dans l’eau de boisson.
glyoxal est utilisé comme intermédiaire de synthèse dans
la préparation de produits pharmaceutiques et de Le métabolisme cellulaire normal entraîne la
colorants, comme agent de réticulation dans la production de glyoxal endogène par toutes sortes de
production de divers polymères, comme biocide et voies enzymo-indépendantes. Le glyoxal endogène
comme désinfectant. Son rejet dans l’environnement résulte également de la métabolisation et de l’oxydation
résulte principalement d’émissions dans l’air ambiant et microsomique d’autres molécules comme le glycol-
dans l’eau. aldéhyde, l’éthylène-glycol, et les β-hydroxy-N-nitro-
samines. La concentration du glyoxal dans le plasma
Les principaux compartiments environnementaux humain serait de 0,1 à 1 µmol/litre, des concentrations
dans lesquels se retrouve le glyoxal sont l’hydrosphère et plus élevées étant observées chez les diabétiques et les
le sol (respectivement dans la proportion de 46 et 54 %). insuffisants rénaux. Dans les produits biologiques, moins
Il est également présent dans l’air, mais dans une de 10 % du glyoxal présent se trouve en solution
moindre mesure (< 1 %). La concentration de glyoxal aqueuse sous forme non liée (glyoxal libre et hydrates),
relevée dans l’air ambiant aux Etats-Unis, en Europe et car la majorité des groupements carbonyles réactifs sont
en Asie va d’environ 0,1 à 10 µg/m3. Dans les cours réversiblement liés aux résidus cystéinyle, lysyle et
d’eau et les eaux souterraines d’Europe, on fait état de argininyle des protéines.
concentrations pouvant aller jusqu’à 12 µg/litre. Le
glyoxal est un sous-produit de la désinfection par Le glyoxal, qui attaque les groupements amino des
l’ozone et on en a mis en évidence dans de l’eau de protéines, des nucléotides et des lipides, est considéré
boisson à des concentrations de quelques µg par litre. comme un important intermédiaire dans la formation des
produits de la glycation avancée (AGE). La glycation
On constate souvent, dans les denrées alimentaires avancée altère la fonction des protéines et inactive les
et les boissons fermentées, la présence de glyoxal enzymes, avec pour conséquence des troubles du
résultant de l’activité microbienne, de l’autooxydation métabolisme cellulaire, une mauvaise protéolyse ainsi
non enzymatique de l’huile ou encore des réactions de qu’une inhibition de la prolifération cellulaire et de la
brunissement des sucres. Dans différentes marques de synthèse protéique. Les effets délétères du glyoxal sont

38
Glyoxal

combattus par un système enzymatique ubiquiste, celui L’expérimentation animale montre que des solutions
de la glyoxalase glutathion (GSH)-dépendante qui à 30 et 40 % de glyoxal provoquent une irritation
transforme le glyoxal en glycolate moins réactif. cutanée légère à marquée, selon la durée de contact. Le
glyoxal est irritant pour les muqueuses et il se comporte
La toxicité aiguë du glyoxal pour les animaux de comme un sensibilisateur cutané chez l’Homme et les
laboratoire est faible à modérée, selon la concentration animaux de laboratoire.
effective du composé dans le produit étudié. Chez le rat
soumis pendant 4 h à l’inhalation d’un aérosol à 40 % de Des effets foetotoxiques n’ont été observés qu’à des
glyoxal, la CL50 est de 2440 mg/m3; la DL50 par voie doses qui étaient elles-mêmes toxiques pour la mère. Les
orale varie de 3000 à 9000 mg/kg de poids corporel études toxicologiques portant sur le développement du
(avec une sensibilité plus marquée chez les femelles), la rat ont permis de fixer à ≥ 300 mg de dihydrate de
DL50 cutanée étant supérieure à 2000 mg/kg de poids glyoxal par kg de poids corporel la dose journalière sans
corporel. Après exposition par la voie respiratoire, l’effet effet embryotoxique observable (NOEL) - soit ≥ 185 mg
prédominant est une irritation des yeux et des voies de glyoxal par kg de poids corporel et par jour) - alors
aériennes, accompagnée d’une hyperémie et d’une que la dose la plus faible provoquant un effet observable
sécrétion spumeuse au niveau pulmonaire. Une exposi- chez la mère (LOEL) (réduction du gain de poids) était
tion par voie orale détermine des effets macroscopiques de 200 mg de ce même dihydrate par kg p.c.par jour
tels qu’une irritation et une congestion des voies (soit 123 mg de glyoxal par kg p.c. par jour). Des études
digestives, la congestion s’étendant également au sur le lapin destinées à déterminer l’intervalle de toxicité
poumon, au rein et aux surrénales. Dans les principaux pour le développement ont permis d’obtenir une NOEL
organes cibles, à savoir le pancréas et le rein, l’action de 200 mg de dihydrate de glyoxal par kg p.c. par jour
toxique du glyoxal conduit à de graves lésions dégénéra- (soit 123 mg/kg p.c. par jour) tant pour la toxicité
tives évoquant celles que provoque le diabète. maternelle que pour la toxicité embryonnaire.

Des études au cours desquelles on a fait inhaler du In vitro, le glyoxal présente une génotoxicité directe
glyoxal à des rats pendant une courte période (29 jours), pour les cellules bactériennes et mammaliennes et
montrent que la dose sans effet observable au niveau du provoque notamment la formation d’adduits avec
larynx (NOEL) est de 0,6 mg/m3 (concentration l’ADN, des mutations, des aberrations chromosomiques,
nominale égale à 0,4 mg/m3), la dose sans effets une réparation de l’ADN, des échanges entre chroma-
généraux observables (contrôle du poids corporel, des tides soeurs et des ruptures monocaténaires de l’ADN. In
paramètres hématologiques et biochimiques, analyse vivo, on a mis en évidence l’activité génotoxique du
d’urine, examen macroscopique et histologique) étant glyoxal au niveau de son point d’application sur la
supérieure à 8.9 mg/m3 (concentration nomimale égale à muqueuse pylorique du rat, par l’observation d’une
10 mg/m3). Une étude de 28 jours pendant laquelle du synthèse non programmée et de ruptures monocaténaires
glyoxal a été administré à des rats dans leur eau de de l’ADN. Après administration par voie orale à des rats,
boisson a permis de fixer à 100 mg/kg p.c. par jour la on a également observé la rupture des brins de l’ADN
dose de composé sans effet nocif observable (NOAEL). dans les hépatocytes. Il n’y a pas eu d’étude de cancéro-
Pour d’autres rats qui en avaient reçu pendant 90 jours génicité in vivo chez des animaux exposés au glyoxal par
dans leur alimentation, la NOAEL s’est révélée égale à la voie respiratoire. Sur un modèle de cancérogénèse en
125 mg/kg de poids corporel par jour (dose correspon- deux étapes (paroi glandulaire de l’estomac du rat
dant à 100 % de glyoxal). Les effets observés dans ces Wistar), on a constaté que le glyoxal se comportait
deux dernières études aux doses les plus élevées con- comme un promoteur tumoral. Par contre, il s’est montré
sistaient en une diminution de la consommation d’eau et inactif lors d’un test à court terme consistant dans la
de nourriture (uniquement dans la première étude) et en recherche de foyers hépatiques positifs. Une étude
un ralentissement du gain de poids (dans les deux destinée à mettre en évidence l’activité tumoro-
études). Lors d’une autre étude portant sur des points promotrice du glyoxal par des tests de transformation
d’aboutissement plus sensibles de l’action toxique cutanée et cellulaire, a donné des résultats négatifs.
(paramètres biochimiques sériques), la plus faible dose
étudiée chez le rat - à savoir 107 mg/kg p.c. par jour (soit En s’appuyant sur l’étude d’inhalation de 29 jours
99 % de glyoxal) - correspondait à la dose la plus faible qui donne une NOEL de 0,6 mg/m3 chez le rat pour les
provoquant un effet nocif observable (LOAEL) obtenue effets localisés au larynx et en appliquant un premier
lors d’une exposition de 90 jours par l’intermédiaire de coefficient d’incertitude de 10 pour tenir compte des
l’eau de boisson. Une étude de 90 jours sur des chiens différences interespèces et un second de 10 également
exposés par la voie alimentaire n’a révélé aucune pour les différences interindividuelles, on arrive à une
anomalie attribuable au composé à la dose journalière concentration tolérable estimative de 6 µg/m3 pour les
maximale de 115 mg/kg p.c. (dose correspondant à effets localisés au larynx en cas d’exposition de brève
100 % de glyoxal). durée.

39
Concise International Chemical Assessment Document 57

Pour établir une évaluation représentative du risque Afin de caractériser de manière représentative le
couru par la population dans son ensemble, on a imaginé risque pour l’environnement aquatique, on a calculé le
un scénario d’exposition correspondant au cas le plus rapport de la concentration environnementale prévisible
grave. En supposant que la dose journalière ingérée par localement (PEC), déterminée sur la base de mesures
voie alimentaire correspond à un maximum de 10 mg de récentes, à la concentration correspondante sans effet
glyoxal, on obtient une dose estimative de 0,16 mg de prévisible (PNEC). La valeur de la PNEC a été estimée à
glyoxal par jour et par kg de poids corporel. Cette valeur 149 µg/litre pour les eaux superficielles en appliquant un
est du même ordre que la dose journalière tolérable coefficient d’incertitude de 1000 à la valeur la plus
d’environ 0,2 mg par kg de poids corporel déterminée faible de la CE50, estimée à 149 mg/litre. Pour obtenir le
pour une exposition par voie orale pendant toute la durée rapport PEC/PNEC, on a pris la valeur la plus élevée de
de l’existence. la concentration en glyoxal trouvée dans les eaux super-
ficielles (1,9 µg/litre), ce qui donne un rapport de 0,013.
Dans une seconde évaluation du risque couru cette Comme cette valeur est inférieure à 1, il n’y a pas lieu
fois par une infirmière, un membre du personnel de d’obtenir d’autres données, ni de pousser plus loin
nettoyage d’un hôpital ou un particulier utilisant un l’expérimentation ou les mesures de réduction du risque.
désinfectant à base de glyoxal, on a supposé que ces
personnes se servaient d’un produit ordinaire contenant La seule étude disponible a permis d’obtenir une
7,5 g de composé pour 100 g - soit 7,5 % de glyoxal - valeur de 68 mg/litre pour la concentration sans effet
ramené à 0,075 % de glyoxal par dilution 1/100ème pour observable (NOEC) sur Helianthus tuberosus, l’effet
désinfecter ou nettoyer certaines surfaces. En arrondis- retenu étant l’inhibition de la prolifération de fragments
sant à 0,1 % la teneur de cette solution et en utilisant un de rhizome. La valeur correspondante de la CE50 était de
modèle de calcul, on arrive à une dose journalière 136 mg/litre. Comme on ne dispose d’aucune autre
absorbée d’environ 4 µg/kg p.c., le poids corporel moyen donnée toxicologique caractéristique concernant les
étant pris égal à 64 kg. C’est donc une valeur beaucoup effets toxiques du glyoxal sur les microorganismes ou
plus faible (environ 50 fois) que la dose tolérable les invertébrés terrestres, on n’a pas été en mesure de
journalière d’environ 0,2 mg/kg p.c. relative à une caractériser de manière fiable et quantitative le risque
exposition sur toute la durée de la vie. Cependant, en auquel ces organismes sont exposés.
prenant le cas le plus grave, c’est-à-dire une exposition à
une solution à 4 % de glyoxal et en partant des mêmes
hypothèses que précédemment, on obtiendrait une dose
absorbée d’environ 0,15 mg/kg p.c., ce qui correspond
approximativement à la dose journalière tolérable
d’environ 0,2 mg/kg p.c. pour une exposition pendant
toute la durée de la vie.

Pour la dernière évaluation du risque, on a pris à


titre d’exemple le cas d’un cultivateur qui pulvérise un
produit biocide à base de glyoxal pour désinfecter une
étable. En tenant compte des hypothèses formulées, le
modèle de calcul utilisé donne, pour cette personne, une
exposition de brève durée à 24 µg de glyoxal par m3
pendant 6 minutes et à 32 µg de glyoxal par m3 pendant
15 minutes. Ces valeurs sont à comparer à la concentra-
tion tolérable estimative de 6 µg/m3 pour l’irritation du
larynx provoquée par une exposition de brève durée.
Dans le cas présenté ici de l’utilisation de glyoxal en
pulvérisations désinfectantes, il y a perception d’un
risque d’effets irritants au niveau du larynx.

On a montré que le glyoxal inhibe l’activité des


bactéries aérobies et anaérobies, des algues vertes (CE50
à 96 h égale à environ 149 mg/litre pour Pseudokirch-
neriella subcapitata - anciennement Selenastrum
capricornutum - et d’une espèce d’invertébré. Sur les
quatre espèces de poissons étudiées, c’est Pimephales
promelas qui présentait la valeur de la CL50 à 96 h la
plus faible, soit 215 mg/litre.

40
Glyoxal

RESUMEN DE ORIENTACIÓN fermentados, como la pasta de soja y el yogur (0,63-


4,2 mg/kg), productos de panadería como el pan (0,07-
1,6 mg/kg), distintos materiales vegetales (3-14 mg/kg)
El presente CICAD sobre el glioxal fue preparado y aceites comestibles (hasta 6,5 mg/kg).
por el Instituto Fraunhofer de Toxicología y Medicina
Experimental de Hannover (Alemania). Se basa en los El glioxal liberado en el medio ambiente se
informes compilados por el Comité Consultivo Alemán transforma con rapidez mediante procesos abióticos,
sobre las Sustancias Químicas Importantes para el como la acción de radicales hidroxilo producidos por vía
Medio Ambiente (BUA, 1997). Se realizó una búsqueda fotoquímica. Debido al bajo coeficiente de sorción en el
bibliográfica amplia en las bases de datos pertinentes suelo (Koc) notificado para este compuesto, es posible su
hasta febrero de 2003 para encontrar cualquier referencia lixiviación hacia el agua freática. Sin embargo, se
publicada después de las incorporadas a esos informes. biodegrada con facilidad y sufre una transformación
La información relativa a la preparación y el examen enzimática rápida por la acción de bacterias y hongos. El
colegiado del documento original se presenta en el bajo valor de su log del coeficiente de reparto octanol/
apéndice 1. La información sobre el examen colegiado agua (Kow) indica que es poco probable la bioacumula-
de este CICAD aparece en el apéndice 2. Este CICAD se ción de glioxal.
aprobó como evaluación internacional en una reunión de
la Junta de Evaluación Final, celebrada en Varna Las principales vías de exposición profesional al
(Bulgaria) del 8 al 11 de septiembre de 2003. La lista de glioxal durante su utilización como desinfectante son por
participantes en esta reunión figura en el apéndice 3. inhalación de aerosoles o absorción cutánea. La expo-
También se reproduce en este documento la Ficha sición de la población general se debe principalmente al
internacional de seguridad química (ICSC 1162) para el consumo de alimentos que contienen glioxal, pero
glioxal, preparada por el Programa Internacional de también se podría producir mediante el aire contaminado
Seguridad de las Sustancias Químicas (IPCS, 2002). de regiones urbanas y la presencia de cantidades ínfimas
en el agua de bebida.
El glioxal anhidro (CAS Nº 107-22-2) tiene un
punto de fusión de unos 15°C. Sin embargo, se suele El glioxal se produce de manera endógena durante
encontrar como solución acuosa (con un contenido el metabolismo celular normal mediante numerosas vías
normal de glioxal del 30%-50%) en la que se hallan enzimáticas independientes. Es también un producto del
presentes oligómeros hidratados. El glioxal se utiliza metabolismo y la oxidación microsómica de otros
como intermediario químico en la obtención de compuestos, como el glicolaldehído, el etilenglicol y las
productos farmacéuticos y sustancias colorantes, como N-nitrosaminas β-hidroxi sustituidas. Se han notificado
agente de reticulación en la producción de una serie de concentraciones de glioxal en el plasma sanguíneo
polímeros diferentes, como biocida y como agente humano de 0,1-1 µmoles/l, con niveles más elevados en
desinfectante. Las emisiones al medio ambiente son pacientes con diabetes o insuficiencia renal. En los
fundamentalmente hacia el aire y el agua. materiales biológicos, la concentración de glioxal
presente en forma no combinada en solución acuosa es
Los compartimentos destinatarios predominantes inferior al 10% (glioxal libre e hidratos), puesto que la
del glioxal en el medio ambiente son la hidrosfera y el mayor parte de los grupos carbonilo reactivos están
suelo (con alrededor del 46% y el 54%, respectivamente) unidos con carácter reversible a residuos de cisteína,
y en menor medida el aire (< 1%). Las concentraciones lisina y arginina de las proteínas.
notificadas de glioxal en el aire atmosférico de los
Estados Unidos, Europa y Asia oscilan entre alrededor Se considera que el glioxal, que ataca los grupos
de 0,1 y 10 µg/m3. En los ríos y las aguas freáticas amino de las proteínas, los nucleótidos y los lípidos, es
europeos se han notificado concentraciones de hasta un intermediario importante en la formación de produc-
12 µg/l. El glioxal es un subproducto de la desinfección tos finales de la glicación avanzada. La modificación de
con ozono y en el agua de bebida se han detectado estos productos altera la función de las proteínas e
concentraciones tan sólo del orden de µg/l. inactiva las enzimas, produciendo trastornos del
metabolismo celular, alteraciones de la proteolisis e
Debido a la actividad microbiana, así como a la inhibición de la proliferación celular y la síntesis de
autooxidación no enzimática del aceite o las reacciones proteínas. Los efectos perjudiciales del glioxal en estado
de caramelización de los sacáridos, es frecuente detectar muy reactivo se contrarrestan mediante un sistema
glioxal en los alimentos y bebidas fermentados. Se ubicuo de glioxalasa dependiente del glutatión, que
encontró en diferentes marcas de cerveza, vino y otros transforma el glioxal en glicolato, menos reactivo.
bebidas, como el té, en concentraciones que variaban
entre unos 20 µg/l (té negro) y 1556 µg/l (vino de jerez). La toxicidad aguda del glioxal en animales de
Además, se detectó en una serie de productos experimentación es de baja a moderada, en función de la

41
Concise International Chemical Assessment Document 57

concentración real de glioxal en el producto que se Sólo se produjeron efectos fetotóxicos con dosis de
examina. En ratas, la CL50 del glioxal al 40% para una glioxal que inducían toxicidad materna. En estudios de
inhalación única de aerosol de cuatro horas es de toxicidad en el desarrollo con ratas, la NOEL para la
2440 mg/m3, el valor de la DL50 por vía oral oscila entre embriotoxicidad fue ≥300 mg de dihidrato de glioxal/kg
3000 y 9000 mg/kg de peso corporal (con sensibilidad de peso corporal al día (correspondientes a ≥185 mg de
más elevada en las hembras) y los valores de la DL50 por glioxal/kg de peso corporal al día), mientras que la
vía cutánea son >2000 mg/kg de peso corporal. Tras la concentración más baja con efectos observados (LOEL)
exposición por inhalación predominan las irritaciones (disminución del aumento de peso corporal) para la
locales de los ojos y los órganos respiratorios, así como toxicidad materna fue de 200 mg de dihidrato de
hiperemia y secreción espumosa en los pulmones. Las glioxal/kg de peso corporal al día (correspondientes a
observaciones macroscópicas después de la exposición 123 mg de glioxal/kg de peso corporal al día). Los
oral al glioxal son de irritación del tracto gastrointestinal estudios para determinar las normas de toxicidad en el
y congestión del tracto gastrointestinal, los pulmones, el desarrollo en conejos dieron una NOEL de 200 mg de
riñón y las glándulas suprarrenales. En los órganos dihidrato de glioxal/kg de peso corporal al día (corres-
destinatarios principales, el páncreas y el riñón, la acción pondientes a 123 mg de glioxal/kg de peso corporal al
tóxica del glioxal provoca cambios degenerativos graves día) para la toxicidad materna y la embriotoxicidad.
semejantes a los inducidos durante la diabetes.
El glioxal es directamente genotóxico in vitro en
En los estudios de exposición breve (29 días) de células de bacterias y de mamíferos, induciendo, por
ratas al glioxal por inhalación se puso de manifiesto una ejemplo, aductos de ADN, mutaciones, aberraciones
concentración sin efectos observados (NOEL) de cromosómicas, reparación de ADN, intercambio de
0,6 mg/m3 (la concentración nominal fue de 0,4 mg/m3) cromátidas hermanas y roturas de cadenas sencillas de
para los efectos locales en la laringe y una NOEL de ADN. In vivo se estableció una actividad genotóxica del
>8,9 mg/m3 (la concentración nominal fue de 10 mg/m3) glioxal en el lugar de aplicación en la mucosa pilórica de
para los efectos sistémicos (examen del peso corporal, ratas mediante la demostración de síntesis de ADN no
parámetros hematológicos y bioquímicos, análisis de programada y roturas de cadenas sencillas de ADN. Tras
orina, examen macroscópico e histológico). En un la aplicación oral se observó también rotura de cadenas
estudio de 28 días en el que se administró a ratas glioxal de ADN en el hígado de la rata. No hay biovaloraciones
en el agua de bebida se obtuvo una concentración sin de la carcinogénesis con la exposición por inhalación al
efectos adversos observados (NOAEL) de 100 mg de glioxal. El glioxal mostró una actividad de inducción de
glioxal/kg de peso corporal al día. La administración de tumores en un modelo de carcinogénesis gástrica
glioxal a ratas con los alimentos durante 90 días produjo glandular en dos etapas con ratas Wistar machos,
una NOAEL de 125 mg/kg de peso corporal al día mientras que fue inactivo en una valoración breve de
(siendo la dosis de glioxal del 100%). Los efectos con focos del hígado. En una valoración de la actividad de
dosis más altas notificados en estos dos últimos estudios inducción de tumores del glioxal en la piel y en
fueron una reducción de la ingesta de agua y de valoraciones de transformación celular se obtuvieron
alimentos (sólo en el primer estudio) y retraso del resultados negativos.
aumento del peso corporal (en ambos estudios). En un
estudio en el que se examinaban los efectos finales más Tomando el estudio de inhalación de 29 días en
sensibles (bioquímica clínica del suero), la dosis más ratas expuestas al glioxal, en el que se obtuvo una NOEL
baja sometida prueba de 107 mg/kg de peso corporal al de 0,6 mg/m3 para efectos locales en la laringe y utili-
día (glioxal al 99%) correspondió a la concentración más zando factores de incertidumbre de 10 para diferencias
baja con efectos adversos observados (LOAEL) para una interespecíficas y 10 para las interindividuales, se estimó
exposición de ratas durante 90 días en el agua de bebida. que la concentración tolerable para los efectos locales en
En un estudio de alimentación de 90 días con perros no la laringe durante una exposición breve era de 6 µg/m3.
se observó ningún cambio relacionado con la sustancia
al utilizar la dosis máxima de 115 mg/kg de peso En una evaluación del riesgo de muestra para la
corporal al día (dosis correspondiente a glioxal al población general se ha compilado un modelo de
100%). exposición como hipótesis del caso peor. Utilizando la
ingesta diaria máxima de 10 mg de glioxal con los
En estudios con animales, el glioxal acuoso al 30% alimentos, se puede calcular una cantidad estimada de
y el 40% provocó irritaciones cutáneas entre ligeras y 0,16 mg de glioxal/kg de peso corporal al día. Esta es
manifiestas, en función del tiempo de aplicación. El semejante a la ingesta tolerable de unos 0,2 mg/kg de
glioxal es irritante de las membranas mucosas y actúa peso corporal al día para la exposición oral al glioxal
como agente sensibilizador cutáneo en las personas y los durante toda la vida.
animales de experimentación.
En una segunda evaluación del riesgo de muestra,
para una enfermera, una persona encargada de la

42
Glyoxal

limpieza en un hospital o un consumidor que utilice En el único estudio disponible se determinó una
desinfectante, se utiliza una marca común de desinfec- concentración sin efectos observados (NOEC) de
tante (7,5 g en 100 g = 7,5% de glioxal) con una dilución 68 mg/l para la inhibición de la proliferación de frag-
del 1% para la desinfección y limpieza de superficies (es mentos de rizoma de Helianthus tuberosus, con un valor
decir, 0,075% de glioxal). Utilizando el redondeo a una correspondiente de la CE30 de 136 mg/l. Dado que no se
solución de glioxal del 0,1% y un cálculo derivado de un dispone de datos adicionales para la caracterización de
modelo se obtiene una ingesta de unos 4 µg/kg de peso los efectos tóxicos del glioxal en los microorganismos o
corporal al día, suponiendo un peso corporal de 64 kg. invertebrados terrestres, no es posible realizar una
Este valor es muy inferior (50 veces) a la ingesta caracterización cuantitativa del riesgo fiable.
tolerable de unos 0,2 mg/kg de peso corporal al día para
la exposición por vía oral durante toda la vida. Sin
embargo, utilizando una exposición en el caso peor a un
4% de glioxal y las mismas hipótesis expuestas más
arriba se obtendría una ingesta de alrededor de 0,15
mg/kg de peso corporal, que es aproximadamente igual a
la dosis diaria tolerable de unos 0,2 mg/kg de peso
corporal al día para la exposición por vía oral durante
toda la vida.

En la evaluación final del riesgo de muestra, se


utilizó como ejemplo el caso de un agricultor que
aplicaba productos biocidas con glioxal mediante
pulverización para desinfectar un establo. El cálculo del
modelo utilizando las hipótesis establecidas pronostica
una exposición breve a una concentración de 24 µg de
glioxal/m3 en seis minutos y de 32 µg de glioxal/m3 en
15. Esto se puede comparar con la concentración
tolerable estimada de 6 mg/m3 para los efectos locales en
la laringe tras una exposición breve. Se detecta un riesgo
de efectos locales en la laringe y de irritación cutánea
debido a la aplicación de glioxal mediante pulverización.

Se ha demostrado que la exposición al glioxal


inhibe las actividades de bacterias tanto aerobias como
anaerobias, de algas verdes (valor de la CE50 a las
96 horas de unos 149 mg/l para Pseudokirchneriella
subcapitata [antes conocida como Selenastrum capri-
cornutum]) y de una especie de invertebrado. En cuatro
especies de peces sometidos a prueba, el valor más bajo
notificado de la CL50 a las 96 horas fue de 215 mg/l
(Pimephales promelas).

Se realizó una caracterización del riesgo de muestra


para el medio acuático calculando la razón entre una
concentración local prevista en el medio ambiente
(PEC), basándose en datos medidos en fecha reciente, y
la concentración prevista sin efectos (PNEC) correspon-
diente. Se estimó una PNEC de 149 µg/l para el agua
superficial a partir del valor más bajo de la CE50 de
149 mg/l, aplicando un factor de incertidumbre de 1000.
Con la concentración más alta de glioxal medida recien-
temente en el agua superficial (1,9 µg/l), se obtuvo un
cociente PEC/PNEC de 0,013. Como este valor es
inferior a 1, no hay necesidad de más información,
pruebas o medidas de reducción del riesgo.

43
THE CONCISE INTERNATIONAL CHEMICAL ASSESSMENT DOCUMENT SERIES

Acrolein (No. 43, 2002)


Acrylonitrile (No. 39, 2002)
Arsine: Human health aspects (No. 47, 2002)
Azodicarbonamide (No. 16, 1999)
Barium and barium compounds (No. 33, 2001)
Benzoic acid and sodium benzoate (No. 26, 2000)
Benzyl butyl phthalate (No. 17, 1999)
Beryllium and beryllium compounds (No. 32, 2001)
Biphenyl (No. 6, 1999)
Bromoethane (No. 42, 2002)
1,3-Butadiene: Human health aspects (No. 30, 2001)
2-Butoxyethanol (No. 10, 1998)
Carbon disulfide (No. 46, 2002)
Chloral hydrate (No. 25, 2000)
Chlorinated naphthalenes (No. 34, 2001)
Chlorine dioxide (No. 37, 2001)
4-Chloroaniline (No. 48, 2003)
Crystalline silica, Quartz (No. 24, 2000)
Cumene (No. 18, 1999)
1,2-Diaminoethane (No. 15, 1999)
3,3’-Dichlorobenzidine (No. 2, 1998)
1,2-Dichloroethane (No. 1, 1998)
1,1-Dichloroethene (Vinylidene chloride) (No. 51, 2003)
2,2-Dichloro-1,1,1-trifluoroethane (HCFC-123) (No. 23, 2000)
Diethylene glycol dimethyl ether (No. 41, 2002)
Diethyl phthalate (No. 52, 2003)
N,N-Dimethylformamide (No. 31, 2001)
Diphenylmethane diisocyanate (MDI) (No. 27, 2000)
Elemental mercury and inorganic mercury compounds: human health aspects (No. 50, 2003)
Ethylenediamine (No. 15, 1999)
Ethylene glycol: environmental aspects (No. 22, 2000)
Ethylene glycol: human health aspects (No. 45, 2002)
Ethylene oxide (No. 54, 2003)
Formaldehyde (No. 40, 2002)
2-Furaldehyde (No. 21, 2000)
HCFC-123 (No. 23, 2000)
Hydrogen sulfide: human health aspects (No. 53, 2003)
Limonene (No. 5, 1998)
Manganese and its compounds (No. 12, 1999)
Methyl and ethyl cyanoacrylates (No. 36, 2001)
Methyl chloride (No. 28, 2000)
Methyl methacrylate (No. 4, 1998)
N-Methyl-2-pyrrolidone (No. 35, 2001)
Mononitrophenols (No. 20, 2000)
N-Nitrosodimethylamine (No. 38, 2001)
Phenylhydrazine (No. 19, 2000)
N-Phenyl-1-naphthylamine (No. 9, 1998)
(continued on back cover)
THE CONCISE INTERNATIONAL CHEMICAL ASSESSMENT DOCUMENT SERIES
(continued)

Polychlorinated biphenyls: human health aspects (No. 55, 2003)


Silver and silver compounds: environmental aspects (No. 44, 2002)
1,1,2,2-Tetrachloroethane (No. 3, 1998)
1,1,1,2-Tetrafluoroethane (No. 11, 1998)
Thiourea (No. 49, 2003)
o-Toluidine (No. 7, 1998)
Tributyltin oxide (No. 14, 1999)
Trichloropropane (No. 56, 2003)
Triglycidyl isocyanurate (No. 8, 1998)
Triphenyltin compounds (No. 13, 1999)
Vanadium pentoxide and other inorganic vanadium compounds (No. 29, 2001)

To order further copies of monographs in this series, please contact Marketing and Dissemination,
World Health Organization, 1211 Geneva 27, Switzerland
(Fax No.: 41-22-7914857; E-mail: bookorders@who.int).
The CICAD documents are also available on the web at http://www.who.int/pcs/ra_site/cicads.htm.

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