International Consensus Report on:
Isocyanates – Risk assessment and
management
Based on a meeting 2001.11.20-22 at
Hotel Norge Hoesbjoer, Norway
Funded by
Nordic Council of Ministers
Organized by
The Norwegian Labour Inspection
Editorial board:
Editor: Jan Vilhelm Bakke
Co-editors: Jan Olof Norén, Syvert Thorud, Tor B Aasen
1
International Consensus Report on:
Isocyanates – Risk assessment and management.
2001.11.20-22, Hotel Norge Hosbjor, Hosbjorvegen, N-2320 Furnes, Norway
Contents:
Contents:....................................................................................................................................2
Abbreviations and glossary......................................................................................................4
Preface .......................................................................................................................................5
Participants ...............................................................................................................................8
Organising committee ..............................................................................................................8
0. Background ...........................................................................................................................9
0.1. Public concern and discussions .......................................................................................9
0.2. Aims/objectives of the meeting .......................................................................................9
0.3. Method.............................................................................................................................9
0.4 Risk management tools..................................................................................................10
0.5. Practical approaches to derive health based exposure limits.........................................10
1. Exposure and use ................................................................................................................11
1.1. Use and occurrence of PUR and isocyanates. Populations and professions at risk.......11
2. Potential for exposures to isocyanates ..............................................................................12
2.1 Volatility.........................................................................................................................12
2.2 Aerosol generation of diisocyanates...............................................................................12
2.3 Prepolymers / polyisocyanates .......................................................................................13
2.4 Processes involving thermal decomposition...................................................................13
2.5 Skin contact ....................................................................................................................13
2.6 Incidents..........................................................................................................................13
3 Health effects.......................................................................................................................13
3.1 What is isocyanate disease?............................................................................................14
3.1.1
Definitions ............................................................................................................14
3.1.2
Diseases ................................................................................................................14
4. Exposure assessment methods...........................................................................................15
4.1 Sampling strategy ...........................................................................................................15
4.2 Measurement methods....................................................................................................16
4.3 Requirements for future research ...................................................................................16
4.4 Biomarkers for exposure ................................................................................................17
4.5 Issues for further research...............................................................................................17
5. Risk assessment...................................................................................................................18
5.1 Dose-Response assessment.............................................................................................18
5.1.1
Estimation of a safe exposure level for the sensory irritation effects...................19
6. Risk management/Foundation for decisions/Decision models........................................19
2
6.1 General principles...........................................................................................................19
6.1.1
Products: ...............................................................................................................20
6.2 Societal responsibilities and options..............................................................................21
6.2.1
Health based exposure limits................................................................................21
6.2.2
Risk communication .............................................................................................21
6.2.3
Labelling, Safety Data Sheets (SDS) as means for risk communication..............21
6.3 Responsibilities and options for the enterprises ............................................................22
6.3.1
Management systems............................................................................................22
6.3.2
Avoidance of exposure (in order of priority)........................................................22
6.3.2.1 Method substitution (change of process) and substitution ...................................22
6.3.2.2 Technical solutions and requirements to avoid exposure.....................................22
6.3.2.3 Personal protective equipment (PPE) ...................................................................22
6.3.2.4 Surveillance programs ..........................................................................................23
7. Research needs ...................................................................................................................24
8. Recommendations..............................................................................................................25
9. References...........................................................................................................................26
10. Appendices ........................................................................................................................35
10.1 Previous consensus statements ....................................................................................35
10.1.1
Nordic statements (Bakke 2001) ..........................................................................35
10.1.2
Isocyanates in Working Life (Levin et al 2000). Conclusions .............................35
10.2 Introductory presentations on the meeting ..................................................................37
10.2.1 Isocyanate-induced respiratory health effects ......................................................37
10.2.2
Exposure Assessment Methods ............................................................................52
10.2.3
Exposure control of isocyanates, aminoisocyanates and amines with special
reference to exposure to thermal decomposition products of polyurethane ........61
10.3 Relevant background documents.................................................................................75
10.3.1
Letter from Sweden to DG-employment 1997 ....................................................75
10.3.2 The ”Nordic isocyanate report 2000”. Summary .................................................76
10.3.3
Levin JO et al. Isocyanates in Working Life. ......................................................78
10.3.4
The Swedish exposure assessment project – “Isocyanate 2000”. Abstract .........84
10.3.5
German OELs regarding isocyanates ...................................................................86
10.3.6 Nordic network on isocyanates (NORDNI) DRAFT ...........................................88
10.3.7. Consensus Report for Toluene Diisocyanate (TDI), Diphenylmethane
Diisocyanate (MDI), Hexamethylene Diisocyanate (HDI) May 30, 2001..........94
10.3.8. Consensus Report for Methylisocyanate (MIC) and Isocyanic Acid (ICA)
December 5, 2001 DRAFT................................................................................119
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Abbreviations and glossary
BIC
Butyl isocyanate
COPD
Chronic Obstructive Pulmonary Disease
Diisocyanates
Isocyanates with two reactive groups (-NCO)
EIC
Ethyl isocyanate
HDI
Hexamethylene diisocyanate
HMDI
Methylene di(4-cyclohexylisocyanate)
IPDI
Isophorone diisocyanate
ICA
Isocyanic acid
Isocyanate adducts Isocyanates with low volatility and known structure eg. Biuret-,
alofanate and isocyanurate adducts.
Isocyanates
Chemicals containing the highly unsaturated N=C=O group
LOAEL
Lowest Observed Adverse Effect Level
MDI
Methylene diphenyl diisocyanate, 4,4´-methylenediphenyl diisocyanate
MIC
Methyl isocyanate
Monoisocyanates
Isocyanates with one reactive group (-NCO)
NDI
Naphthalene-1,5-diisocyanate
NOAEL
No observed adverse effect level
OEL
Occupational Exposure Limit
OHS
Occupational Health and Safety
PIC
Propyl isocyanate
PhI
Phenyl isocyanate
Polyisocyanates
Dimers and higher polymeric isocyanates
PPE
Personal Protective Equipment
Prepolymers
Isocyanates partly reacted with higher alcohols. Two kinds:
1. Isocyanates in excess reacted with alcohols and containing free
isocyanates;
2. Isocyanates reacted in excess of alcohols and containing no free
isocyanates
PUR
Polyurethane
RADS
Reactive Airways Dysfunction Syndrome
RD50
The concentration that decrease the respiratory rate in mice by 50%
SDS
Safety Data Sheet
STEL
Short Term Exposure Level
TDI
Toluene diisocyanate
TLV
Threshold Limit Value
TWA
Time Weighted Average
4
Preface
A grant from The Nordic Council of Ministers made it possible for The Norwegian Labour
Inspection to take the responsibility for the accomplishment of this project. It is part of
following up one of the outcomes and recommendations from a consensus project, which
covered the same topics, performed and reported in 2000 by the Nordic Governmental Work
Environment Authorities represented by their Occupational Health and Safety (OHS) agencies
(Bakke 2001 http://www.arbeidstilsynet.no/publikasjoner/rapporter/rapport1eng.html). The
need for such work was triggered by discussions and conflicts emerging after new exposure
assessment methods had identified other substances (amines, isocyanic acid, etc) and new
sources of potential exposure, including exposure to methylisocyanate (MIC) and isocyanic
acid (ICA) on occasions when polyurethanes or production involving isocyanates were not
present.
Occupational airway diseases in general, and certain particularly potent exposures, like
isocyanates, have for a long time not been given the priority they deserve, compared to other
effects and exposures in working life. We must, from a prevention and management point of
view, assess the potential to reduce “asthma attributable to occupational exposure” (Wagner
& Wegman 1998, Milton et al 1998). The preventive potential can then be an order of
magnitude higher than recognised in occupational lung disease surveillance efforts (Ross et al
1997, Meredith & Nordman 1996). We should include irritants inducing new asthma (Brooks
et al 1985, Tarlo & Broder 1989, Brooks 1992, Kipen et al 1994, Bakke & Nordman 1997) as
well as elicitation and exacerbation of pre-existing asthma. This means inclusion of irritantinduced asthma as well as distinguishing between:
1.
Onset of new asthma resulting from specific sensitisation to agents in the
workplace
2.
Asthma resulting form exposure to irritants in the workplace
3.
Pre-existing asthma re-induced or exacerbated by workplace environmental
exposures
The importance of pre-existing asthma increases in parallel to the growth of childhood-onset
asthma that are followed by corresponding increases in the working force when these
asthmatic cohorts enter working life (Bakke & Nordman 1997).
This means that we must also take into consideration the reactive and irritating potential as
well as the specific sensitising properties of isocyanates in the risk assessments. It is however
of high importance to keep the risk assessment within the scientific field and let the different
parties and stakeholders use their influence when it comes to risk management and what
should be the level of “acceptable risk” for the exposed populations. There are still
controversies on how to assess and manage these risks.
It is acknowledged that the level of “acceptable risk” is to be decided by the technical,
economical and political possibilities that are available. These are based on normative values,
societal awareness and the prevailing “risk perception” as well.
Risk assessment is the foundation for rational risk management in the enterprises as well as
for the OHS-agencies on a societal level. The output of risk assessments constitutes the
scientific foundation on which our risk management policies have to be based: risk
communication, information, education, establishing standards and norms, setting exposure
limits, TLVs and other regulations, inspections and audits. They must be based on the best
available risk estimates that can be provided including considerations of the level of
5
uncertainty in these estimates. The risk assessments must also include evaluations of the
management of the risk and be part of a continuous quality assurance of the work
environment. Continuous processes of information and preventive actions in feed-back-circles
as well as risk communication as dialogues among the parties involved are therefore needed.
A basic objective for risk communication is to bring risk perception among all the involved
parties as far as possible in accordance with what is the actual scientific knowledge in the
field. It must include motivation and understanding on how and why preventive measures
should be undertaken. This is a prerequisite for rational risk management at all levels and
underline the importance of good scientific foundation and professional risk communication
on such complicated areas. A more consentual assessment and perception of risk in the field
of exposure to isocyanates, as well as how they should be managed, is for the time being
highly desirable.
Scientific risk assessments and consensus must be based on data that has been through a
quality assurance process. A necessary, but not sufficient prerequisite, is open publication,
transparency and availability of data through peer reviewed scientific journals. Scientific
statements can not be based on anecdotal data or undocumented assertions. Better and more
precise data are needed to increase our level of precision in the assessments. It is expected
from the society and the involved parties that we as professional experts and scientists shall
convey the best available foundation for risk assessment and management. The greatest
challenge for us in doing this seems to be the communication of the limits of knowledge and
precision in our assessments.
This leads to the statements that was given the highest priority on the meeting, other
statements points to lack of knowledge and need of research:
Consensus statements:
S1:
This report is based on publicly available information judged by the invited experts
present to be reliable. Some highly relevant data may be held privately and there is
information that other studies have been conducted, and not published, which could
clarify many of the questions we are posing regarding isocyanates, their prevalence
and effects. Publication of such studies would be of great use in risk assessment as a
foundation for rational management of risk. We urge publication of all relevant
information in order to improve understanding and prevention.
S48:
There is sufficient information on isocyanate-related diseases to base comprehensive
preventive actions; we however encourage continuing research work in the field as
several aspects of the association between exposure to isocyanates and respiratory
health warrant further work.
The participants in this meeting were invited as individuals because of their professional
knowledge and accomplishments and not as official representatives of their employers or
professional organizations. This meeting concentrated as far as possible solely on scientific
matters. At a later stage other parties have to consider economical, technical and political
aspects connected to decision-making regarding acceptable risk, regulations, inspections and
other means to implement preventive measures.
6
I want, on behalf of The Labour Inspection and myself, to thank all the participants that have
taken part on the meeting and in the process, for their kind helpfulness, cooperative and
positive approach, all the time and competence they provided to us, and all the work they
have done without any compensation other than the professional satisfaction in doing a good
job on a common field in a multidisciplinary setting.
The Nordic Council of Ministers is to be acknowledged for making the project possible by
giving funding independent of any of the different stakeholders in the field.
I also want to express my sincere gratitude to the organisational committee and editorial board
for vital technical and scientific support during the process. I want at last, but not least, to give
my compliments to Professor Thomas Lindvall, The Institute of Environmental Medicine
(IMM), Karolinska Institutet, Stockholm. He has acted as my mentor by providing me with
advise, skills and experiences that encouraged me to meet such a challenging and worthwhile
project as to arrange a consensus conference in this field.
Gjoevik April 11th 2002
Jan Vilhelm Bakke
7
Participants
The participants in this meeting were invited as individuals because of their professional
knowledge and accomplishments and not as official representatives of their employers or
professional organizations. Their institutional affiliations are listed for purposes of
identification only.
Ann-Beth Antonsson, IVL Swedish Environmental Research Institute Ltd, Sweden
Jonas Brisman M.D. Ph.D., Occupational and Environmental Medicine, Göteborg, Sweden
Richard H Brown, Dr, Health and Safety Laboratory, Sheffield, UK
Sherwood Burge, Consultant Chest Physician, Birmingham, UK
Gunnar Johanson, Professor PhD, Head of Division, Division of Occupational Toxicology,
Institute of Environmental Medicine, Karolinska Institutet, Stockholm
Ute Latza, Dr. rer. nat., MPH, Research Scientist, University of Hamburg, Germany
Jan-Olof Levin, Professor, National Institute for Working Life, Umeå, Sweden
Jean-Luc Malo, Professor M.D., Université de Montréal and Hôpital du Sacré-Coeur,
Montréal, Canada
Gunnar Damgaard Nielsen, Senior Researcher, National Institute of Occupational Health,
København, Denmark
Henrik Nordman, Associate Professor MD PhD, Finnish Institute of Occupational Health,
Helsinki, Finland
Christina Rosenberg, PhD, Senior Research Scientist, Finnish Institute of Occupational
Health, Helsinki, Finland
Torben Sigsgaard, lecturer, PhD., The Department of Environmental and Occupational
Medicine, Aarhus University, Denmark
Gunnar Skarping, Associate Professor, Work and Environmental Chemistry, Hässleholm,
Sweden
Gregory R. Wagner, M.D. Director, Division of Respiratory Disease Studies. National
Institute for Occupational Safety and Health, USA
Hans Welinder, Associate Professor, Ph.D., Lund University Hospital, Sweden
Organising committee
Jan Vilhelm Bakke, Norwegian Labour Inspection Authority, Gjovik, Norway
Jan Olof Norén, Chemistry and Microbiology Division, Swedish Work Environment
Authority, Solna, Sweden
Geir Teigen, Norwegian Labour Inspection Authority, Oslo, Norway
Syvert Thorud, National Institute of Occupational Health, Oslo, Norway
Tor B. Aasen, Department of Occupational Medicine, Haukeland University Hospital,
Bergen, Norway
Arne Ulven, Department of Occupational Medicine, Haukeland University Hospital, Bergen,
Norway
8
0.
Background
0.1. Public concern and discussions
In the Nordic countries, particularly in Sweden and Norway, there has been an intense debate
about isocyanates. Special attention has been drawn to the risk entailed by the thermal
degradation of polyurethane (PUR) plastics and products containing polyurethanes (Karlson
et al 2000, Lilja et al 2000, Prevent 2000). Some of these degradations have previously been
unknown and overlooked. What is also new, is the generation of low-molecular isocyanates
that occur when heating up materials containing some combinations of phenol-formaldehydeurea (Karlsson et al 1998). In addition to methylisocyanate (MIC) (H3C-N=C=O) and other
monoisocyanates, isocyanic acid (H-N=C=O) has been identified in significant concentrations
(Karlsson et al 2000 a & b, 2001). Examples of workplaces where isocyanates will occur,
include heating of mineral wool in oven insulation, of binders for core making in the foundry
industry, and hot work in car repair shops.
0.2. Aims/objectives of the meeting
The aims of the meeting were to establish the scientific foundation for rational risk
management ”unbiased” by economic and other particular interests represented by the parties
involved. The planned outcome was to produce a report that could serve as the foundation for
further work in the field for the authorities, enterprises and others responsible for managing
the risks.
Risk management should be founded on risk assessment based on the best knowledge
available. It is important to bear in mind that there are levels of uncertainties in these
assessments practically in all occasions. The range of uncertainty in these assessments should
be borne in mind as a part of the decision-making process.
0.3. Method
A multidisciplinary group of prominent and independent researchers and experts in the fields
of risk assessment and management of exposure to isocyanates were assembled for a
consensus conference in Norway at Hoesbjoer. The meeting had been prepared beforehand by
an editing committee producing a “skeleton document” as a framework for the final report.
Our methods were basically to organise the statements on the meeting in the following
categories
relevant consensus statements
protocol of scientific disagreements
list of research needs
and to fill inn texts in the “skeleton document”.
Some of the conference members prepared presentations for the meeting covering the main
topics to be discussed. The process also consisted of discussions in subgroups to produce the
statements that were adopted for discussion and final formulation of consensus in the plenary
meetings. All consensus statements, which have been marked in the text, were adopted
without objection in plenary meetings.
There were no significant scientific disagreements except where stated in the report.
9
0.4 Risk management tools
The aims of the meeting were to provide the foundation for risk management. Several
approaches to risk management are available for the various responsible parties and may be
categorised in several ways. The enterprises and the governmental authorities are the two
most important parties in the management of risks connected to isocyanates. They have
different roles, responsibilities and tools available for their preventive actions:
-
governmental authorities may have available risks managements tools like:
o risk communication
o establishing standards and norms
o regulations, including occupational exposure limit values
o inspection, control, audits and supervision
o incentives
o cooperation with others (insurance, the parties and other stakeholders, research
institutions, occupational health institutes etc)
o assessment of the actual work environment conditions in terms of exposures, risk
assessment and management in the enterprises. This also includes notification
systems for occupational diseases and occupational disease compensation data
o Availability of practical and reliable solutions in risk management in the
enterprises
-
The enterprises are obliged to manage their risks by implementing the regulations
and to establish a form of quality assurance (Internal Control) to ensure that they are
actually implemented. This includes responsibility for characterising exposure,
performing proper risk assessment of conditions and taking the necessary preventive
measures. Their tools are to
o Keep account of their own risks, risk assessment and prevailing regulations
o Establish internal goals for work environments based on risk assessment
o Keep the employees informed and instructed, to have sufficient knowledge
available to manage risks and ensure that the employees participate in the Health
and Safety (H&S)-work.
o Assess dangers and problems, measure exposure if necessary
o Carry out preventive measures:
Substitution of chemicals, products, methods or processes
Technical measures (encapsulation, confinement, exhaust devices)
Organisational measures
Hygienic measures (clothing, availability of lockers and showers etc)
Providing personal protective equipment (PPE)
o Perform internal audits, in form of verifications as well as revisions, surveillance
and evaluation of preventive measures
0.5. Practical approaches to derive health based exposure limits
The term “No Observed Adverse Effect Level” (NOAEL) may be used in several context.
First, it may be possible to identify a NOAEL in a particular study (Nielsen et al 1999).
Second, it may be possible to establish a best available NOAEL from a number of similar
studies. To reach a no effect level or "safe level" at the population level, it is common practice
to multiply the best available NOAEL with a safety factor (Renwick & Lazarus 1998). This
product may be considered to be the no effect level for the population. However, the value
10
reached is not necessarily a true no effect level for the population as the NOAELs from the
different studies may not have been able to reveal an effect (type II error). There is also a
possibility that the available studies have not included rare cases with enhanced sensitivity
(Kriebel et al. 2001).
Asthma is generally acknowledged as the critical effect of exposure to isocyanates, but the
sensitizing properties of isocyanates lead to the question whether the control measures should
aim to protect
the normal, not primary sensitized population
the increasing number of the population with atopy, asthma or other hypersensitivity
as well
or in addition those workers that are allready specifically sensitized to isocyanates
1.
Exposure and use
1.1. Use and occurrence of PUR and isocyanates. Populations and professions at risk
Highly reactive isocyanates (R-N=C=O), including di-isocyanates and polyisocyanates, are
nowadays used in many workplaces. They may become airborne in gaseous or aerosolised
forms. When inhaled, they bind to human tissues, proteins and DNA, forming toxic adducts
and metabolites which may cause adverse health effects. Bronchial asthma is the most
frequent clinical diagnosis in exposed isocyanate workers. Further diseases caused by these
chemicals include chronic obstructive pulmonary diseases (COPD), non-obstructive
bronchitis, rhinitis, conjunctivitis, dermatitis, extrinsic allergic alveolitis and cancer.
Industrial uses of isocyanates include manufacture of polyurethane foam, surface coatings,
adhesives and textiles, and occupational exposure can occur, particularly in processes
involving heating and spraying isocyanates.
Isocyanates are used together with other substances as e.g. amines. When PUR is thermally
degradated, many other substances are formed. These other substances may also cause health
effects and are important to consider. In this document, however, we focus only on
isocyanates. Other compounds of importance are for example aromatic amines.
Isocyanates are found in various forms, as gases, droplets or particles, and in many industrial
and technical fields in which polymers are used, e.g.:
• The automotive industry - paints, glues, insulation, sealants and fibre bonding
• The casting industry - foundry cores
• The building and construction industry - in sealants, glues, insulation material, fillers,
lacquers, finishes on synthetic floorings and other applications
• The electricity and electronics industry - in cable insulation, PUR coated circuit boards
• The mechanical engineering industry - insulation material
• The paints industry – lacquers
• The plastics industry - soft and hard plastics, plastic foam and cellular plastic
• The printing industry – inks and lacquers
• The timber and furniture industry - adhesive, lacquers, upholstery stuffing and fabric
coatings
• The white goods industry - insulation material
• The textile industry – synthetic textile fibers
11
•
•
•
The medical care – PUR casts
The mining industry – sealants and insulating materials
The food industry – packaging materials and lacquers.
Not only are isocyanates present in the manufacture of polymers, they are also generated
when materials containing polyurethanes are heated, e.g. when cutting, grinding or welding
and at fires.
Products containing urea-formaldehyde have been shown to emit aliphatic mono-isocyanates
when heated. Methyl isocyanate (MIC) and isocyanic acid (ICA) seem to be the most
important (Karlsson et al 1998, Henriks-Eckerman et al 2000, Karlsson et al 2001).
2. Potential for exposures to isocyanates
2.1 Volatility
S2:
The potential for worker exposures to isocyanates is determined by several factors.
One important factor is the volatility of the isocyanates. If isocyanates are handled
at normal temperatures (room temperature), only the volatile isocyanates will
vaporise and thus be present in significant concentrations in workplace air.
Isocyanates that easily vaporise are, for example, toluene diisocyanate (TDI) and
hexamethylene diisocyanate (HDI). Phenyl isocyanate (PhI) is also volatile and
may be present as a contaminant in methylene diphenyl diisocyanate (MDI). Other
isocyanates, such as MDI, isophorone diisocyanate (IPDI), naphthalene-1,5diisocyanate (NDI), and prepolymers and polyisocyanates, will not have a
significant vapour pressure, and significant concentrations cannot be expected,
except in some cases which are described below.
S3:
Low molecular weight aliphatic monoisocyanates are all volatile, but generally
they are only formed from thermal decomposition of polyurethane and some other
materials. See below.
2.2 Aerosol generation of diisocyanates
Significant concentrations of commercially used diisocyanates may be present if aerosols of
isocyanates are formed. Aerosols are formed mainly due to spraying and heating.
S4:
In some applications, diisocyanates are sprayed and the spray aerosol may contain
high concentrations of diisocyanate vaporous monomers as well as particulate
isocyanates, regardless of which isocyanate is used. The particles in the aerosol
formed through spraying have an aerodynamic diameter >0,1 µm and usually >20
µm. If the droplets contain volatile substances, their size can rapidly decrease
(Ackley 1980, Bosseau et al 1992).
S5:
Aerosols may also be formed if isocyanates are heated (below the thermal
degradation temperature), increasing their volatility. Emitted vapours then cool to
room temperature, the vapours condense and a ‘condensation aerosol’ is formed.
These particles are small with an aerodynamic diameter of less than/about 0.1
micrometer which make them airborne and respirable with the potential to reach
the small airways and alveoli, creating harm.
.
12
2.3 Prepolymers / polyisocyanates
S6:
In many commercial applications, isocyanate-containing intermediates have been
developed, in order to reduce the content of free (monomeric) diisocyanates. A
common method is to use adducts of diisocyanates, prepolymers or
polyisocyanates instead of diisocyanates. Products containing prepolymers /
polyisocyanates usually do not give rise to significant concentrations in
surrounding air (unless aerosolised). There are however some exceptions. The
content of residual monomer in prepolymer and polyisocyanate preparations can
vary, both between manufacturers and with time. Information about the chemical
nature of the isocyanates and residual monomers should be given in safety data
sheets (SDS).
2.4 Processes involving thermal decomposition
S7:
Heating of polyurethane-containing materials above 150-200 oC may give rise to
the original monomeric diisocyanates, but also other isocyanates such as the low
molecular aliphatic monoisocyanates isocyanic acid (ICA), methyl isocyanate
(MIC), ethyl isocyanate (EIC), propyl isocyanate (PIC) and buthyl isocyanate
(BIC) (Karlsson et al 2000 b, Karlsson et al 2001). Aminoisocyanates (and amines)
and other isocyanate-containing species, of varying chemical complexity, may be
formed (Skarping et al, 1985, Dalene et.al. 1988 and the Thesis by Karlsson 2001).
When heated to even higher temperatures (e.g. over 300-400 oC), the
monoisocyanates are often the main airborne isocyanate products.
Monoisocyanates may also be formed from thermal decomposition of other
nitrogen-containing materials, e.g from phenol/formaldehyde/urea resins (Karlsson
et al. 1998, Karlsson et al 2001).
2.5 Skin contact
S8:
Skin contact may occur with products containing isocyanates. As skin contact is
suspected to be significant for isocyanate-induced disease, it is important to
consider potential skin exposure in an overall monitoring strategy (Karol 1986,
Schröder et al 1999, Liu Y et al 2000, Petsonk 2000, Låstbom et al in press).
2.6 Incidents
S9:
There is also strong circumstantial evidence that short-term high exposures may be
significant for isocyanate-induced disease (Petsonk et al 2000). (But other
evidence points to mean exposure levels as the more significant factor). Incidents
resulting in spillage of isocyanate-containing products or attempts to remove cured
PUR-material with heat may give rise to such peak exposures.
3
Health effects
Isocyanates are probably the most important group of reactive low-molecular chemicals that
are reported to cause asthma and hypersensitivity in the airways (Bernstein & Jolly 1999,
Baur 1996, Vandenplas et al 1993). In the production of diisocyanates and in conjunction with
the use of PUR products including prepolymers, a large number of cases of occupational
asthma among exposed workers have been documented (van Kampen et al 1998, Simpson et
al 1996, Mapp et al 1999). The use of MDI insulation foam in the construction industry may
13
lead to unacceptable exposure (Crespo & Galan 1999). Attention has also been called recently
to the risk that tunnelers using PUR products as sealants may develop asthma (Ulvestad et al
1999). In Great Britain, according to “Surveillance of Work-Related and Occupational
Respiratory Disease in the UK (SWORD), isocyanates are the most important recorded cause
of occupational asthma (Madan 1996, with reference to Sallie et al, 1994). It is also probable
that isocyanate asthma is underdiagnosed. TDI, MDI and HDI are well known for their
sensitising properties (Gerald et al 2000). The mechanisms for the development of isocyanate
asthma have not yet been elucidated, but it seems that different immunological, irritative and
toxic mechanisms are involved (Raulf-Heimsoth & Baur 1998).
3.1
What is isocyanate disease?
A presentation of “state-of-the-art” is given by Jean-Luc Malo and Ute Latza in Annex 10.2.1.
3.1.1 Definitions
S10:
Problems may arise from unclear definition of concepts (Knudsen & Bakke 1993,
WHO 1997, Johansson et al 2001). The notion “sensitisation” was discussed.
Agents causing asthma can be said to cause hypersensitivity, i.e., exposure results
in increased responsiveness to that agent. Such a specific sensitisation of the
airways often results in a more generalized hyper-responsiveness to irritants and
other stimuli (e.g., cold air) found inside and outside the workplace. Sensitisation
to occupational agents may result from either allergic or non-allergic mechanisms.
S11:
Asthma-inducing agents (asthmagens) include both specific sensitising agents and
irritating exposures:
1.
Agents causing asthma with a latency period. Reaction to non-irritating
levels of suspected agent
a. With immunological responses
b. Without identified or verified immunological responses
2.
Agents causing asthma without a latency period. Asthma resulting from a
single high-exposure (Reactive Airways Dysfunction Syndrome/RADS)
3.
Asthma resulting from multiple exposures to irritating agents at lower
levels (Tarlo & Broder 1989, Brooks 1992, Kipen et al 1994).
3.1.2 Diseases
S12:
Although di-isocyanate and poly-isocyanate disease is not confined to asthma
combined with verified specific hypersensitivity, measurements designed to
prevent asthma from isocyanate exposure are likely to prevent other di-isocyanate
related respiratory health effects.
S13:
Diagnostic criteria used for compensation are too restricted to be used as a useful
measure for preventive potential.
S14:
The effects of exposure to isocyanates in the population are likely to include a
significant amount of asthma-like symptoms, asthma, and COPD which have not
been specifically attributed to isocyanate exposure. In addition there are many
workers with isocyanate-induced symptoms who may not be identified because of
removal from exposure and/or concurrent anti-inflammatory treatment before they
are referred. The preventive potential can be assumed to be much higher than the
14
number of individually diagnosed cases.
S15:
Although diisocyanates (and possibly other polyisocyanates) cause rhinitis and
conjunctivitis, they do so less commonly than most other causes of occupational
asthma with a latency period for which an IgE-mediated mechanism has been
identified (Malo et al 1997). However, an increased prevalence of work-related
complaints from eyes and upper airways is reported in cross-sectional studies of
exposed workers (Skarping et al 1996, Jakobsson, 1997, Randolph, 1997, SariMinodier, 1999, Özdemir, 1998, Omae, 1992, Welinder et al 1998, Littorin et al
2000).
S16:
All types of di-isocyanates including pre-polymerised isocyanates must be
considered as hazardous.
S17:
Short-term high exposures are likely to increase the risks of isocyanate induced
disease (Tornling et al 1990, after citation from Malo, Petsonk et al 2000). Thus,
information on exposure, either from direct short-term monitoring, biological
monitoring or from historical data, may be needed as a supplement or instead of
average exposure measurement.
S18:
Skin contact seems to be a risk factor for di-isocyanate respiratory diseases
(Schröder et al 1999, Liu Y et al 2000, Petsonk et al 2000). It may therefore be an
advantage to supplement air monitoring with biological monitoring.
S19:
The reported adverse effects of mono-isocyanates are toxic and irritant, and
include asthma (Beckett 1998, Cullinan et al 1997, Kamat et al 1992). Therefore
exposures should be controlled.
4.
Exposure assessment methods
4.1 Sampling strategy
S20:
A detailed description of sampling strategy depends critically on the measurement
task, e.g. compliance with limit values, epidemiological studies, assessment of
effectiveness of control measures, assessment of “worst-case” scenarios (Levin et
al 2000, Brown 2002, Brown: Annex nr 11.2.2, Skarping et al Annex nr 11.2.3).
A useful guide (particularly directed at occupational hygiene assessment) is the
CEN guide EN 689:1996 (CEN 1996). EN 689 gives guidance on measurement
strategies for compliance, but also covers representative and “worst-case”
measurements, periodic measurements to check efficiency of control measures,
etc.
Nevertheless, some general comments can be made here, with specific reference to
isocyanates.
S21:
The measurements have to be done by a skilled person.
15
S22:
A sufficient number of samples is needed, considering the variability of the
exposure levels in space and time, and the measurement task
S23:
The siting of the exposure assessment is critical, particularly in the case of thermal
degradation
S24:
The exposure assessment should be representative of the worker’s actual exposure:
this is normally interpreted as taking samples in the “breathing zone” of the worker
S25:
Bearing in mind that regulatory requirements may determine the sampling time,
this time should be relevant to the process or job giving rise to potential isocyanate
exposures. Limitations in the sensitivity of the analytical method may also
introduce a minimum practical sampling time
4.2
Measurement methods
Methods for analysis of exposure in air.
S26:
A measurement method that is appropriate for the measurement task should be
selected.
S27:
The measurements have to be done by a skilled person
S28:
Any selected method should have been validated against a recognised performance
standard (e.g. the CEN standard EN 482 (CEN 1994)) and be subject to
appropriate quality control and quality assurance. Different analytical reagents for
measuring isocyanates will not be discussed in this report.
S29:
For the choice of method, the analytical laboratory or a skilled industrial hygienist
should be consulted. Some guidance in selecting an appropriate procedure is being
developed by ISO (draft document ISO/TC146/SC2 N299, October 2000) and
Nordic Network on Isocyanates (NORDNI) (Molander et al in press, Appendix
11.3.6). See also Levin et al (2000) and Brown section 11.2.2 – based on Brown
2002, Norén 1998 and 2000, Streicher et al 2000, Skarping et al Appendix 11.2.3,
and the Thesis of Karlsson 2001.
S30:
The selection of a measurement procedure should take into account that the
isocyanates to be measured may not necessarily be those predicted to be present,
as new isocyanate-containing species are continuously being identified.
4.3
S31:
Requirements for future research
There will be a need for more cost-effective and user-friendly methods for
measuring isocyanates. We note the need for an accurate and practical continuous
exposure monitoring system that is useful for all commercially important
isocyanate products.
S32:
Research should also be directed at methods for determining short-term high
exposures and for assessing dermal exposure.
16
4.4
Biomarkers for exposure
Metabolites of isocyanates and their adducts are biomarkers of exposure (Skarping et al
1994a, Skarping et al 1994b, Skarping et al 1996, Dalene et al 1995, Brunmark et al 1995,
Dalene et al 1996, Dalene et al 1997, Brorsson et al 1991, Brorsson et al. 1990, Tinnerberg et
al 1995, Tinnerberg et al 1997, Lind et al 1996a, Lind et al 1996b, Lind et al 1997a, Lind et al
1997b, Littorin et.al. 2000).
S33:
Biomarkers can be used as indicators of exposure (Marczynski et al 1999).
S34:
At present, biomarkers are only available for a limited number of isocyanates.
S35:
Potentially, biomarkers could indicate exposure or risk resulting from both
inhalation and dermal exposure.
S36:
Metabolites of isocyanates in hydrolysed urine may be used as an indicator of
exposure over a work-shift.
S37:
Some useful relationships between levels in air and urine have been presented for
TDI, HDI and MDI (as monomeric diisocyanates)(Rosenberg & Savolainen 1986,
Brorsson et al 1990, Brorsson et al 1991, Maître et al 1993, Sepai et al 1995,
Schutze et al 1995, Lind et al 1996 (a) and 1997, Maître et al 1996, Dalene et al
1997, Tinnerberg et al 1997, Williams et al 1999, Engström et al 2001, Kääria et
al 2001 a,b)
S38:
Metabolites of diisocyanates in hydrolysed plasma and/or haemoglobin can be
used as an indicator of accumulated dose over about a month (Brorsson et al 1991,
Sepai et al 1995, Schutze et al 1995, Lind et al 1996 a/b and 1997a/b, Dalene et al
1996 and 1997, Tinnerberg et al 1997, Sabbioni et al 2000).
S39:
Biomarkers can be used for inter- and intra-individual comparisons and for studies
of time-trends.
S40:
Biomarkers can be used for studies of the effects of personal protection equipment.
S41:
Biomarkers cannot at present be used for the assessment of outcome, in terms of
health effects, due to lack of knowledge.
S42:
Biomarkers are determined in samples taken after exposure. This makes it possible
to analyse samples taken by the initiative of the individual worker, physician or
industrial hygienist.
S43:
If peak exposures are significant for the outcome of exposure to isocyanates,
biomarkers may have a poor relation to outcome.
4.5
S44:
Issues for further research
The methods for analysis of biomarkers should be standardised.
17
S45:
The relationships between biomarkers and levels of isocyanates in air should be
further evaluated.
S46:
The relationship between biomarkers and outcome, in terms of health effects,
should be evaluated in prospective studies.
S47:
The relationship between dermal exposure and levels of biomarkers should be
studied
5.
S48:
Risk assessment
There is sufficient information on isocyanate-related diseases to base
comprehensive preventive actions; we however encourage continuing research
work in the field as several aspects of the association between exposure to
isocyanates and respiratory health warrant further work.
S49:
The risks related to the handling of isocyanates should be investigated and
evaluated, in order to form the basis for decisions on control measures.
S50:
When needed, measurements of isocyanates should be done in order to assess
exposure and to form the basis for decisions on control measures.
S51:
Exposure to thermal degradation products constitutes a challenge regarding both
risk assessment and risk management. These products may be a more serious
problem than other exposure to isocyanates but their extent and levels are not
known. Many of the exposed are not aware that they are, or have been, exposed
(Karlsson et al 1998, Karlsson et at 2000 b, Karlsson et al 2001, Skarping et.al.
Appendix 11.2.3). When exposure to thermal degradation products is possible,
worker health surveillance is needed. These programs need to be well designed
and carefully executed whenever processes involve heating, abrasion, sawing, etc.,
of isocyanate derived materials.
S52:
Although there may be genetically determined variability in susceptibility,
prevention strategies should have the objective of preventing disease in all nonsensitised workers exposed to isocyanates (Piirila et al 2001, Wikman et al 2002).
5.1
Dose-Response assessment
There are reports on dose-relationships on irritation as well as on primary sensitisation by
exposure to diisocyanates, but data on primary sensitisation are few and insufficient (Karol
1986, Arbetslivsinstitutet 2001).
Aliphatic low-molecular isocyanates such as methylisocyanate and isocyanic acid have not
been shown to have specific sensitising properties (Beckett 1998, Cullinan et al 1997, Kamat
et al 1992). The reported adverse effects of mono-isocyanates are toxic and irritant, and
include asthma (S19).
18
5.1.1 Estimation of a safe exposure level for the sensory irritation effects
It has been shown that, for a number of volatile substances with irritation in the eyes and
upper respiratory tract as the critical effect, the ACGIH TLV correlates well with 0.03 x
RD50, where RD50 is the concentration causing a 50% decrease in respiratory rate in mice
(Alarie & Luo 1986, Alarie 1987, Schaper 1993). The RD50 of MIC has been reported to 2.9
ppm (ICR mice, 30-min exposure, Janes et al 1987) and 1.3 ppm (Swiss-Webster mice, 90min exposure, Ferguson et al. 1986). Applying the 0.03 x RD50 correlation, these data
suggest that exposures below 0.04 ppm will not cause irritation in the eyes and upper airways
of humans. MIC possesses other toxicological properties, including pulmonary irritation
(Ferguson et al. 1986) and corrosive effects on eyes, skin and respiratory tract (Kamat et al
1992, Cullinan et al 1997, Beckett 1998). These effects must also be controlled. For
comparison, the OEL for MIC is 0.005 ppm in Denmark and Norway, whereas the TLV is
0.02 ppm.
INCHEM has published a document on MIC: Occupational exposure limits (OELs): TLV (as
TWA): 0.02 ppm; 0.047 mg/m3 (skin). Based on acute corrosive effects on the eyes, skin and
respiratory tract and long term effects that may cause skin sensitisation
http://www.inchem.org/documents/icsc/icsc/eics0004.htm.
These data and considerations indicate that the level of the exposure limit for MIC in any case
should be kept at the same order of magnitude as for diisocyanates.
6. Risk management/Foundation for decisions/Decision models
Exposure control is the ultimate object and condition for risk management (either through
substitution or engineering controls supplemented by personal protective equipment when
essential). There is sufficient information on isocyanate-related diseases to base
comprehensive preventive actions; we however encourage continuing research work in the
field as several aspects of the association between exposure to isocyanates and respiratory
health warrant further work (S48).
6.1
S53:
General principles
Risk communication in form of education, written information, dialogues on risk
in different settings, is generally considered as the most important tool for risk
management (Wallerstein 1992, Israel et al 1994, Johnson 1997, Arbeidstilsynet
2001, WHO 2002). All parties that are involved in decisions regarding handling of
products that may emit isocyanates, should be informed about the potential health
risks and how to manage them.
S54:
S51: Exposure to thermal degradation products constitutes a challenge regarding
both risk assessment and risk management. These products may be a more serious
problem than other exposure to isocyanates but their extent and levels are not
known. Many of the exposed are not aware that they are, or have been, exposed
(Karlsson et al 1998, Karlsson et at 2000 b, Karlsson et al 2001, Skarping et.al.
Appendix 11.2.3). When exposure to thermal degradation products is possible,
worker health surveillance is needed. These programs need to be particularly well
designed and carefully executed whenever processes involve heating, abrasion,
sawing, etc., of isocyanate derived materials.
19
S55:
S52: Although there may be genetically-determined variability in susceptibility,
prevention strategies should have the objective of preventing disease in all nonsensitised workers exposed to isocyanates (Piirilä et al 2001, Wikman et al 2002).
S56:
S49: The risks related to the handling of isocyanates should be investigated and
evaluated, in order to form the basis for decisions on control measures.
S57:
S50: When needed, measurements of isocyanates should be done in order to assess
exposure and to form the basis for decisions on control measures.
S58:
Substitution is the primary control measure to be considered. Substitution includes
both changes in products and processes. The effects of substitution should be
evaluated.
S59:
If the use of isocyanates cannot be avoided, less volatile isocyanates should be
chosen. This argument should not however lead to a false sense of safety and
inadequate protection.
S60:
Intervention by reducing actual exposures has been shown to have a decisive effect
on risk reduction and has to be the primary option for technical management of
risk of exposure to isocyanates.
S61:
Skin contact can cause skin sensitisation and may be a risk factor for respiratory
disease and should be avoided (Karol 1986, Petsonk et al 2000, Låstbom et al in
press).
S62:
If isocyanates are to be used, appropriate control measures to reduce both
inhalation and skin exposure should be undertaken.
S63:
Significant exposure to isocyanates should be restricted to a specific area and to a
minimum number of people.
S64:
When other control measures are not suitable or do not give enough protection,
personal protection equipment (PPE) is needed. PPE should only be used in
conjunction with other control measures and not be relied on as the sole control
measure. PPE should be appropriate for the task and used only as part of a
comprehensive programme including education and fit testing (Williams et.al.
1999).
S65:
Incidents such as spills and removal of spills using heat may cause peak exposures
to isocyanates and should therefore be avoided. If such incidents occur, safe
procedures, which should be decided in advance should be applied.
S66:
Written handling and safety instructions necessary for the work shall be adapted to
the work and shall be kept available at the workplace.
6.1.1
S67:
Products:
Many products contain PUR and thus constitute a potential risk; particularly if
they are heated above 150-200oC. There is a need for providing information
related to these products.
20
6.2
Societal responsibilities and options
6.2.1 Health based exposure limits
Recently, the toxicology of several isocyanates has been reviewed (Appendix 11.3.6).
S68:
There should be an effort to establish and revise occupational exposure limits
(OELs) for exposure to the various isocyanates (EUR 19253 EN). These should
include indications of exposure levels at which there have been no observed
adverse effects (NOAEL). Because of the potential importance of short-term peak
exposures, short term exposure levels (STEL) should also be established. Lowest
observed adverse effect level (LOAEL) will depend on the adequacy of available
data. For asthma-causing agents, data on which to base a LOAEL are rarely
available. It is however possible to establish levels under which no case has been
reported. Once primary sensitisation has occurred, it is not possible to identify a no
effect level.
S69:
TLVs must be based on prevention of primary sensitisation. It is not possible to set
levels that can protect those that have acquired specific hypersensitivity to
isocyanates.
6.2.2 Risk communication
S70:
Education (“risk communication”) is an important risk management tool for all
potential exposed groups to raise awareness of risk and protective action. This has
been proved effective for reducing the risk of isocyanate asthma (refer to S52)
S71:
There should be a system of reporting adverse effects of exposure to sensitisers, to
a central public registry that can inform the parties involved
S72:
Data from the occupational asthma notification system should be systematically
used in communication of risk
S73:
Any isocyanate content of a product should be identified on the safety data sheet
S74:
Any ability of a product to liberate isocyanates after heating should be identified
on the safety data sheet.
S75:
Producers of products containing, or potentially liberating, isocyanates, should
make their toxicological information generally available.
S76:
Use of pre-polymerised isocyanates and isocyanate adducts may lead to unjustified
reduced awareness of risk.
6.2.3 Labelling, Safety Data Sheets (SDS) as means for risk communication
S77:
Any residual isocyanate content of a product should be identified and stated on the
SDS as well as on labelling. This includes e.g. the presence of residual momoners
in prepolymers and polyisocyantes. Di-isocyanates are potent sensitisers that may
provoke serious asthmatic reactions at very low concentrations. This must be taken
into considerations when applying the criteria for labelling on the SDS.
21
S78:
Any ability of chemical products including the materials produced from them to
liberate isocyanates when heated, should be stated on the SDS.
S79:
Lists of substances causing asthma (van Kampen 2000,
http://www.remcomp.com/asmanet/asmapro/agents.htm) may be of use for
warning about risks. There are however other isocyanates not on the list that can
cause disease.
6.3
Responsibilities and options for the enterprises
6.3.1 Management systems
(Internal control, Quality assurance of Health, Safety and Environment (HSE))
S80:
Management systems are a systematic way of dealing with hazards, that will
contribute to controlling risks with isocyanates.
S81:
There are difficulties in implementing and maintaining management systems,
especially in small companies.
6.3.2 Avoidance of exposure (in order of priority)
6.3.2.1 Method substitution (change of process) and substitution
S82:
Survey and investigate the possibilities of replacement. This comprises
• Replacement or change of methods, which involves identification of other
methods that can solve the problems concerned and may make it possible to
eliminate or reduce risks in the working environment.
• Replacement by completely different products.
• Perform risk assessment comparing different isocyanates or alternative
chemical substances, for instance epoxy and acrylate systems. It is evident that
there are large differences in risks between these, but they are insufficiently
documented
S83:
In principle substitution is a good option. However, evidence should be available
that the substituted material has a health advantage. Current evidence suggests that
poly-isocyanates should be subject to the same controls as di-isocyanates.
S84:
Substitution with epoxy must be considered in connection with possible skin effect
and respiratory effects of acid anhydrides and low molecular amines.
6.3.2.2 Technical solutions and requirements to avoid exposure
S85:
Source control (e.g. encapsulation) is needed, general ventilation (dilution) is
generally not sufficient.
6.3.2.3 Personal protective equipment (PPE)
S86:
Use of PPE should be confined to situations where other means to avoid exposure
are not feasible or to provide an increased margin of protection after adoption of
adequate engineering controls.
22
S87:
High-pressure equipment should then be used when possible.
S88:
Air purifying respirators can also give adequate protection provided sufficient
airflow for the workload, and use of relevant filters (combined aerosol-charcoal
filters).
S89:
Ordinary filter masks will not give sufficient protection, mainly because of
leakage, but may be useful as a supplement to other effective control measures.
S90:
Skin protection proved impenetrable to isocyanates is necessary.
6.3.2.4 Surveillance programs
S91:
Health surveillance programs should be conducted in conformance with high
ethical and quality standards including appropriate attention to data quality
assurance, data storage, worker notification of results, confidentiality, and
assurance of access to referral resources.
S92:
Health surveillance programs can be effective for secondary prevention (Tarlo et al
1997). They should include all potentially exposed workers:
• They should primarily be based on questionnaires but may also include lung
function test when there are communication problems or need to pick up nonsymptomatic workers.
• If positive outcome they should be referred to somebody having competence in
occupational asthma
• Questionnaires are rather sensitive but non-specific
S93:
Health surveillance information should be correlated with ongoing exposure data
to identify targets for control. However, strict control of workplace exposures
should not await the demonstration of adverse effects in the particular workforce.
S94:
Health surveillance programs should be directed toward referral for early
diagnosis. Upon confirmation of diagnosis, removal from additional exposure is
essential for limiting long-term morbidity (Pisati, 1993; Paggiaro, 1984, Lemiere,
1996, Chan-Yeung & Malo 1999).
General standards for the management of occupational asthma in the workplace
Consensus statements (modified after World Asthma meeting Barcelona 1999).
S95
Workers exposed to isocyanates should be offered both active health surveillance
and education to encourage early recognition and reporting of symptoms
consistent with occupational asthma. Workers with such symptoms should be
referred rapidly for more definitive evaluation.
S96
Efforts should proceed rapidly to confirm, objectively, a diagnosis of occupational
asthma before worker relocation. The objective confirmation process should
proceed immediately and rapidly on reasonable suspicion that occupational asthma
may have developed, and in no instance should take longer than 12 months from
onset of symptoms to conclude.
23
S97:
An affected worker should be relocated away from exposure to the causative agent
as soon as possible.
It was proposed to add “..and latest within 12 months of the first symptom of occupational
asthma” because this relates to the minimum realistic time between health assessment
contacts in a health surveillance scheme. Risk for permanent disability of asthma is
significantly increased if the duration of exposure is longer. It is the experience of clinicians
in the field that subjects with symptoms for less than 12 months are more likely not to suffer
permanent disability than subjects who have experienced symptoms for a longer interval.
Binding up resources in the occupational health by demands of too frequent health assessment
contacts in the surveillance scheme should be avoided and rather used on risk communication
and environmental risk assessments. The best way to identify persons that have emerging
symptoms of asthma may be to inform them to consult the occupational health service in case
such symptoms should occur. This is dependent on good education and risk communication
with the potentially exposed workers.
S98:
The affected worker should be left with worthwhile employment without loss of
current or future pay.
S99:
The risk assessment should be revised after the documentation of a new case of
occupational asthma
7.
Research needs
S100:
The importance of peak exposures compared to average exposures in causations of
asthma and other respiratory effects (Karol 1986, Petsonk et al 2000)
S101:
Multiple irritation incidents as causes of asthma
S102:
Studies of exposures and response relationship
S103:
Sensitisation by skin exposure (Karol 1986, Petsonk et al 2000)
S104:
Isocyanic acid, including assessment of RD-50 (a project is in progress in Umeaa,
Sweden, performed by the FOI/Swedish Defence Research Agency).
S105:
S31: There will be a need for more cost-effective and user-friendly methods for
measuring isocyanates. We note the need for an accurate and practical continuous
exposure monitoring system that is useful for all commercially important
isocyanate products.
S106:
S32: Research should also be directed at methods for determining short-term high
exposures and for assessing dermal exposure.
S107:
S44: The methods for analysis of biomarkers must be standardised.
S108:
S45: The relationships between biomarkers and levels of isocyanates in air must be
further evaluated.
24
S109:
S46: The relationship between biomarkers and outcome, in terms of health effects,
should be evaluated in prospective studies.
S110:
S47: The relationship between dermal exposure and levels of biomarkers should be
studied.
8.
Recommendations
S111:
S1: This report is based on publicly available information judged by the invited
experts present to be reliable. Some highly relevant data may be held privately and
there is information that other studies have been conducted, and not published,
which could clarify many of the questions we are posing regarding isocyanates,
their prevalence and effects. Publication of such studies would be of great use in
risk assessment as foundation for rational management of risk. We urge
publication of all relevant information in order to improve understanding and
prevention.
S112:
S48: There is sufficient information on isocyanate-related diseases to base
comprehensive preventive actions; we however encourage continuing research
work in the field as several aspects of the association between exposure to
isocyanates and respiratory health warrant further work.
S113:
S51: Exposure to thermal degradation products constitutes a challenge regarding
both risk assessment and risk management. These products may be a more serious
problem than other exposure to isocyanates but their extent and levels are not
known. Many of the exposed are not aware that they are, or have been, exposed
(Karlsson et al 1998, Karlsson et at 2000 b, Karlsson et al 2001, Skarping et.al.
Appendix 11.2.3). When exposure to thermal degradation products is possible,
worker health surveillance is needed. These programs need to be particularly well
designed and carefully executed whenever processes involve heating, abrasion,
sawing, etc., of isocyanate derived materials.
S115:
S52: Although there may be genetically determined variability in susceptibility,
prevention strategies should have the objective of preventing disease in all nonsensitised workers exposed to isocyanates.
S116:
S68: There should be an effort to establish and revise occupational exposure limits
(OELs) for exposure to the various isocyanates. These should include indications
of exposure levels at which there have been no observed effects (NOAEL).
Because of the potential importance of short-term peak exposures, short term
exposure levels (STEL) should also be established. Lowest observed adverse
effect level (LOAEL) will depend on the adequacy of available data. For asthmacausing agents, data on which to base a LOAEL are rarely available. It is however
possible to establish levels under which no case has been reported. Once primary
sensitisation has occurred it is not possible to identify a no effect level.
25
9.
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26
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34
10.
Appendices
10.1
Previous consensus statements
10.1.1 Nordic statements (Bakke 2001)
The term isocyanates includes monomers as well as prepolymers.
Sensitising properties have only been shown in di- and higher isocyanates, not
by exposure to methylisocyanate or other monoisocyanates.
Demands should be made on training of workers that may be primary or
secondary exposed to isocyanates (thermal decomposition, welding, soldering,
and grinding of polyurethane surfaces).
Secondary exposure could be a more serious problem than primary exposure
because extent and level are not known and many of the exposed do not know
that they are, or have been, exposed.
Secondary exposure constitute a serious challenge regarding risk assessment as
well as risk management
Primary exposure seems to be under reasonably good control in terms of the
authorities’ responsibility. Possible effects of skin exposure may represent an
exception.
Handling of uncured isocyanates should not involve any exposure to skin owing
to irritative effects, possible airways-sensitising effects by skin exposure and
the risk for uptake through skin at conceivable system-toxic levels.
It is need of applying new exposure assessment methods, particularly in cases
of mixed exposures comprising gas- as well as particulate matter
10.1.2
Isocyanates in Working Life (Levin et al 2000). Conclusions
Approximately 20 scientists in the field from Europe and the US participated in the
meeting which concluded that:
Isocyanates result in more reported cases of occupational asthma and similar
respiratory disorders, than any other group of chemicals. Industrial uses of
isocyanates include manufacture of polyurethane foam, surface coatings,
adhesives and textiles, and occupational exposure can occur, particularly in
processes involving heating and spraying isocyanates.
Most countries have adopted occupational limit values based on monomeric
isocyanates. However, polyisocyanates (diisocyanate polymers or prepolymer
adducts with polyamines) and low molecular weight isocyanates (such as
methylisocyanate) are also used or can occur industrially. Toxicological
evidence suggests that they should also be included in setting appropriate
harmonised limit values.
Methods exist for the determination of airborne isocyanates. These are mostly
complicated, expensive, and require a high degree of technical competence.
There is a need for simpler, more cost-effective methods. This would facilitate
monitoring by Small and Medium Sized Enterprises (SMEs).
There is a need for the further development of sampling and analytical methods
for isocyanates, particularly airborne, but also for dermal exposure and
biological monitoring. Where possible, such methods should be simple and
cost effective, and distinguish between vapour and particulate isocyanates.
Sampling and analysis methods should be supported by validation (such as
according to EN 482), quality control, quality assurance and certified reference
materials.
35
-
-
-
-
-
-
The relative toxicity and metabolism associated with health effects of different
isocyanate species should be further investigated in particular connection with
setting limit values and improving biological monitoring. The parent
compounds and metabolites may be genotoxic or carcinogenic, in addition to
having allergenic potential. The metabolism of aromatic and aliphatic
isocyanates has not been studied in detail. There is also a lack of
epidemiological studies on isocyanate workers. Therefore, it is strongly
recommended that such investigations are carried out.
Cases of occupational asthma have been observed where no measurable
isocyanate in air were identified, implying a deficiency in the sampling and
analytical methods used and/or an incorrect limit value and/or exposure via
routes other than inhalation. For this reason, air measurements should be seen
as part of an occupational hygiene assessment that might also include estimates
of surface contamination, skin absorption and/or biological monitoring and
health surveillance.
In cases where isocyanate exposure cannot be prevented by substitution or
minimised by engineering controls, and is controlled by the use of personal
protective equipment; particular attention should be paid to the correct
selection, maintenance and use of such personal protective equipment.
There is debate about the current levels of exposure using available
technologies and methods. All too often measurements are infrequent,
governed by the requirements of law. Occupational hygienists should be
encouraged to do more assessment.
There is a discussion of prevention, as opposed to monitoring. There is an
opportunity to address this issue for politicians. What is wanted is control of
the environment, rather than the requirement to dress up workers in special
clothing. Regular monitoring can reduce the incidence of exposure,
accompanied by health surveillance.
There are difficulties in predicting particular problems in individual
workplaces. There is a need for improved education and communication.
International practice is already affected by requirements of environmental
legislation, such as requirements of the US Environmental Protection Agency,
as it affects the workplace; there can be obligations to report when particular
materials are in use.
36
10.2
Introductory presentations on the meeting
10.2.1 Isocyanate-induced respiratory health effects
Ute Latza, Xaver Baur, Institute for Occupational Medicine,University of Hamburg,
Hamburg, Germany
Jean-Luc Malo, Université de Montréal and Hôpital du Sacré-Coeur, Montréal,
Canada
1. Introduction on occupational asthma
The definition of occupational asthma (OA) that has been retained in one textbook on
the subject is as follows:
“Occupational asthma is a disease characterized by variable airflow limitation and/or
airway hyperresponsiveness due to causes and conditions attributable to a particular
occupational environment and not to stimuli encountered outside the workplace. Two
types of occupational asthma are distinguished by whether they appear after a latency
period: 1. Immunological (...); 2. Nonimmunological (...)...(1).”
In the case of the immunological type, there is a latency period, and the immunological
mechanism has been identified for most high- and for some low-molecular-weight agents. The
nonimmunological type encompasses irritant-induced asthma (IrIA) or Reactive Airways
Dysfunction Syndrome (RADS), which may occur after single (RADS) or multiple exposures
to high concentrations of nonspecific irritants.
Asthma currently represents the most frequent respiratory occupational ailment. A
cause in the workplace is to be suspected in 5 to 10% of all cases of adult-onset asthma (2)
(3). From the pathological point of view, OA has the same consequences as common asthma,
specifically, airway inflammation and remodeling. The diagnosis is based on a step-by-step
approach that incorporates several tools (4) (5). Questionnaires on respiratory symptoms have
a high sensitivity but low specificity (6). Immunological assessment helps to detect
sensitization, but sensitization does not equate to the disease. Evaluation of airway caliber and
responsiveness can confirm that asthma exists and is present or worsens at work. Specific
inhalation challenges with serial physiological monitoring, with recently proposed monitoring
of the status of airway inflammation through non-invasive means (induced sputum, exhaled
NO) represent the gold standard for confirming the diagnosis. There are long lists of
occupations and agents at risk of causing OA (agents noted as R 42 by the European Union)
(7). Useful lists are available on Web sites (asmanet.com; asthme.csst.qc.ca). The natural
history of OA is characterized by the persistence of asthma symptoms and increased airway
responsiveness in the majority of cases after removal from exposure. Early removal from
exposure is the key for a better prognosis, therefore justifying surveillance programs in highrisk workplaces. This medicolegal condition is not satisfactorily compensated in most
countries.
2
Isocyanates and respiratory health
The risk potential of isocyanates for respiratory health was recognized early (8). The
reactive -N=C=O groups react, among others, with NH2 and OH groups, especially in the
presence of catalysts, and are able to alter cellular proteins. This may lead to hypersensitivity
reactions (9), irritations and diseases of skin, eyes, airways, and lungs. Four specific types of
ailments to respiratory health from isocyanate exposure can be identified as reviewed (10)
(11):
37
1.
2.
3.
4.
Occupational asthma (OA) with a latency period (1) (12)
OA without a latency period (Irritant-Induced-Asthma and RADS) (13)
Hypersensitivity pneumonitis or extrinsic allergic alveolitis (EAA)
Chronic obstructive lung diseases.
Hypersensitivity pneumonitis reactions are self-limited and occur relatively
infrequently (14) (15). The development of chronic obstructive lung diseases was reported by
Baur (15) (see Table 1). However, the long-term effect of exposure to isocyanate on FEV1
decline, the key functional marker of COPD, is still controversial (see below). This review
will mainly focus on the first two types of isocyanate-induced airway involvement.
Table 1: Frequencies of clinical diagnosis in isocyanate workers with work-related symptoms (Baur and
coworkers, 1994, reference no.17)
_________________________________________________________________
Number of workers with symptoms / Total Number of workers: 247 / 621 (38%)
Bronchial asthma
153 (62%)
Chronic obstructive pulmonary disease (COPD)
26 (11%)
Nonobstructive bronchitis
43 (17%)
Rhinitis
42 (17%)
Conjunctivitis
26 (11%)
Urticaria, Erythema
7 (3%)
Eczema
5 (2%)
Fever
6 (2%)
Extrinsic allergic alveolitis (EAA)
4 (2%)
__________________________________________________________________
A significant proportion of the literature on OA is related to isocyanates, and the
interested reader is referred to summary accounts (10) (12) and reviews of recent literature
(16).
2.1.
Frequency
2.1.1. Information from case series, and health surveillance
Health surveillance of exposed workers provides indications of the health hazard of
isocyanates. Asthma is a frequently described sequelae of isocyanate exposure. The
evaluation of 247 cases with work-related symptoms occurring in the German isocyanateprocessing industry shows asthma to be the most frequent diagnosis (17) (Table 1). Chronic
obstructive pulmonary disease (COPD), non-obstructive bronchitis, and rhinitis--common
disorders in the general population--were less frequently found in connection with isocyanate
exposure.
In a case series of patients who were undergoing inhalative workplace exposure tests,
positive skin-prick results, nasal reactions, and particularly specific IgE were strongly
associated with isocyanate-specific bronchial reaction (Table 2). However, the majority of
subjects (85%) who had an asthmatic reaction during the workplace simulation challenges
with isocyanates showed no specific antibody reaction. Hypersensitivity reactions have been
observed mainly with both aliphatic and aromatic oligo-, and polyisocyanates but also with
monoisocyanates (18). In subjects with isocyanate asthma due to an exposure to TDI, MDI or
HDI, cross-reacting IgE antibodies to MIC and PI have been described (19).
38
Table 2: Association of asthmatic response after inhalative workplace-related exposure with MDI and
isocyanate-specific IgE antibodies in a case series of MDI-exposed workers with suspected
isocyanate asthma (N=166) (Baur, Latza, Barbinova, personal communication)
Skin prick test:
weal > 3 mm
weal < 3 mm
Isocyanate-specific IgE: > 0.35 kU/L
(CAP system)
< 0.35 kU/L
Frequency of asthmatic response
Percent
Odds Ratio
(95% confidence interval)
76.2%
11.8%
7.5 (2.6-21.6)
1 (reference)
58.8%
41.2%
24.0 (7.7-74.4)
1 (reference)
Hypersensitivity pneumonitis occurs in only about 1 to 2% of affected subjects. In
these individuals, increased specific IgG antibodies have been consistently detected.
RADS that has been described in case reports as reviewed, (13) represents a particular
subunit of irritant-induced asthma, namely the form that originates from a single incident with
very high concentrations (20). Persistent airway obstruction and hyperresponsiveness were
found among methyl-isocyanate (MIC)-exposed survivors of the Bhopal disaster (21) (22).
RADS represents 10 to 15% of all cases of OA according to medicolegal statistics from
Ontario, Canada (23).
In Germany, there is a mandatory medical surveillance program for all (primary
exposed) isocyanate workers (G 27) that includes work history, anamnesis, physical
examination performed by qualified physicians and lung-function tests every two to three
years (more than 20 000 examinations annually).
2.1.2. Epidemiological studies on symptoms and signs
Numerous descriptive epidemiological studies show an increased prevalence of
asthma and workplace-related airway complaints. The prevalence of respiratory symptoms,
airway responsiveness, and diagnosed occupational asthma in different studies varies to a
large extent depending on the outcome variable, the level of exposure, the selection of the
study population, and the reference group. In some studies prevalences up to 36% (24) or
even 68% (25) have been observed. Due to the healthy-worker effect, the information
obtained by cross-sectional investigations into the chronic effects of isocyanates is limited. In
longitudinal studies, the annual incidence of occupational asthma in a study conducted by the
chemical industry (26), and within a steel coating plant (27) was between 0.7% and 1.8%. The
incidence of asthma-like symptoms in a wood product plant ranged from 0 to 15% depending
on the exposure level (28).
2.1.3. Longitudinal studies on lung function
We could identify 20 longitudinal studies on lung function changes in diisocyanateexposed workplaces from the literature (reviewed by Latza and Baur in 2001 (29)). The
follow-up ranged from one to nine years. The quality of studies varies and the results are not
uniform.
In most studies, the number of study participants or subjects in subgroups was
relatively low. In particular, some of the older investigations lack data on appropriate
comparative groups, information on selection and characteristics of the study group or
information on exposure of the control group to airway-irritating or sensitizing substances
(including isocyanates). In most retrospective studies, two lung function measurements in
39
consecutive examinations are a prerequisite of being included in the study group. As a
consequence, workers who had left the company due to isocyanate-induced asthma were not
included. Even the results of more recent studies (30) (31) show a bias towards risk
underestimation. More than 40% of subjects participating in the newer studies were lost to
follow-up (32-34). With the exception of the investigations by Jones and coworkers (34)and
Clark and coworkers (33), there is little information on whether occupational asthma was the
reason for it. Age above 55 years, breathlessness, and wheeze were significant factors for
losses to follow-up in a study within the TDI foam production (33).
Information bias is a problem in most of the studies. If lung function measurements
were undertaken for routine purposes, the quality assurance measures did not necessarily meet
consensus criteria (corresponding to the one proposed by the ATS). The exposure assessment
was insufficient in most studies. In addition to known problems in ambient monitoring, the
numbers of measurements, if available, were generally low and the applied detection methods
prone to error. Continuous individual measurements were rare. Biological markers of
isocyanate exposure were not determined.
While in most studies lung function parameters were on the average not below the
reference values or not below those of the control group, four authors reported deteriorated
lung functions (34-37). Four additional studies demonstrated exposure-dependent lung
function declines (32, 38-40). Other studies did not detect such effects (26, 34, 41) Several
investigations showed individual differences or stronger effects on smokers and subjects with
pre-existing lung deteriorations, e.g., two newer studies within the TDI production (26, 33).
Although annual FVC and FEV1 decline were not associated with exposure, the subgroup of
subjects with first TDI exposure showed a significant association with the average daily TDI
exposure (33). In the other study, the average annual change in lung function in males was not
exposure-dependent (26). However, in the few females studied, annual change in FEV1
among exposed females was significantly higher than in controls.
2.1.4. Registration of work-related respiratory disorders
A statement about the actual prevalence of isocyanate exposure within the workforce
is not possible because of incomplete? registration of workers exposed to isocyanates.
According to figures based on assumptions, about 200,000 workers and 18,000 to 50,000
workers are estimated to be exposed to isocyanates in the US and Germany, respectively.
Most secondary exposures are not included.
In 1993, isocyanate-induced diseases were included in the German list of occupational
diseases (No 1315). More than 100 isocyanate-induced cases are reported each year to the
statutory accident insurance institutions of the industrial sector (Gewerbliche
Berufsgenossenschaften). Approximately half of them are recognized as occupational diseases
mainly emanating from the metal, chemical and construction industries.
In Switzerland about 54 new cases of isocyanate-induced OA are compensated each
year (42). The figures for Germany have remained relatively stable with over 50 recognitions
annually (Table 3). In the United Kingdom, more than 100 cases of suspected isocyanateinduced occupational asthma are reported per year. Since the changes in the SWORD system
in 1990 that have lead to an increase in the total number of reported cases, the percentage of
isocyanate asthma in relation to all suspected cases of occupational asthma decreased from
22% to 14% (Table 3). In Québec and in Finland the number of suspected and confirmed
cases of OA due to isocyanates has dropped during the last few years (Table 3) (Henrik
Nordman, Finnish Institute of Occupational Health, personal communication). For example,
in Québec, the number of cases has gone from 17 to 24 a year for the period 1988-1993 to 7 to
40
11 a year for the period 1994-2000. Several countries regard isocyanates as the main cause of
occupational asthma (Table 4). In Germany, probably because of the existence of many small
bakeries, flour dust is ranking highest. A statement about the actual prevalence and incidence
of an occupational disease in Germany is not possible because of the above-mentioned
missing data on the number of exposed subjects, selection effects during the registration of
occupational diseases, and a reservation in the wording of the law resulting in an
underestimation of the number of concerned subjects (e.g., the abandonment of activities
causing the isocyanate-induced disease is required for the recognition of this occupational
disease in Germany).
Table 3: Incidence of isocyanate-induced occupational diseases by country and time period
Canada, Quebec:
Workers’ Compensation
Board1
Germany: Industrial
Statutory Accident
Insurance Institutions2
United Kingdom:
SWORD3
Finland: Finnish Registry
of Occupational Diseases4
Year Number of
recognitions of
occupational
asthma
Year Number of
isocyanate-induced
diseases:
Period
Period Number of
recognitions of
occupational
asthma
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
1988-99:
17
17
18
23
16
24
8
7
11
7
8
9
165
claims recognitions
1993
115
1994
131
1995
120
1996
114
1997
107
1998
127
1999
108
1993-99: 822
36
54
59
79
62
53
63
406
Number of cases
of suspected
occupational
asthma (percent
of all suspected
cases of OA)
1989-91:
336 (22%)
1992-94:
437 (15%)
1995-97:
410 (14%)
1989-97:
1183
1989-95:
103
1985-95:
103
1
Québec Workers’ Compensation Board, Québec, Canada
Report on business results of Industrial Statutory Accident Insurance Institutions, German Federation of
Industrial Statutory Accident Insurance Institutions, 1994-2000, Hauptverband der Gewerblichen
Berufsgenossenschaften (HVBG), St Augustin, Germay
3 reference no. 43
4 reference no. 44
2
Table 4: Incidence of Occupational Asthma (adopted from Karjalainen and coworkers 2000, reference
no.44)
Country, year
Source of data
Finland, 1989-95
Physician’s reports + compensation scheme
Sweden, 1990-92
Self-reported
Germany, 1995
Compensation scheme
France, 1996
Physician’s reports
USA, Michigan 1986-94
Physician’s reports + other sources
Canada, B.C., 1991
Physician’s reports
Canada, Quebec, 1986-88
Compensation scheme
UK, West Midlands 1990-97
Physician’s reports
UK, 1989
Physician’s reports
*Diisocyanates were the causative agents in 5% of the cases
41
Most common causative agent
(% of all)
Animal epithelia (38%)*
n.d.
Flour dust (40%)
Flour dust (20%)
Isocyanates (25%)
Red cedar (42%)
Isocyanates (25%)
Isocyanates (13%)
Isocyanates (22%)
According to a Canadian study, significantly more claims of isocyanate-induced
occupational asthma occurred in companies with a maximal workplace concentration of at
least 5 ppb than in companies with lower concentrations (45). These findings are in agreement
with our opinion based on our case series. Frequently, asthmatic reactions below the OELs in
Germany (5 or 10 ppb, depending on the type of monomeric diisocyanate, respectively can be
found after sensitization (46). These data indicate that avoidance of peak exposures and shortterm exposure levels below 5 ppb would reduce the frequency of isocyanate asthma
dramatically.
The results from diisocyanate exposure tests in “naive” subjects (healthy and
asthmatic controls) indicate that the response to isocyanates at low exposure levels (10-20
ppb) is rarely due to a non-specific bronchial hyperreactivity. After a single exposure to 10
ppb of TDI over 1 hour, none out of ten healthy controls without hyperreactive airways had an
asthmatic response and responded with a 100% increase of airway resistance amounting to
values > 0.5 kPa/l/s (17). One out of 15 asthmatic controls without previous occupational
exposure to isocyanates responded to 10 pbb (Figure 1A). After an interval of 45 minutes
followed by a second exposure to 20 ppb over 1 hour, one out of the remaining 13 asthmatic
controls had an asthmatic response (the asthmatic responder in the first challenge and a
subject who refused a second challenge were not tested) (Figure 1B).
Figure 1
Bodyplethysmographically measured airway resistance (Raw) before and after exposure to TDI in asthmatic
hyperreactive controls (criterion of bronchial hyperreactivity: PD100 Raw <0.1 (●) / 0.1-0.4 (Ο) / 0.4-1 (∆) mg
acetylcholine)
0,9
0,7
Raw (kPa·l-1·s)
Raw (kPa·l-1·s)
0,9
0,5
0,5
0,3
0,3
0,1
0,7
Rest
TDI, 20 ppb; 60 min
0,1
Rest
TDI, 20 ppb; 60 min
post TDI
45 min
B
A
42
post TDI
45 min
2.2. Mechanisms
Candidate gene HLA polymorphisms have recently been explored for some agents
causing OA, including isocyanates (47). An excess of HLA-DQB1*0503 (enhancing effect)
and of HLA-DQB1*501 (protective effect) have been reported as reviewed (12) but not
confirmed by other groups of researchers (48) (49). More recently, polymorphism of the
glutathione-S-transferase GSTP1 locus has been reported by two groups of researchers (50)
(51). For the time being, these findings should be interpreted as interesting avenues for
generating hypotheses (47).
Animal models of isocyanate-induced health effects have been developed. In a recent
one, Matheson and coworkers have been able to successfully induce airway
hyperresponsiveness, increased specific IgG and total IgE antibodies, influx of lymphocytes
and neutrophils and increased mRNA expression of several mediators (52). Boschetto and
coworkors have recently demonstrated a modification of the contractility of tracheal smooth
muscle following preincubation with sera from sensitized guinea pigs (53). Both eosinophils
and neutrophils seem to be involved in the reaction as found in an early report (54). Serum
neutrophilic chemotactic activity is increased after challenges (55). The discrepancies of
findings in terms of eosinophilic and/or neutrophilic influx might be related to the timing of
the examinations. It is known that neutrophilic inflammation can also occur in nonoccupational asthma..
As regards the role of antibodies, increased specific IgE antibodies are present in about
10-20% of the subjects with isocyanate-induced OA (17, 56-58) although its association with
OA seems to be specific for the disease if the level is high (RAST test score of three or more)
(59). Increase in specific IgG antibodies may reflect exposure or disease (56) (57).
Isocyanates as polymers seem to be more antigenic for specific IgG response than as
monomers (60).
Epithelial cell proteins react with isocyanates and form adducts (hapten-like nature of
the complex), enhancing lymphocyte proliferation (61). In particular, isocyanates conjugate to
(a property that has often been used for antibody assessments) and modify (62) human serum
albumin (HSA) as well as hemoglobin (63).
Evidence for absorption through the skin in causing sensitization has recently been
confirmed (64). The hypothesis for neuromodulation of the reaction through C-fiber
stimulation still warrants further work.
2.3. Clinical aspects
Symptoms in subjects affected with OA are similar to those found with common
asthma and OA induced by other agents. Initially, symptoms are only present at work but,
with time, the relationship with work is more difficult to ascertain. A unique feature of OA
induced by isocyanates is that subjects can get symptoms from exposure to minute amounts of
isocyanates. There are case reports of subjects with OA in whom the condition was induced
by indirect exposure in nearby workplaces (65). Isocyanates cause little upper airway
involvement, which is a different situation for occupational agents that act through an IgEbased mechanism (66) (67). It is also of interest that the time-course for onset of symptoms is
more rapid than for high-molecular-weight (protein-derived) agents, with approximately 50%
of workers with the disease acquiring symptoms in the first two years after starting exposure
(68). This information is relevant in terms of surveillance programs, as it supports the notion
that such programs should be implemented early after starting exposure to isocyanates.
43
Baur and coworkers have found that a combination of compatible occupational asthma history
and a positive methacholine inhalation test has a better specificity than sensitivity in
association with the results of specific inhalation challenges to isocyanates. Indeed, 74 of 84
subjects (88%) who did not have the combination of a compatible history and positive
methacholine challenge had negative challenges to isocyanates, whereas 11 of the 30 subjects
(37%) who had a combination of a positive history and a positive methacholine challenge had
positive inhalation challenges to isocyanates (69). These results indicate that specific
inhalation challenges represent the gold standard in the diagnosis of isocyanate asthma. The
study does not mention how many subjects were investigated at a time they were still at work.
The diagnosis is best achieved through specific inhalation challenges in which subjects
are exposed to isocyanates in a dose-dependent way. Closed-circuit equipment (70) now
allows for exposing subjects to concentrations of isocyanates of one ppb only, as generated as
vapor or aerosol. This allows for safe and reliable exposure. The pattern of asthmatic
reactions on exposure to isocyanates on a day-to-day progressive dose increment is not
necessarily linear, although it is most often so (71) (Figure 2). Preliminary results show that
inflammatory changes in terms of changes in eosinophils and/or neutrophils in induced
sputum can occur before functional changes occur and at concentrations of isocyanates as low
as one ppb (Table 5), therefore confirming findings obtained in a recent study where subjects
were exposed to several agents, some to isocyanates (72).
Figure 2
Shape of the dose-response curve
for progressive day-to-day exposure to diisocyanate *
linear
sudden
5
no.38
no.1
-5
Changes
in FEV1 -15
(%)
-25
-35
1
10
100
1000
10000
1
10
doses of isocyanates (ppb X min)
apparent tachyphylaxis
5
no. 15
-5
Changes
in FEV1
(%)
-15
-25
* from reference no. 71
-35
1
10
100
1000
10000
doses of isocyanates (ppb X min)
44
100
1000
10000
Table 5
control day
total
cells
(106/ml)
exposure one ppb
last day of exposure
neutros
%
eosinos
%
total
cells
(106/ml)
neutros
%
eosinos
%
total
cells
(106/ml)
neutros
%
eosinos
%
Reactors to one ppb
no. 1
3.8
no. 3
1.4
no. 4
2.5
73
22
55
0.8
0.2
1.5
114
5.5
4.2
98
60
67
0.5
0
16
ND
ND
ND
ND
ND
ND
ND
ND
ND
Reactors to 15 ppb
no. 2
no. 5
no. 6
no. 7
no. 8
23
50
81
50
50
22
1.2
2.3
7.8
0
1.1
1.1
21
0.5
1.0
68
32
78
46
49
4
0.2
2.5
6.3
0
1.2
1.3
14
16
2.3
57
54
81
52
37
5
2.5
5.5
35
0.2
1.9
1.0
22
1.8
1.0
Legend: Therefore, some subjects (nos. 1, 3, 4) can show inflammatory changes at concentrations as
low as one ppb, and even in the absence of functional changes (no.2);all subjects show changes after
reaction to 15 ppb.
From: Malo JL and Lemière C. In preparation.
2.4. Outcome and prevention
It is of the utmost importance to remove workers shortly after they start having
symptoms in order to secure them a better prognosis and a chance for a cure. In a long-term
follow-up of subjects with OA after removal from exposure, Perfetti and coworkers found that
those with OA due to low-molecular-weight agents (chemicals), including isocyanates, have a
better prognosis than those with OA due to high-molecular-weight agents (73). In the specific
instance of isocyanates, persistence of asthmatic symptoms after removal from exposure to
isocyanates was confirmed in several studies (74). The largest follow-up series of subjects
with OA due to isocyanates, which included 245 workers removed from exposure, has shown
that those with HDI-induced asthma and those with higher levels of specific IgE antibodies to
isocyanates had a more favorable prognosis (75).
Tarlo and coworkers have shown that it is possible to diminish the occurrence of OA
due to isocyanates by a combined environmental and medical surveillance program (45).
Biomonitoring of urinary isocyanate metabolites might be useful in confirming that subjects
are no longer significantly exposed to isocyanates (76-79).
3. Research needs and conclusions
Epidemiological studies have significantly contributed to the recognition of health
risks by isocyanates. According to animal experiments, isocyanate asthma may also develop
after dermal exposure in addition to the uptake by inhalation (80). However, it has not yet
been clarified as to which extent the dermal exposure of humans plays a role. Using a
semiquantitative procedure, Liu and coworkers were able to detect isocyanates in workplaces
45
and equipment of car repair shops as well as on hands, arms and faces of employees after
specific operational steps (81).
There is a need for meaningful longitudinal epidemiological studies among workers
with low exposure to isocyanates (< 5 ppb) on the incidence of isocyanate-related symptoms
and lung function changes under consideration of dermal exposure, secondary exposure due to
thermal decomposition with individual, quantitative exposure assessment to determine doseresponse relationships. A quantitative risk estimate based on epidemiological studies requires
further development of analytical methods to quantify air concentrations of isocyanates in
each state of aggregation that are realizable in the workplace and to improve biomonitoring..
Moreover, it would be of interest to conduct these studies in subjects starting exposure to
isocyanates, e.g., using a model that has been successfully proposed for other occupational
agents (82) (83). Further epidemiological studies on the carcinogenic potential of isocyanates
are also needed.
Regarding mechanisms, it would be interesting to assess the time-course of cellular
and mediator events after exposure to diisocyanates. The most relevant biologically active
antigen also needs to be identified. Improvement in diagnostic means should focus on
laboratory generation of lower concentrations of isocyanates for specific inhalation
challenges. The validity of using non-invasive tools (induced sputum, exhaled NO) for
detecting early inflammatory changes should also be assessed. Finally, the implementation
and assessment of surveillance programs in high-risk workplaces are required.
All these studies require a multidisciplinary approach from epidemiologists, industrial
hygienists, chemists and health-care practitioners.
According to our experience, further important topics regarding the prevention of
isocyanate asthma include the development of methods for ambient monitoring of all
isocyanates in all states of aggregation, the development of human biomonitoring, and
regulations with OELs for all isocyanates that include all states of aggregation.
Acknowledgments
The authors express their gratitude to Lori Schubert for revising the text.
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35. Adams WG. Lung function of men engaged on the manufacture of tolylene
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36. Tornling G, Alexandersson R, Hedenstierna G, Plato M. Decreased lung function and
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38. Peters JM. Cumulative pulmonary effects in workers exposed to tolylene diisocyanate.
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40. Diem JE, Jones RN, Hendrick DJ, Glindmeyer HW, Dharmarajan V, Butcher BT,
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41. Musk AW, Peters JM, DiBerardinis L, Murphy RL. Absence of respiratory effects in
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48
43. McDonald JC, Keynes HL, Meredith SK. Reported incidence of occupational asthma in
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45. Tarlo SM, Liss GM, Banks DE. Assessment of the relationship between isocyanate
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47. Newman-Taylor AJ. Genetics and occupational asthma. In: Bernstein IL, Chan-Yeung
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48. Rihs HP, Barbalho-Krolls T, Huber H, Baur X. No evidence for the influence of HLA
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49. Bernstein JA, Herd ZL, Munson J, Balakrishnan K, Leikauf GD. T-lymphocyte
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50. Piirila P, Wikman H, Luukkonen R, Kaaria K, Rosenberg C, Nordman H, Norppa H,
Vainio H, Hirvonen A. Glutathione S-transferase genotypes and allergic responses to
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51. Mapp CE, DeMarzo N, Pozzato V, Jovine L, Fryer AA. Polymorphism at the
glutathione S-transferase, GSTP1 locus is associated with isocyanate-induced asthma.
Eur Respir J 2000;16, suppl 31:329s.
52. Matheson JM, Lange RW, Lemus R, Karol MH, Luster MI. Importance of inflammatory
and immune components in a mouse model of airway reactivity to toluene diisocyanate
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53. Boschetto P, Jovine L, Chitano P, DeMarzo N, Plebani M, Faggian D, Fabbri LM,
Mapp CE. Serum-mediated relaxant response to toluene diisocyanate (TDI) in isolated
guinea-pig bronchi. Respir Med 2001;95:357-362.
54. Fabbri LM, Boschetto P, Zocca E, Milani G, Pivirotto F, Plebani M, Burlina A, Licata
B, Mapp CE. Bronchoalveolar neutrophilia during late asthmatic reactions induced by
toluene diisocyanate. Am Rev Respir Dis 1987;136:36-42.
55. Park HS, Jung KS, Kim HY, Nahm DH, Kang KR. Neutrophil activation following TDI
bronchial challenges to the airway secretion from subjects with TDI-induced asthma.
Clin Exp Allergy 1999;29:1395-1401.
56. Cartier A, Grammer L, Malo JL, Lagier F, Ghezzo H, Harris K, Patterson R. Specific
serum antibodies against isocyanates: association with occupational asthma. J Allergy
Clin Immunol 1989;84:507-14.
57. Park HS, Kim HY, Nahm DHo, Son JW, Kim YY. Specific IgG, but not specific IgE,
antibodies to toluene diisocyanate-human serum albumin conjugate are associated with
toluene diisocyanate bronchoprovocations test results. J Allergy Clin Immunol
1999;104:847-851.
58. Baur X, Chen Z, Flagge A, Posch A, Raulf-Heimsoth M. EAST and CAP specificity for
the evaluation of IgE and IgG antibodies to diisocyanate-HSA conjugates. Int Arch
Allergy Immunol 1996;110:332-338.
59. Tee RD, Cullinan P, Welch J, Burge PS, Newman-Taylor AJ. Specific IgE to
isocyanates: A useful diagnostic role in occupational asthma. J Allergy Clin Immunol
1998;101:709-715.
49
60. Aul DJ, Bhaumik A, Kennedy AL, Brown WE, Lesage J, Malo JL. Specific IgG
response to monomeric and polymeric MDI conjugates in subjects with respiratory
reactions to isocyanates. J Allergy Clin Immunol 1999;103:749-755.
61. Wisnewski AV, Lemus R, Karol MH, Redlich CA. Isocyanate-conjugated human lung
epithelial cell proteins: a link between exposure and asthma? J Allergy Clin Immunol
1999;104:341-347.
62. DeMarzo N, Jovine L, Rizzotti P, Cassetti P, Boschetto P, Miotto D, Saetta M,
Maestrelli P, Mapp CE. Modification of serum proteins in guinea pigs immunised and
challenged with toluene diisocyanate. Scand J Work Environ Health 2000;26:153-160.
63. Sabbioni G, hartley R, Henschler D. Isocyanate-specific hemoglobin adduct in rats
exposed to 4,4'-methylenediphenyl diisocyanate. Chem Res Toxicol 2000;13:82-89.
64. Scheerens H, Buckley TL, Muis T Leusink, Garssen J, Dormans J, Nijkamp FP,
Loveren H Van. Long-term topical exposure to toluene diisocyanate in mice leads to
antibody production and in vivo airway hyperresponsiveness three hours after intranasal
challenge. Am J Respir Crit Care Med 1999;159:1074-1080.
65. DeZotti R, Muran A, Zambon F. Two cases of paraoccupational asthma due to toluene
diisocyanate (TDI). Occup Environ Med 2000;57:837-839.
66. Malo JL, Lemière C, Desjardins A, Cartier A. Prevalence and intensity of
rhinoconjunctivitis in subjects with occupational asthma. Eur Respir J 1997;10:15131515.
67. Christiani DC, Malo JL. Upper airways involvement. In: Asthma in the Workplace.
Bernstein IL, Chan-Yeung M, Malo JL, Bernstein DI, eds. Marcel Dekker Inc., New
York 1999:331-339.
68. Malo JL, Ghezzo H, D'Aquino C, L'Archevêque J, Cartier A, Chan-Yeung M. Natural
history of occupational asthma: relevance of type of agent and other factors in the rate of
development of symptoms in affected subjects. J Allergy Clin Immunol 1992;90:937944.
69. Baur X, Huber H, Degens PO, Allmers H, Ammon J. Relation between occupational
asthma case history, bronchial methacholine challenge, and specific challenge test in
patients with suspected occupational asthma. Am J Ind Med 1998;33:114-122.
70. Vandenplas O, Malo JL. Inhalation challenges with agents causing occupational asthma.
Eur Respir J 1997;10:2612-2629.
71. Malo JL, Ghezzo H, Elie R. Occupational asthma caused by isocyanates: Patterns of
asthmatic reactions to increasing day-to-day doses. Am J Respir Crit Care Med
1999;159:1879-1883.
72. Lemière C, Chaboilliez S, Trudeau C, Taha R, Maghni K, Martin JG, Hamid Q.
Characterization of airway inflammation after repeated exposures to occupational
agents. J Allergy Clin Immunol 2000;106:1163-1170.
73. Perfetti L, Cartier A, Ghezzo H, Gautrin D, Malo JL. Follow-up of occupational asthma
after removal from or diminution of exposure to the responsible agent. Chest
1998;114:398-403.
74. Chan-Yeung M, Malo JL. Natural history of occupational asthma. In: Asthma in the
workplace. Bernstein IL, Chan-Yeung M, Malo JL, Bernstein DI., eds. Marcel Dekker
Inc., New York 1999:129-143.
75. Piirila PL, Nordman H, Keskinen HM, Luukkonen R, Salo SP, Tuomi TO, Tuppurainen
M. Long-term follow-up of hexamethylene diisocyanate-, diphenylmethane
diisocyanate-, and toluene diisocyanate-induced asthma. Am J Respir Crit Care Med
2000;162:516-522.
50
76.
77.
78.
79.
80.
81.
82.
83.
Sepai O, Schütze D, Heinrich U, Hoymann HG, Henschler D, Sabbioni G. Hemoglobin
adducts and urine metabolites of 4,4'-methylenedianiline after 4,4'-methylenediphenyl
diisocyanate exposure to rats. Chem-Biol Interact 1995;97:185-198.
Dalene M, Hakobsson K, Rannug A, Skarping G, Hagmar L. MDA in plasma as a
biomarker of exposure to pyrolysed MDI-based polyurethane: correlations with
estimated cumulative dose and genotype for N-acetylation. Int Arch Occup Environ
Health 1996;68:165-169.
Skarping G, Dalene M, Svensson BG, Littorin M, Akesson B, Welinder H, Skerfving S.
Biomarkers of exposure, antibodies, and respiratory symptoms in workers heating
polyurethane glue. Occup Environ Med 1996;53:180-187.
Williams NR, Jones K, Cocker J. Biological monitoring to assess exposure from use of
isocyanates in motor vehicle repair. Occup Environ Med 1999;56:598-601.
Karol MH, Hauth BA, Riley EJ, Magreni CM. Dermal contact with toluene diisocyanate
(TDI) induces respiratory tract hypersensitivity in guinea pigs. Toxikol Appl Pharmakol
1981;58:221-230.
Liu Y, Sparer J, Woskie SR, Cullen MR, Chung JS, Holm CT, Redlich CA. Qualitative
assessment of isocyanate skin exposure in auto body shops: A pilot study. Am J Ind
Med 2000;37:265-274.
Gautrin D, Ghezzo H, Infante-Rivard C, Malo J-L. Incidence and determinants of IgEmediated sensitization in apprentices: a prospective study. Am J Respir Crit Care Med
2000;162:1222-1228.
Gautrin D, Infante-Rivard C, Ghezzo H, Malo JL. Incidence and host determinants of
probable occupational asthma in apprentices exposed to laboratory animals. Am J Respir
Crit Care Med 2001;163:899-904.
51
10.2.2 Exposure Assessment Methods
Richard H. Brown. Health and Safety Laboratory, Broad Lane, Sheffield S3 7HQ, UK.
International Consensus Conference on Isocyanates, Norway, November 2001
Abstract: Historically, a large number of alternative methods have been devised for the
measurement of airborne isocyanates. Nearly all these methods rely on the derivatization of
the reactive isocyanate groups to products that can be analyzed, usually by some form of
chromatography. The choice of an ideal method relies partly on the requirements of the
regulatory authorities, but there are also technical considerations concerning the validity and
reliability of the various methods and the cost and availability of instrumentation. It would be
comforting if we had a consistent body of advice from the regulatory authorities concerned.
However, NIOSH (USA) recommends three methods, OSHA (USA) recommends two
methods, ASTM (USA) recommends three methods, NIWL (Sweden) recommends one
method and the HSE (UK) recommends two methods. All of these methods are different, with
the exception of the 1-(2-methoxyphenyl)piperazine (2-MP) and the 1-(2-pyridyl)piperazine
(2-PP) methods, which appear twice.
Can the International Standardization Organization help? Actually, ISO is preparing
four technical specifications. First, it has agreed a method based on the 2-MP reagent (ISO
16207, in press). Second, it is preparing a method based on the 9-(1-methylanthracenyl)piperazine reagent (ISO/DIS 17735). Two further methods, based on the
dibutylamine method and the Iso-Chek™ method have been agreed as new work items and
initial committee drafts are being written. So many alternative methods would seem
inconsistent with the ISO objective of variety reduction. The reason is that, in addition to
having different areas of application, all existing methods have some disadvantages. Thus, a
fifth (guidance) standard is being developed which will explain in more detail the advantages
and disadvantages of each method and it is hoped, will point to the development of a
genuinely universal method.
Keywords: isocyanates, air quality, measurement methods, standardization
Introduction
“WARNING - Isocyanates result in more cases of occupational asthma than any other
group of chemicals. You should only use isocyanates if there are no reasonable substitutes
available. If you do use them, you must take strict precautions. Occupational asthma is a
very serious condition triggered by breathing in isocyanate vapor or aerosols. High exposures
can occur during heating and spraying. Following this guidance closely will help you reduce
the risks.”
The above is a quotation from the Health and Safety Executive (HSE) Guidance Note
EH16 [1] on Isocyanates, Health Hazards and Precautionary Measures. This indicates the
seriousness of potential industrial exposure to isocyanates. Such exposures are generally
considered to be most significant by the airborne route, since isocyanates are recognized as
being potent allergenic respiratory sensitizers. Some authors [2] believe that the dermal route
is also significant as contributing to respiratory sensitization, but the majority of studies on
isocyanate exposure have concentrated on the measurement of airborne exposure.
The nature of the isocyanate species involved is complex, Guidance Note EH16 citing
twelve industrial processes where exposure may occur, including the manufacture and use of
polyurethanes and other isocyanate-derived polymers, and processes where these polymers
may be subjected to thermal stress, e.g. flame bonding or soldering. Historically, interest
52
centered initially on the monomeric diisocyanates (Table 1), as these were the building blocks
of the commonly occurring polyurethanes.
Table 1 – Monomeric Isocyanates
Abbreviation
Chemical Name
Formula
TDI
MDI
HMDI
HDI
Toluene diisocyanate
Methylene bis (4-phenylisocyanate)
Methylene bis (4-cyclohexylisocyanate)
Hexamethylene diisocyanate
CH3-Ph-(NCO)2
OCN-Ph-CH2-Ph-NCO
OCN-C6H10-CH2-C6H10-NCO
OCN-(CH2)6-NCO
However, more recently, prepolymers or oligomers of the isocyanates (collectively
polyisocyanates, Table 2) have been used as they exhibit much lower vapor pressures than the
monomers, and hence should be associated with lower exposures.
In addition, a number of other compounds containing isocyanate functional groups
have become of interest, particularly in relation to the thermal degradation of isocyanatederived polymers (Table 3). Under certain conditions, the isocyanate polymers can
depolymerize, or result in the formation of amines or mixed amine/isocyanates. Low
molecular weight isocyanates, such as methyl isocyanate or isocyanic acid may also be
produced.
Table 2 – Polyisocyanates
Abbreviation
Chemical Name
Formula
Poly-HDI
Poly-MDI
HDI biuret (trimer)
Poly-(methylene bis
(4-phenylisocyanate))
2TDI + Ethylene glycol
OCN –(CH2)6 –N-[CONH-(CH2)6 –NCO]2
OCN-Ph-CH2-(Ph-CH2)n-Ph-NCO
TDI prepolymer
CH2-O-CO-NH-Tol-NCO
|
CH2-O-CO-NH-Tol-NCO
Table 3 – Thermal Degradation Products
Abbreviation
Chemical Name
Formula
MDA
MDI/MDA
aminoisocyanate
MIC
ICA
Methylene dianiline
4-Isocyanatophenyl4-aminophenylmethane
Methyl isocyanate
Isocyanic acid
H2N-Ph-CH2-Ph-NH2
OCN-Ph-CH2-Ph-NH2
53
CH3 NCO
HNCO
Limit Values
Notwithstanding the wide variety of isocyanate species that may be causative agents
for occupational asthma, National regulatory bodies have taken different views on setting
occupational exposure levels. In the USA, the Occupational Safety and Health Administration
(OSHA) has set Threshold Limit Values (TLVs) only for monomeric isocyanates (Table 4). In
addition, guidance values are promulgated by the American Conference of Governmental
Industrial Hygienists (ACGIH). This professional society originally recommended values for
TDI and MDI (at 0.02 ppm) which were the same as the OSHA limits, but in 1986 [3], the
values were changed to 0.005 ppm. By this time, HDI and methylene bis(4cyclohexylisocyanate) had also been added. The value for methyl isocyanate, adopted in
1977, remained at 0.02 ppm and is also an OSHA regulated limit. The UK and most other
countries followed the USA lead, at least initially. Thus, the UK reprinted the ACGIH list in
its entirety in 1965 [4], but in 1984 [5], the HSE introduced new limits, calculated as
extrapolations of the monomer limit values, but expressed as total isocyanate functional
groups. This was in response to the introduction of polyisocyanates (see above) and a single
limit, expressed in mg NCO/m3 was adopted for all isocyanate species, based on then current
toxicological evidence. Australia has also adopted the UK approach, and other European
countries an intermediate one (Table 5).
Table 4 – USA (ACGIH) Limit Values
Compound
Limit Values
Comments
HDI
0.005 ppm TWA1
0.034 mg/m3 TWA
0.005 ppm TWA1
0.051 mg/m3 TWA
As monomer
0.005 ppm TWA
0.054 mg/m3 TWA
0.005 ppm TWA
0.036 mg/m3 TWA
0.02 ppm TWA1
0.047 mg/m3 TWA
As monomer
MDI
HMDI
TDI
MIC
1
As monomer
As monomer
OSHA limit is 0.02 ppm
Table 5 – Non-USA Limit Values
Country
Limit Values
Comments
UK
0.02 mg/m3 TWA
0.07 mg/m3 STEL
0.02 mg/m3 TWA
0.07 mg/m3 STEL
0.005 ppm TWA
0.01 ppm STEL
0.035 mg/m3 STEL
as NCO groups
Australia
Sweden
Finland
as NCO groups
as ppm;
Polyisocyanate not quantified
as NCO groups;
Isocyanate form not specified
54
Measurement Methodologies
Historically, a large number of alternative methods have been devised for the
measurement of airborne isocyanates. Nearly all these methods rely on the derivatization of
the reactive isocyanate groups to products that can be analyzed, usually by some form of
chromatography. The detection systems have become increasingly complex: from ultraviolet
(UV) adsorption, through to electrochemical (EC) and fluorescence (fluor) detection. The
latest methods are now more likely to utilize mass spectometry (MS) or even MS/MS. Table 6
gives a summary of the more important developments, in roughly historical order, with their
principles of operation, advantages and disadvantages and significant literature references.
The choice of an ideal method relies partly on the requirements of the regulatory authorities,
but there are also technical considerations concerning the validity and reliability of the various
methods and the cost and availability of instrumentation. These are dealt with elsewhere [24].
Table 6 – Isocyanate Measurement Methods
Method
Principle
Advantages
Disadvantages
References
Marcali
Acid impinger/
diazotization with
nitrous acid and
N-2-aminoethyl-1naphthylamine
On-site
colorimetric
analysis.
Similar response
for polymeric
isocyanates
Marcali, 1957 [6]
Ethanol
Impinger, forms
urethane
analyzable by
HPLC
Separation of
isocyanates
(mainly
monomers)
Only aromatic
isocyanates.
Amine interference
messy and
inconvenient.
Reagent potentially
carcinogenic
Only aromatic
isocyanates (UV
detection)
Nitro reagent [N(4-nitrobenzyl)-npropylamine]
Impinger/ glass
wool tube, forms
urea analyzable by
HPLC
Less sensitive than
ethanol for
aromatic
isocyanates
Reagent unstable
HPLC column
degradation
Dunlap,
Sandridge &
Keller, 1976 [8]
MAMA
[9-(N-methylaminomethyl)
anthracene]
Impinger/ filter,
forms urea
analyzable by
HPLC.
Isocyanates
identified by
detector ratio
(fluor/UV)
Impinger/ filter,
forms urea
analyzable by
HPLC.
Isocyanates
identified by
detector ratio
(EC/UV)
Separation of
isocyanates
(mainly
monomers).
Equal sensitivity
for aliphatic and
aromatic
isocyanates
Can quantify
polyisocyanates.
Near universal UV
response factor
Variable
fluorescent yield
per NCO
Sango &
Zimerson, 1980
[9]
Can quantify
polyisocyanates
Analysis is more
complex.
EC detector
unstable
Warwick, Bagon
& Purnell, 1981
(monomer)
Bagon, Warwick
and Brown, 1984
(total) [10,11]
2-MP
[1-(2methoxyphenyl)pi
perazine]
55
Bagon & Purnell,
1980 [7]
Method
Principle
Advantages
Disadvantages
References
2-PP
[1-(2-pyridyl)
piperazine]
Impinger/ filter,
forms urea
analyzable by
HPLC
Polyisocyanates
still difficult
Hardy & Walker,
1979
Goldberg et al
1981 [12,13]
Tryptamine
[2-(2-amino
ethyl)indole]
Impinger, forms
urea analyzable by
HPLC.
Isocyanates
identified by
detector ratio
(fluor/EC)
Impinger/ filter,
forms urea
analyzable by
HPLC.
Isocyanates
identified by
detector ratio
(fluor/UV)
Separation of
isocyanates
(mainly
monomers).
Filter option more
convenient
Can quantify
polyisocyanates.
More constant
fluorescent yield
per NCO
EC detector
unstable.
Exposure hazard
from DMSO
Wu, Gaind, et al
1987. 1990
[14,15]
Can quantify
polyisocyanates.
Near universal UV
response
factor/sensitive
UV detection.
Compatible with
Ph gradient
elution
Variable
fluorescent yield
per NCO.
Stability of
derivatives
uncertain.
MAP not
commercially
available.
MAP artifact peaks
Non-routine,
expensive analysis.
Quantifying
polyisocyanates
requires standards
Streicher, 1996
[16]
Impurities may give
high blank of
cleavage product
Streicher, 2000
[22]
Short-term
sampling (15 mins).
Sample may not
react efficiently
Lesage, 1992
[23]
MAP
[9-(1-methyl
anthracenyl)
piperazine]
DBA
[dibutylamine]
Impinger, forms
urea analyzable by
LC/MS.
Isocyanates
identified by MS
Can quantify
isocyanates and
amines.
Faster reaction
times
PAC
[9-anthracenyl
methyl-1piperazine
carboxylate]
Impinger, forms
urea analyzable by
HPLC.
PAC derivatives
can also be
cleaved to single
product
Iso-Chek™
Combination of
PTFE (postreacted with 2MP) and MAMAdoped filter
No chromatographic losses of
isocyanate
species.
Simple
chromatogram.
No response factor
variability
between
isocyanates
Separates vapor
and aerosol.
Adopted by
ASTM
Dalene,
Skarping, et al.
1996-8 [17-21]
National Approved Methods
One might expect a consistent body of advice from the regulatory authorities
concerned. However, NIOSH (USA) recommends three methods, OSHA (USA) recommend
two methods, NIWL (Sweden) recommends one method and the HSE (UK) recommends two
methods (Table 7).
56
Table 7 – Nationally Approved Methods
Authority
Method
Reagent
Status
NIOSH1
5521
2-MP
NIOSH
5522
Tryptamine
NIOSH
2535
NIOSH
OSHA2
5525
42, 47
Nitro on glass
wool
MAP
2-PP on filter
OSHA
54
2-PP on XAD-2
ASTM
D-5932-96
MAMA
ASTM
D-5836-95
2-PP
ASTM
Iso-Chek
HSE
D-6561-00
D-6562-00
Arbete och
Haelsa 97:6
MDHS 25/3
HSE
MDHS 49
Marcali
Ref. HSE: unrated Monomer
+ polyHDI
Ref. Ontario: partial
“Estimates” oligomers
Full
TDI, HDI monomer
Draft method
Established
Diisocyanate monomers only
Established
Methyl isocyanate
Validated
TDI vapor only
Validated
TDI vapor only
Validated
HDI aerosol/vapor only
Ref. Skarping
No status
Evaluated to EN 482
Monomers and
polyisocyanates
Published 1985
Out of print4
NIWL3
DBA-LCMS
2-MP
1
National Institute for Occupational Safety and Health (USA)
Occupational Safety and Health Administration (USA)
3
National Institute for Working Life (Sweden)
4
Out of print, but not formally withdrawn
2
All of these methods are different, with the exception of the 1-(2methoxyphenyl)piperazine (2-MP) and the 1-(2-pyridyl)piperazine (2-PP) methods, which
appear twice. Some of the differences between the advice from the regulatory authorities are
due to the differing requirements of the TLVs. Thus, OSHA (but not ASTM or NIOSH) has
concentrated on methods for monomeric diisocyanates, while the UK has concentrated on
methods that can deal with all isocyanates, irrespective of type. But there are obviously other
considerations, such as the prevalence of particular industries or processes involving potential
exposure to isocyanates. Also, not unnaturally, countries tend to adopt methods developed “at
home”.
International Standards
The International Standardization Organization (ISO) might be expected to be more
objective in its selection of methods to which it appends its seal of approval. (ISO methods
are recommended, but not mandatory.) Actually, ISO is preparing four standards as technical
specifications (Table 8). First, it is preparing a method based on the 2-MP reagent (ISO/FDIS
16207). Second, it is preparing a method based on the 9-(1-methylanthracenyl)piperazine
reagent (agreed New Work Item). Two further methods, based on the dibutylamine method
and the Iso-Chek method (as used in ASTM method D-5932-96) have been agreed as
potential new work items but have not been balloted yet. So many alternative methods would
57
seem inconsistent with the ISO objective of variety reduction. The reason is that, in addition
to having different areas of application, all existing methods have some disadvantages. Thus,
a fifth, guidance, standard is being developed which will explain in more detail the
advantages and disadvantages of each method and discuss the major causes of measurement
uncertainty in such methods – during collection, derivatization, sample handling, separation,
identification and quantification.
Table 8 – ISO ”Approved” Methods
Method
Reagent
Status
ISO 16207
DIS 17735
Pre-draft
Pre-draft
Pre-draft
2-MP
MAP
DBA
Iso-Chek
Guide
Agreed for publication, June 2001
Agreed to DIS distribution, October 2001
CD being prepared, October 2001
CD being prepared, October 2001
CD being prepared, October 2001
Conclusions
There are a large number of alternative methods available for the measurement of
airborne isocyanates. As discussed, these all have advantages and disadvantages and may be
more or less appropriate, depending on the isocyanate species involved and its physical form.
Local requirements of the relevant TLVs must also be taken into account.
Some guidance on the selection of procedures may be gained from an examination of
those methods recommended by National Authorities or by ISO. In particular, ISO is
developing a guidance standard that will explain in more detail the advantages and
disadvantages of each method and, it is hoped, point to the development of a genuinely
universal method.
References
[1]
Health and Safety Executive, “Isocyanates: Health Hazards and Precautionary
Measures,” Guidance Note EH 16, HSE Books, Sudbury, Suffolk, UK, 1999.
[2]
Kimber, I., “The Role of the Skin in the Development of Chemical Respiratory
Hypersensitivity,” Toxicology Letters, Vol. 86, 1996, pp.89-92.
[3]
American Conference of Governmental Industrial Hygienists, “1993-1994 Threshold
Limit Values for Chemical Substances and Physical Agents and Biological Exposure
Indices,” ACGIH, Cincinnati, 1993.
[4]
Ministry of Labour, “Dust and Fumes in Factory Atmospheres,” Safety, Health and
Welfare, New Series No. 8, HMSO, London, UK, 1965.
[5]
Health and Safety Executive, “Occupational Exposure Limits, 1984,” Guidance Note
EH 40, HMSO, London, UK, 1984.
58
[6]
Marcali, K., “Microdetermination of Toluene Diisocyanates in the Atmosphere,”
Analytical Chemistry, Vol. 29, 1957, pp.552-558.
[7]
Bagon, D., and Purnell, C. J., “Determination of Airborne Free Monomeric Aromatic
and Aliphatic Isocyanates by HPLC,” Journal of Chromatography, Vol. 190, 1980,
pp. 175-182.
[8]
Dunlap, K. L., Sandridge, R .L. and Keller, J., “Determination of Isocyanates in
Working Atmospheres by High-performance Liquid Chromatography,” Analytical
Chemistry, Vol. 48, 1976, pp.497-499.
[9]
Sango, C., and Zimerson, E., “A New Reagent for Determination of Isocyanates in
Working Atmospheres by HPLC using UV or Fluorescence Detection,” Journal of
Liquid Chromatography, vol.3, 1980, pp.971-990.
[10]
Warwick, C. J., Bagon, D. and Purnell, C. J., “Application of Electrochemical
detection to the measurement of Free Monomeric Aromatic and Aliphatic Isocyanates
in Air by HPLC,” The Analyst, Vol. 106, 1981, pp.676-685.
[11]
Bagon, D., Warwick, C. J., and Brown, R. H., “Evaluation of Total Isocyanate-in-air
Method using 1-(2-Methoxyphenyl)piperazine and HPLC,” American Industrial
Hygiene Association Journal, Vol. 45, 1984, pp.39-43.
[12]
Hardy, H. L., and Walker, R. F., “Novel Reagent for the Determination of
Atmospheric Isocyanate Monomer Concentrations,” The Analyst, Vol. 104, 1979,
pp.890-891.
[13]
Goldberg, P. A., Walker, R. F., Ellwood, P. A. and Hardy, H. L., “Determination of
Trace Atmospheric Isocyanate Concentrations by Reversed-phase High-performance
Liquid Chromatography using 1-(2-Pyridyl)piperazine. Journal of Chromatography,
Vol. 212, 1981, pp. 93-104.
[14]
Wu, W. S., Nazar, M. A., Gaind, V. S., and Calovini, L., “Application of Tryptamine
as a Derivatising Agent for Airborne Isocyanates Determination. Part 1: Model for
Derivatisation of Methyl Isocyanate Characterised by Fluorescence and Amperometric
Detection in HPLC. The Analyst, Vol. 112, 1987, pp.863-866.
[15]
Wu, W. S., Stoyanoff, R. E., Szklar, R. S. and Gaind, V. S., “Application of
Tryptamine as a Derivatising Agent for Airborne Isocyanates Determination. Part 3:
Evaluation of Total Isocyanates Analysis by Reversed-phase High-performance Liquid
Chromatography with Fluorescence and Amperometric Detection in HPLC. The
Analyst, Vol. 115, 1990, pp.801-807.
[16]
Streicher, R. P., Arnold, J. E., Ernst, M. K., and Cooper, C. V., “Development of a
Novel Derivatising Reagent for the Sampling and Analysis of Total Isocyanate Groups
in Air and Comparison of its Performance with that of Several Established reagents,”
American Industrial Hygiene Association Journal, Vol. 57, 1996, pp.905-913.
[17]
Spanne, M., Tinnerberg, H., Dalene, M. and Skarping, G., “Determination of Complex
Mixtures of Airborne Isocyanates and Amines. Part 1: Liquid Chromatography with
59
Ultraviolet Detection of Monomeric and Polymeric Isocyanates as their Dibutylamine
Derivatives,” The Analyst, Vol. 121, 1996, pp 1095-1099.
[18]
Tinnerberg, H., Spanne, M., Dalene, M. and Skarping, G., “Determination of Complex
Mixtures of Airborne Isocyanates and Amines. Part 2: Toluene Diisocyanate and
Aminoisocyanate and Toluenediamine after Thermal degradation of a Toluene
Diisocyanate-Polyurethane,” The Analyst, Vol. 121, 1996, pp 1101-1106.
[19]
Tinnerberg, H., Spanne, M., Dalene, M. and Skarping, G., “Determination of
Complex Mixtures of Airborne Isocyanates and Amines. Part 3: Methylenediphenyl
Diisocyanate and Methylenediphenylamino Isocyanate and
Methylenediphenyldiamine and Structural Analogues after Thermal Degradation of
Polyurethane,” The Analyst, Vol. 122, 1997, pp 275-278.
[20]
Karlsson, D., Spanne, M., Dalene, M. and Skarping, G., “Determination of Complex
Mixtures of Airborne Isocyanates and Amines. Part 4: Determination of Aliphatic
Isocyanates as Dibutylamine Derivatives using Liquid Chromatography and Mass
Spectrometry,” The Analyst, Vol. 123, 1998, pp 117-123.
[21]
Karlsson, D., Dalene, M. and Skarping, G., “Determination of Complex Mixtures of
Airborne Isocyanates and Amines. Part 4: Determination of Low Molecular Weight
Aliphatic Isocyanates as Dibutylamine Derivatives,” The Analyst, Vol. 123, 1998, pp
1507-1512.
[22]
Streicher, R. P., Ernst, M. K., Williamson, G. Y., Roh, Y. M., and Arnold, J. E., ,
“Several Strategies for the Analysis of Airborne Isocyanate Compounds in Workplace
Environments,” Isocyanate 2000: First International Symposium on Isocyanates in
Occupational Environments, Stockholm, June 2000, pp. 73-75.
[23]
Lesage, J., Goyer, N., Desjardins, F., Vincent, J.-Y., and Perrault, G., “Workers’
Exposure to isocyanates,” American Industrial Hygiene Association Journal, Vol. 53,
1992, pp.146-153.
[24]
Streicher, R. P., Reh, C. M., Key-Schwartz, R. J., Schlecht, P. C., Cassinelli, M. E. and
O’Connor, P. F., “Considerations in Isocyanate Method Development and Method
Selection,” ASTM Symposium on Isocyanates: Sampling, Analysis and Health
Effects, Florida, October 2000.
60
10.2.3 Exposure control of isocyanates, aminoisocyanates and amines with special
reference to exposure to thermal decomposition products of polyurethane
Gunnar Skarping, Marianne Dalene, Daniel Karlsson, Åsa Marand and Jakob Dahlin
Work Environment Chemistry, Lund University,
P.O.B. 460 S-281 38 Hässleholm, Sweden
www.amk.lu.se
The industrial introduction of polyurethane (PUR) started in the middle of the twentieth
century and subsequently, reports on isocyanate induced occupational diseases started to
appear (Fuchs 1951, Swensson 1955). Today, many people are still affected by isocyanate
exposure, despite legislation and safety precautions (Tarlo et al. 1997, Sari-Minodier et al.
1999, Ott et al. 2000). The use of isocyanates for production of PUR is steadily expanding and
in 1999 the global production was 8 million tonnes and with a calculated yearly increase of
5% (Vik 2000). The occupational exposure to isocyanates occurs mainly during the production or processing of PUR. In the USA about 206 000 workers were exposed to diisocyanates,
polyisocyanates and prepolymers (Seta et al. 1993), and in 1996 about 100 000 workers were
exposed to diisocyanates (Bernstein, 1996).
In addition to industrial handling of PUR and isocyanates, handling may also occur in home
environment (Skarping et al. 1999, Arbetarsskydd No:2 1998, Arbetarsskydd No:15, 1998
and Vår Bostad 2001). A few cases of environmental exposure have also been reported in
addition to the Bhopal accident in 1983 (Agency for Toxic Substances and Disease Registry,
1998, Swedish Rescue Services Agency, 2000, Ulvestad et al. 1999). The effect of PUR in
breast implants has also been debated (Sepai et al. 1995).
Exposure to isocyanates is associated with respiratory disorders and is a common cause of
occupational asthma (Littorin et al. 1994, Meredith et al. 1996, Lagier et al. 1990, Rosenman
et al. 1997, Meyer et al. 1999, van Kampen et al. 2000, Karjalainen et al. 2000). During
thermal degradation of PUR, amines and aminoisocyanates are formed in addition to
isocyanates. The Swedish occupational exposure limits (OELs) for all isocyanates are 5 ppb
for an 8 h workday and 10 ppb for a 5 minutes period (Swedish National Board of
Occupational Safety and Health 2000). These are based on longitudinal studies on reduction
of lung function among workers producing toluene diisocyanate (TDI) and TDI-,
methylenediphenyl diisocyanate (MDI)-PUR (Arbete och Hälsa 1988). In Australia, Finland
and the United Kingdom (UK), the OELs are based on the total reactive isocyanate group
(TRIG). In UK the TRIG is set to 20 µg NCO/m3 (International Labour Office 1991).
Biological exposure index limit (BEIL) for isocyanates in urine has been suggested by
Deutsche Forschungsgemeinschaft (DFG) for MDA to 5.7 nmol/mmol creatinine. Maitre et
al. has proposed a value for hexamethylene diamine (HDA) of 18.5 nmol/mmol creatinine
(1996) and for toluene diamine (TDA) a value of 19.5 nmol/mmol creatinine (1993).
Personal respiratory protection devices (PRPD) are widely used in the industry. Recently, it
has been described that workers are being exposed even when PRPD are used (Skarping et al.
1999, Williams et al. 1999).
The pathophysiology is not fully understood, but different isocyanates are expected to cause
different responses, and have different toxicity.
The dermal sensitization capabilities of hexamethylene diisocyanate (HDI), MDI,
hydrogenated MDI (HMDI), and TDI were determined for mice (Thorne et al. 1987). The
SD50 for HDI was calculated to be 0.088 mg/kg (60 times more potent than TDI). This study
also found that the order of potency for dermal sensitization of the isocyanates tested was:
61
HDI>HMDI>MDI>TDI. For all isocyanates tested the severity of the dermal reactions was
greatest when rechallenged. The LD50 (oral, rat) and (skin, rabbit) was 1.05 and 1.25 g/kg for
HDI, 4.9-6.7 and 16 g/kg for TDI, and 31.6 and 10 g/kg for MDI (Kennedy and Brown 1992).
For OSHA 4,4’,-methylenedianiline (MDA) is a regulated chemical (Group X). For IARC
4,4’-MDA is a possibly carcinogenic to humans, Group 2B (IARC 1986). For NTP 4,4’-MDA
is a reasonably anticipated to be human carcinogens (R; Group 2). For ACGIH 4,4’-MDA is a
confirmed animal carcinogen with unknown relevance to humans (Group A3).
2,4-TDA has been shown to be carcinogenic for animals, but there is inadequate evidence to
evaluate the carcinogenic potential of 2,5- and 2,6-TDA. All 3 of these isomers have been
shown to be mutagenic (WHO 1987). For IARC 2,4-TDA is a possibly carcinogenic to
humans, Group 2B (IARC 1978). TDI and MDI were found to be mutagenic after metabolic
activation and the effect is probably due to hydrolysis of the isocyanates to the corresponding
amine (Andersen et al. 1980).
The minimal risk level (MRL) is an “estimate of the daily human exposure to a hazardous
substance that is likely to be without appreciable risk of adverse non-cancer health effects
over a specified duration of exposure”. Only one isocyanate is listed. HDI intermediate
inhalation (2 – 52 weeks) MRL is 0.03 ppb and chronic inhalation (>52 weeks) MRL is 0.01
ppb (ATSDR, 2002).
At present both air methods and methods for the determination of biomarkers in exposed
humans are available.
Simultaneous monitoring of airborne isocyanates, aminoisocyanates and amines
The sum of isocyanates, aminoisocyanates and amines has been measured by collection of air
samples in acidic solution and after the hydrolysis, derivatisation of the amines with
heptafluorobutyric anhydride (Skarping et al. 1981, 1983). Methods based on derivatisation of
isocyanates using ethanol and the free amine groups using pentafluoropropionic anhydride
have been described (Skarping et al. 1985, 1988, Dalene et al. 1988). Simultaneous
determination of amines, aminoisocyanates and isocyanates have been presented using di-nbutylamine (DBA) as a reagent for isocyanate derivatisation and ethyl chloroformate to
convert the amines to carbamate esters and LC-MS analysis, Figure 1 (Tinnerberg et al. 1996,
1997, Skarping et al. 1999, Karlsson et. al. 2002). The DBA method for sampling isocyanates
and amines in the gas and particle phases is based on collection of gas phase and large
particles (> 1.5 µm) in the impinger flask and small particles (0.01-1.5 µm) on the filter, after
the impinger flask. Stable derivatives, fast reaction rates and stability towards interfering
compounds were reported for the DBA reagent (Spanne et al. 1996, Karlsson et al. 1998).
62
EXPOSURE
“Traditional” isocyanate exposure
During the production of PUR-foam, volatile isocyanates may be emitted to the atmosphere
and the exothermic reaction will increase the emission. The exposure to TDI is mainly
described during the manufacturing of flexible PUR-foam (Tinnerberg et al. 1997b, Kääriä et
al. 2001a, Rando et al. 1987). The exposure to MDI during production of rigid PUR foam has
also been described (Kääriä et al. 2001b). Due to the low volatility of MDI, the air
concentrations when compared with TDI are much lower, during production of flexible foam.
However when isocyanates with low vapour pressure, such as MDI or prepolymerised HDI
are used for example in spraying applications, high concentrations of isocyanates can be
found in the working atmosphere (Crespo and Galan 1999, England et al. 2000, Maitre et al.
1996, Myer et al. 1993). During spray painting operations, with a HDI-based lacquer, several
different HDI adducts were present in the samples, resulting in air concentrations up to the mg
m-3 level. The observed isocyanates were: HDI monomer, HDI dimer (uretidone), HDI biuret
adduct, HDI isocyanurate adduct, HDI isocyanurate-uretidone adduct and HDI diisocyanurate
adduct (Karlsson et al 1998, Römyhr et al. 2002).
PIC-DBA
EIC-DBA
d3-MIC-DBA
PhI-DBA
MIC-DBA
ICA-DBA
d4-HDA-Et
HDA-Et
TAI-EtDBA
HAI-EtDBA
d2-MDAEt
d3-TDI-DBA
TDI-DBA
d4-HDI-DBA
d2-MDIDBA
MDI-DBA
MDA-Et
d3-TDA-Et
HDI-DBA
(isocyanurate)
HDI-DBA
TDA-Et
HDI-DBA
(isocyanurateuretidone)
HDI-DBA
(di-isocyanurate)
MDI-DBA
(three-ring)
MDI-DBA
IPDIDBA
(four-ring)
HDI-DBA
(biuret)
MAI-Et-DBA
m/z=156
m/z=130
5
15
Time / min
25
Figure 1. LC-MS chromatograms of a standard solution, containing isocyanate-DBA, amine-Et and aminoisocyanate DBA-ET derivatives. The MS was working in the electrospray mode monitoring selected positive
molecular ions (Karlsson D, 2001).
63
Thermal degradation of PUR
The urethane bonding in a PUR polymer will start to dissociate at temperatures above 150200°C (Joel and Hauser 1994, Gupta et al. 1994). The thermal stability depends on both the
type of isocyanate and the type of polyol used in the PUR system and are in decreasing order
of thermal stability: alkyl isocyanate-alkyl polyol > aryl isocyanate-alkyl polyol > alkyl
isocyanate-aryl polyol > aryl isocyanate-aryl polyol (Ulrich 1996). During thermal
degradation of PUR, exposure to diisocyanates may occur in both the gas phase and the
particle phase (Streicher et al. 1994). MDA, aminoisocyanates, phenylisocyanate (PhI) and
oligomers were released in addition to MDI during casting in sand moulds with PUR resins
(Renman et al. 1986). The exposure to thermal degradation products of PUR has also been
reported during work operations such as: processing of PUR coated metal sheets in car repair
shops (Skarping et al. 1988); flame lamination of PUR with textiles (Tinnerberg et al. 1996)
and production of PUR coated wires (Rosenberg et al. 1984).
Using impinger flask the derivatisation reagent will be readily available for the isocyanates, if
the concentration is high enough, and efficient derivatization will occur. However, the
collection efficiency for collecting small particles will decrees dramatically for particle
smaller than 2µm (Spanne et al. 1999). This could lead to an underestimation of the air
concentrations when thermally generated particles are a part of the exposure pattern
During welding in pipes insulated with MDI-based PUR foam used for district heating, high
concentrations of amines, aminoisocyanates and isocyanates were observed in air (Karlsson et
al. 2002). The necessity of using a filter in series after the impinger flask was clearly
demonstrated. The monoisocyanates were efficiently collected in the impinger flasks, whereas
the isocyanates with lower vapour pressure were dominantly in the particle phase. MDA,
methylenediphenyl aminoisocyanate (MAI) and monomeric MDI dominated on the filter. The
MDI-three ring derivatives were exclusively found on the filter (Figure 2).
Figure 2. Isocyanate, aminoisocyanate and amine concentrations in an air sample collected during welding in a
district heating pipe. Air samples were collected using impinger flask containing DBA in toluene and a glass
fibre filter in series. The amine groups were derivatised with ethyl chloroformate in a subsequent work-up
procedure. Separate analysis, using LC-MS, of the derivatives in the impinger flask (□ ) and on the filter (■ )
was performed (Karlsson D 2001).
When lacquers from PUR coated metal sheets were thermally degraded in laboratory studies a
variety of different isocyanates were observed (Karlsson et al. 2000 and 2001). There were
great differences in amounts and types of isocyanates emitted between different coatings. In
addition to aliphatic diisocyanates, aromatic isocyanates were present in almost all of the
64
studied PUR-coatings. This could be explained by the fact that the PUR-coating consists of
many different layers of lacquers. They are present to give the different lacquers special
properties. The top layer needs however to be a PUR that is based on an aliphatic isocyanates
since it must be stable against UV-light. Isocyanic acid (ICA) dominated completely the
isocyanate content in the degradation products.
8
Total number conc. / cm
-3
10
Cutting
10
7
10
6
Cutting with fume hood
position optimized
Grinding
Welding
5
10
B
A
10
Brushing
D
C
3
0
40
80
Time / min
120
160
Figure 3. The total particle number concentration (Dp = 0.014-0.7µm) during grinding, cutting and welding in
painted car metal sheet. The duration of each work task was about 5 min. The car repair shop was recently built
and had a mechanical displacement type ventilation. Each data point indicates samples taken during 135 s each,
about 40 cm from the working area. Particle size measurements of the workplace aerosol were made with an
electrical differential mobility analyser (DMA). The DMA was combined with a condensation particle counter
(CPC) to a Scanning Mobility Particle Sizer model 3934, consisting of an Electrostatic Classifier model 3071
and a CPC model 3022A. Each measurement was made during 135 s (Tup = 90 s, Tdown = 45 s), in the particle
diameter (Dp) range 0.014 – 0.7 µm (Karlsson et al. 2000).
Figure 4. Short duplicate samples (10-40s), collected in a car repair shop during a welding operation. The mean
total NCO concentration was 160 µg/m3 and the maximum total NCO concentration was 1730 (t=20s). The total
NCO concentration was calculated from MIC, PhI, TDI and IPDI. The air samples were collected using
impinger flask containing DBA and a filter in series followed by LC-MS (Karlsson et al. 2000).
65
High amounts of amines, aminoisocyanates and isocyanates were emitted to the working
atmosphere during operations that involved thermal degradation of the PUR-coating
(Karlsson et al. 2000). The concentrations and types of airborne isocyanates varied greatly
depending on the work task and type of coatings on the metal sheets. The monoisocyanates
were collected in the impinger flasks and the diisocyanates in both the impinger flasks and on
the glass fibre filters. When the emitted airborne particles were studied, high concentrations of
ultra-fine particles (<0.1 µm) were observed and during a cutting operation an increase with
up to 50 000 times the background level of the ultra-fine particle concentration, was observed
(figure 3). The concentrations of airborne contaminants in a car repair shop during work
operations such as welding and cutting in PUR-coated metal sheets depends largely on factors
such as type of PUR, ventilation, work task and the individual work procedure. During the
work operations the typical exposure is to short and high exposure peaks (figure 4) and in
order to get representative exposure estimations in a car repair shop it is necessary to collect
many samples at different occasions, when different materials are processed.
Thermal degradation of urea- based resins
ICA and methyl isocyanate (MIC) were emitted when urea-based resins were thermally
degraded (Karlsson et.al. 1998 and 2001). ICA was the dominating isocyanate present. When
bakelite was thermally degraded, up to 14% of the total weight was emitted as ICA and 0.1%
as MIC. The amounts of ICA and MIC released depended on the applied heat and on the
duration of the heating.
High amounts of MIC were emitted when a new electrical oven was started for the first time
(Karlsson et al. 1998). The oven was insulated with mineral wool. Mineral wool is commonly
used as insulating material for hot pipes and tubing. Compared to the Swedish short time (5
min) exposure limits of 10 ppb (24 µg m-3 of MIC) in working atmosphere, the amount of
MIC that can be found in every kitchen where a new oven is started for the first time is truly
remarkable (Figure 5). In addition ICA will be present in great amounts (at the time of this
study ICA determinations were not performed). Extrapolating more recent data regarding ICA
(Karlsson et al. 2001) the total isocyanate content should be at least 3 times higher.
The exposure to MIC during thermal degradation of urea based resins was reported in 1998
(Karlsson et al. 1998) and to ICA in 1999 (Skarping et al. 1999). This is a new area of
isocyanate exposure. Limited information on health effects of occupational exposure to MIC
is available, but for ICA such information is completely missing. In the absence of
toxicological data, the authorities in Sweden have established the same OEL for ICA as for all
other isocyanates (Norén 2001).
Exposure to isocyanates such as ICA and MIC has also been studied during sand casting in an
iron foundry (Karlsson et al. 2001). The urea-based resin that was used in the sand moulds
emitted high amounts of ICA and MIC to the working atmosphere when melted steel was
thermally degrading the resin (up to 700 µg m-3).
66
A
B
C
D
200
200
200
200
300
100
100
300
100
300
100
300
°C
°C
°C
°C
0
0
0
0
Figure 5. Air samples were collected, when a new electrical oven was started for the first time, when (A) the
temperature rose to 100°C during 6 min, (B) the temperature rose to 200°C during 6 min, (C) the temperature
rose to 275°C during 10 min and (D) when the temperature was maintained at 275°C for 20 min. Each bar
represents a mean air concentration of four samples. The air samples were collected using impinger flasks
containing DBA and analysed using LC-MS (Karlsson D. 2001).
BIOMARKERS
The monitoring of exposure by the collection of air samples is generally inadequate for the
determining of each worker’s uptake. It does not take into account each individual’s breathing
rate or variation in uptake, distribution, metabolism or elimination of the xenobiotic. In
addition, dermal exposure or the efficiency of the used protection equipment can not be
evaluated by air monitoring. For the determination of the internal dose, biological monitoring
is important.
Methods for the assessment of isocyanate exposure through the determination of corresponding amines in hydrolysed biological samples have been presented (Rosenberg and
Savolainen 1986, Persson et al. 1993, Kääriä et al. 2001a,b, Maitre et al. 1993 and 1996a,
Schutze et al. 1995, Sepai et al. 1995, Skarping et al. 1991, 1994abc, 1995ab, 1996, 1999b,
Dalene et al 1990, 1994ab, 1996, 1997, Brorsson et al. 1989, 1990b, 1991, Tinnerberg et al.
1995, Lind et al. 1996). Biomarkers of isocyanate monomers are determined as the
corresponding amines, in hydrolysed urine (U; TDI, MDI, NDI and HDI), plasma (P; TDI,
MDI and NDI) and erythrocytes (E; TDI and MDI) from exposed workers. The amines are
typically determined using capillary gas chromatography-chemical ionisation mass
spectrometry monitoring negative ions. After hydrolysis, the free amines are extracted. The
amines are derivatised to perfluorofattyamides. Hydrolysis is necessary to release the amines
and indicates that strong bondings are involved in urine, plasma and erythrocytes from
isocyanate exposed workers. The amount of released amines is greatly affected by the
hydrolysis medium, temperature and duration of the hydrolysis. The amount of released
amines in comparison to the total level is not known, and the released amount must be seen as
a relative measure.
Protein adducts of TDI were found after TDI-exposure. In plasma, all TDI was found to be
covalently bound to albumin and in erythrocytes most likely to haemoglobin. In urine from
TDI-exposed workers, several TDI-modified biomolecules were observed (Lind 1997, Lind et
al. 1997). Protein adducts of MDI among workers have been studied (Sepai et al. 1995,
Schütze et al. 1995).
67
In volunteers exposed to toluene diisocyanate (TDI), urinary half-lives of about 1-5 h for
TDA were found (Brorson et al. 1991, Skarping et al. 1991). Linear relations between the
dose and the urinary cumulative excreted amounts were found (Brorson et al. 1991). The halflives in plasma from volunteers were 2-5 h of 2,4- and 2,6-TDA in a first phase and >6 days
in a second phase (Brorson et al. 1991). A half-life of TDA of ca 10 days was found in plasma
from one volunteer exposed to TDI (Tinnerberg et al. 1997). Volunteers exposed to TDI
showed increasing P-TDA with time (Brorson et al. 1991, Lind 1997). For 1,6-hexamethylene
diisocyanate (HDI) and isophorone diisocyanate (IPDI) the urinary half-lives were 2.5 and 2.8
h, respectively (Dalene et al. 1990, Brorson et al. 1990b, Tinnerberg et al. 1995).
In workers the same urinary elimination pattern was found as for volunteers (Lind et al. 1996,
1997). Relationships have been found between concentrations of isocyanates in air and
biomarkers among exposed workers (Maître et al. 1993, Lind et al. 1996, Lind 1997,
Tinnerberg et al. 1997). The half-lives of TDA in plasma from 29 workers at 3 different TDI
plants (workers in one were exposed to thermal decomposition products) were found to be ca
20 days when blood was sampled before and after vacations. About the same half-live of PMDA was found as for P-TDA (Persson et al. 1993, Lind et al. 1996, 1997, Dalene et al.
1997).
Biomarkers among workers exposed to thermal decomposition products.
A variation of TDA, and MDA concentrations were seen in urine during and between
workdays, while only limited variations in plasma concentrations were seen (Skarping et al.
1995a, 1996, Littorin et al. 1994, Lind et al. 1996, Dalene et al. 1996, 1997). A significant
linear relation was observed between the P-TDA and E-TDA (Lind et al. 1997). When
plotting the P-TDA and E-TDA against the TDI air levels, significant linear relationships
were seen, except for E-2,6-TDA (Lind et al. 1997). The linear correlations between the mean
daily urinary elimination rate of TDA and P-TDA and E-TDA among five TDI workers
increased with the number of days after cessation of work. The urinary half-life of TDA in the
slow phase of 18-19 days among five TDI-workers is about the same as the half-life of TDA
found in plasma (Lind et al. 1997). When P-TDA is plotted against the urinary elimination
rate of TDA together with data from workers at another factory and volunteers, after
exposure, it can be seen, even if the hydrolysis conditions were different, that a relation
between plasma and urine data are about the same (Lind 1997). A relationship was also seen
between the P-MDA and the urinary elimination rate of MDA among MDI-workers, three
days after the cessation of work (Dalene et al. 1997). This indicates that modified protein
breakdown products in plasma dominate in urine a few days after exposure cessation.
DISCUSSION
There are many reasons to believe that workers exposed to thermal degradation products
outnumber the ones exposed in the traditional isocyanate industry. Still, the main focus among
industrial hygienists and researchers are on the traditional isocyanate industry. In work places
where PUR is thermally decomposed detailed knowledge regarding isocyanate chemistry may
be missing, workers are often not educated on isocyanates and problems thereof. In addition,
safety protection devices are often inadequate or missing. The determination of thermal
degradation products requires more sophisticated analytical methods. LC-MS provides the
necessary selectivity, low detection limits and structural information. The instrumentation is
indispensable and is routine in pharmaceutical industries, for biochemical and
biotechnological applications, for environmental analysis etc (Niessen 1999).
68
Within the scientific community, there is a consensus that isocyanates may cause adverse
health effects among exposed workers. However, the knowledge regarding mechanisms and
safe levels of exposure is sparse. There are numerous different kinds of isocyanates present in
the industry. The toxicity varies, but detailed information is missing. As many workers are
being exposed, there is an urgent need of toxicological data regarding different isocyanates
and the occupational exposure to thermal degradation products from PUR and urea-based
resins. It needs to be stressed that many polymers may give rise to other toxic airborne
thermal decomposition products. If only isocyanates are monitored the risk assessment could
be greatly misleading.
Work environment data among industries handling isocyanates or PUR are sparsely made
public knowledge. Many companies that have successfully solved problems with isocyanate
exposure do not inform others or make their findings known. In addition, detailed content of
isocyanates or PUR products are often not presented in safety data sheets. This results in
tedious work for the industrial hygienists. There is also a problem with availability of pure
analytical standards, which make quantification troublesome.
In most countries independent professionals and researchers have limited access to workplaces where workers are exposed. This results in lack of knowledge about the conditions in
various industries and sparse exposure data.
The choice of the used air monitoring method will greatly affect the obtained estimation of the
exposure, especially when air samples are collected during thermal degradation of PUR. It has
clearly been demonstrated, that in addition to isocyanates also aminoisocyanates and amines,
at high concentrations, may occur during the thermal decomposition of PUR. Often
isocyanates such as ICA and MIC dominate in air. Using earlier presented methods, which
have essentially been developed for monitoring of isocyanates in the traditional PURindustry, not taking into account low molecular weight isocyanates, aminoisocyanates and
amines, may result in severe underestimation of the air concentrations. High concentrations
may also have been underestimated due to the consumption of the reagent. Interfering
compounds may have affected the recovery of the derivatization. Severe losses of particle
borne isocyanates may occur if an inadequate sampling technique has been used. It is
therefore difficult to interpret old exposure data where different methods have been used.
Clearly the toxicity for different isocyanates varies. Still, methods based on the determination
of total reactive isocyanate group (TRIG) are in use. Several potentially hazardous
compounds will be formed during the thermal decomposition of PUR. Many of these have no
TLVs and others are known toxicants or carcinogens. The comparison of obtained air data
with TLVs is common practise, but it has great limitations when compounds are present that
does not have any TLV. There are no known safe exposure levels for the development of
respiratory disorder and the MRL is extremely low. Therefore, the quality of the air method
needs to be such that even air concentrations well below the TLV can be determined.
Amines in hydrolysed biological fluids are not specific biomarkers of the exposure to
isocyanates, but also to amines, aminoisocyanates or other compounds that will release the
amines during hydrolysis. Even if basic data regarding metabolism, uptake etc. is missing,
biomarkers are important indicators of exposure. Biomarkers are complementary to air data
and can provide enhanced quality to the exposure assessment. Presence of biomarkers reflects
exposure by some route and reasonable estimation of the exposure can be done, at least for
TDI, MDI and HDI.
At present, air- or biomonitoring is only rarely performed. This is especially the case for
companies outside the traditional PUR industry. When monitoring is performed only a few
samples are collected per year. Sometimes only the work environment for one worker out of
69
hundreds is studied. When levels are considered low the number of samples collected are even
fewer when monitored next time. Typically exposure peaks that occur during incidents and
other non routine handling are not studied. Without exposure data problems may occur for
workers to achieve compensation due to work related disease.
For an accurate exposure assessment the sampling protocols are a critical factor and must take
into account alternative routes of exposure, such as dermal contact, and changes in work
practice. Air measurements of isocyanates and degradation products of PUR are of great
importance to improve workers safety and health. Focus on the cost, for air monitoring, may
result the less sophisticated method possibly giving misleading information and unawareness
of exposure risks.
No perfect method is available, but minimum requirements of an air method are: 1. Efficient
collection that makes it possible to analyse gas and particles separately; 2. Efficient and robust
derivatisation of the collected species; 3. Selective determination of collected substances; 4.
Detection limit 2-3 orders of magnitude lower than the TLVs or < the MRLs. In addition,
stable derivatives and reagents, access to reference compounds and easy sampling procedure
are also important aspects to consider. The most suited method for the situation to be
monitored needs to be used, with the knowledge of its limitations.
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10.3
Relevant background documents
10.3.1 Letter from Sweden to DG-employment 1997 regarding newly discovered risks of
isocyanates 1997
(Letter to The European Commission from The National Board of Occupational Health and
Safety with Copy to the Ministry of Labour August 28 1997 by Executive officer Jan Olof
Norén, ref: 71 YKE2940197)
Newly discovered risks of Isocyanates
In this letter the National Board of Occupational Health and Safety would like to draw the
attention of the other member-states to the newly discovered risks of isocyanates created
during the decomposition of Polyurethanes.
In Sweden attention has been focused on the risks arising from the thermal decomposition of
polyurethane plastic and products containing polyurethanes. Some of the products of such
decomposition have been unrecognised or disregarded. At one industrial plant in southern
Sweden, 30 employees have had to quit on developing allergies after heating polyurethane
adhesives. The employees were unaware that the adhesives they were heating decomposed
and that they were therefore exposing themselves to high levels of isocyanates. Similar
problems have been reported from garages where polyurethane coated steel was being
welded.
Isocyanates belong to the group of chemical substances that are being used in increasing
quantities and within many industries. They are used principally in the production of
polyurethane polymers. Polyurethane polymers are very important and are used in many
industries. This use is increasing.
New measurement techniques to detect the thermal decomposition of polyurethanes.
Determination of the decomposition process of polyurethane has been made possible largely
thanks to the new measurement techniques developed by a group of researchers led by
Gunnar Skarping and Marianne Dalene in Lund. These new measurement techniques enable
study of the products of the decomposition of polyurethanes, which has previously been
impossible. It has been possible to determine what other components can be found in
technical isocyanate products apart from the simplest isocyanates. These new measurement
techniques, unlike earlier methods, have disclosed that considerable levels of isocyanates can
arise during the welding, for example, of polyurethane-coated steel plate.
Measuring devices providing instant read-outs have been developed so that it is now possible
to study the level of isocyanates during comparatively brief processes and to establish which
elements in that process are critical. New methods of revealing the impact of isocyanates
using urine samples and blood samples have also been developed.
Measuring methods and critical levels
The traditional methods of gauging isocyanates have been based on establishing levels of the
smallest constituent isocyanate components (monomers). Methods have been developed for
doing this. Critical levels have been established on the basis of these methods.
Most of the countries in western Europe have the same critical levels as Sweden (.005 ppm).
The USA and Canada also use these values. In the United Kingdom the critical value is
75
calculated on a different basis but is after conversion comparable with those of other
countries.
The dangers of isocyanates
Isocyanates constitute a health risk principally when inhaled in the form of vapor, dust or
mist. Inhaling can also give rise to irritation of the mucous membrane with symptoms similar
to asthma or bronchitis and reduced lung function. There is a great risk of hypersensitivity.
Isocyanates can also have an irritant effect on the eyes, skin and respiratory organs. Repeated
contact with isocyanates can give rise to eczema and in certain cases skin allergies.
Isocyanates have very low critical levels. An allergic individual may be occasioned obvious
discomfort when levels are far below the minimum hygienic levels.
In Sweden it is apparent that isocyanate related injuries are under-reported, often due to the
fact that medical problems are not linked to exposure to isocyanates. In most countries there
are strong warnings about the risks involved in handling isocyanates.
Further work in Sweden on isocyanates.
At the moment the work of establishing those jobs involving risk is being carried out in
Sweden, both by the Labour Inspectorate and through the work of the research group in Lund
and other groups. The new measurement techniques are being evaluated by the Labour
Inspectorate.
The National Board of Occupational Health and Safety is going to mount a major information
campaign to warn people of the newly discovered risks linked to the thermal decomposition
of isocyanates. In the future activities of the Labour Inspectorate, priority will be given to
direct inspection measures in this problem area.
Communication
It is the desire of the National Board of Occupational Health and Safety that the Commission
will draw the attention of the other states within the European Union to the risks involved in
the decomposition of polyurethanes when heated. In addition it is proposed that funds should
be made available for further research and standardisation within this field to throw light on
the relationship between exposure and health risks. It is important to attain uniformity in the
different member states with regard to the assessment and specification of levels of protection
required when handling isocyanates and during thermal processing of polyurethanes.
10.3.2 Bakke JV, Ed. Isocyanates – risk assessment and preventive measures. The
”Nordic isocyanate report 2000”. Meeting of the Nordic supervisory authorities
in Copenhagen on 27 April 2000. Summary
(The complete report is available at
http://www.arbeidstilsynet.no/publikasjoner/rapporter/rapport1eng.html)
Exposure to diisocyanates is in some countries the most important specific single cause of
occupational asthma. In spite of this, isocyanate asthma is probably underdiagnosed. This
group of chemicals may constitute the most important specific chemical hazards in working
life today and should be given high priority by the authorities (inspection work). New
exposure assessment methods have identified other substances (amines, isocyanic acid, etc)
and new sources of exposure, including situations in which polyurethane or production
involving isocyanates is not present. Great improvements in exposure assessment methods
76
may alter the existing scientific foundation for risk assessments and TLVs / OELs (Threshold
Limit Values / Occupational Exposure Limits).. The Labour Inspectorate in Norway therefore
initiated a Nordic co-ordination meeting between the Nordic labour authorities to explore the
opportunities for a holistic strategy to meet these challenges. A main objective was to
examine the need and opportunity to develop scientific consensus as the foundation for risk
evaluation and management in the longer run. At the same time we wanted to get an overview
of relevant and effective preventive measures that can be implemented immediately.
The meeting reached consensus on the following statements
The term isocyanates includes monomers as well as prepolymers.
It is only exposure to di- and higher isocyanates, not to methylisocyanate or other
monoisocyanates, which has been shown to have sensitising properties,
Requirements should be imposed to train workers who may be primarily or
secondarily exposed to isocyanates (thermal decomposition, welding, soldering, and
grinding of polyurethane surfaces).
Secondary exposure may be a more serious problem than primary exposure because its
extent and level are not known and many of the exposed are not aware that they are, or
have been, exposed.
Secondary exposure constitutes a serious challenge regarding both risk assessment and
risk management
Primary exposure seems to be under reasonably good control as far as the authorities
are concerned. Possible effects of skin exposure may represent an exception.
In view of irritative effects, possible airways-sensitising effects by skin exposure and
the risk of uptake through the skin at conceivable system-toxic levels, handling of
uncured isocyanates should not involve any skin exposure
There is a need for new exposure assessment methods, particularly in cases of mixed
exposure comprising gaseous and particulate matter
The meeting reached a number of common recommendations on the basis of the above
consensus.
We recommend that the Nordic authorities initiate a broad international inter- and
multidisciplinary consensus conference on isocyanates to develop and establish a competent
and qualified state of the art in the field. This conference should be arranged in 2001. The
report from this meeting can then be used as the basis in bringing up the issue to the EU (DG
Employment) for setting OEL (Occupational Exposure Limits).
77
10.3.3 Levin JO et al. Isocyanates in Working Life. Report from a workshop organised
by the Swedish National Institute for Working Life, and held in Brussels, 26th28th April 1999 (Levin et al.1999)
Isocyanates in Working Life
http://www.niwl.se/wl2000/workshops/workshop29/report_en.asp
April 26--28, 1999, Brussels.
Report from a workshop organised by the Swedish National Institute for Working Life, and
held in Brussels, 26th-28th April 1999.
Jan-Olof Levin1, Richard H. Brown2, Richard Ennals3, Roger Lindahl1, and Anders Östin1
1.
2.
3.
National Institute for Working Life, Department of Chemistry, POB 7654, SE-907 13 Umeå, Sweden.
Health and Safety Laboratory, Broad Lane, Sheffield S3 7HQ, UK
Kingston University, Kingston Business School, Kingston Hill, Kingston upon Thames, Surrey KT2
7LB, UK
Introduction
The Swedish National Institute for Working Life (NIWL) organised an international
workshop with the title “Isocyanates - Measurement Methodology, Exposure and Effects” in
Brussels 26-28 April 1999 (Levin 2000). It was one of a series of workshops preceding the
conference “Worklife 2000”, January 22-25, 2001, in Malmö, Sweden.
Approximately 20 scientists in the field from Europe and the US were invited to participate,
see list below. The workshop was of an informal nature with ample time for discussion.
Below a summary of the presentations is given together with some conclusions from the
workshop.
Isocyanates - Effects and exposure
Highly reactive isocyanates (R-N=C=O) are nowadays used in many workplaces. They may
become airborne in gaseous or aerosolised forms. When inhaled, they bind to human tissues,
proteins and DNA, forming toxic adducts and metabolites which may cause adverse health
effects. Bronchial asthma is the most frequent clinical diagnosis in isocyanate workers.
Further diseases caused by these chemicals include non-obstructive bronchitis, rhinitis,
conjunctivitis, dermatitis and extrinsic allergic alveolitis.
The diagnosis of isocyanate-induced disorders is based on a stepwise approach, starting with a
detailed occupational case history, measurement of specific isocyanate-IgE antibodies, lung
function testing, follow-up during working hours and spare time and, in doubtful situations,
occupational-type inhalative challenge with the suspected causative agent. Due to the
heterogeneous pathogenic mechanisms, negative immunological tests (seen in 85% of
isocyanate asthma cases) and the absence of bronchial hyperreactivity to methacholine do not
exclude isocyanates as causative substances. To ensure reversibility, the early diagnosis of
isocyanate-induced disorders is required.
Since the health risk is concentration-dependent, the most important preventive measure is the
reduction of exposure levels. Concentrations at or below the current occupational exposure
limits (OELs) (mostly 10 ppb) do not exclude effects. Therefore, the development of
improved routine analyses of all airborne isocyanates as well as of methods for biological
78
monitoring is urgently required. Further, where possible, a health-based OEL comprising all
isocyanate groups should be stipulated, and workers at risk should undergo regular medical
surveillance programmes.
In the US, health surveys of plants using isocyanates have been conducted by the US National
Institute for Occupational Safety and Health (NIOSH). The construction of a new facility
provided the opportunity to study the workers' health, prior to, and after, the introduction of
diisocyanate. Several tools have been used to evaluate workers' respiratory status. A health
questionnaire was administered prior to, and twice a year for two years after, the introduction
of isocyanate. Occupational and work practice questionnaires were also obtained. Lung
function testing and skin testing to common allergens were performed. Blood was drawn for
isocyanate specific and total IgE measurements. Nasal lavage was performed on workers at
the end of their work shifts.
Workers are also potentially exposed to other work place antigens such as raw, unfinished
wood and isocyanate finished wood products in places where isocyanate is used as a wood
binder. Extracts from each of these materials were used to screen for potential IgEs.
Preliminary data showed that specific IgE to both isocyanate associated antigens and other
work place antigens can be found in workers from plants using diisocyanates in their
processes.
Workplace asthma caused by exposure to isocyanates has shown no decrease in the UK, with
some 400 cases per year, while the overall use of isocyanates by UK industry is increasing
slowly. Levels of occupational asthma do not appear to have fallen, although reporting levels
may have risen through increased awareness. Analysis of the summarised health data shows
that incidence of asthma is not restricted to the motor vehicle industry, but dangers may be as
great in other isocyanate using industries, such as, for example, spraying isocyanates into
moulds to form rigid foam.
In Sweden there is an intense debate about isocyanates. Special attention has been drawn to
the risk entailed by the thermal degradation of polyurethane plastics and products containing
polyurethanes. Some of these degradations have been unknown or overlooked. What is also
new is the newly discovered generation of low-molecular isocyanates which occur when
heating up materials containing some combinations of phenyl-formaldehyde-urea. Examples
of workplaces where isocyanates will occur, will include heating of mineral wool in oven
insulation, of binders for core making in the foundry industry, and hot work in car repair
shops.
The Polyurethane (PU) Industry routinely carries out occupational hygiene measurements,
both in-house and at their customers' factories, to assess workplace exposures during the
manufacture and use of PU chemicals. A wide variety of compounds are used by the PU
industry, e.g. release agents, blowing agents, cleaning agents, fire retardants, surfactants and
isocyanates for routine manufacture of a vast range of products, such as rigid and flexible
foams, elastomers, adhesives, coatings, paints, binders, etc. ICI for example, has carried out
occupational hygiene studies and surveys in-house and at customer premises to measure the
concentration of 4,4«-diisocyanatodiphenylmethane (MDI) in the workplace during the
manufacture and use of polyurethanes. Data from over a thousand personal samples have been
generated. Exposure assessments have included personnel who had the potential, by way of
their job activities, to be exposed, e.g. line operatives, line supervisors, maintenance staff,
product finishers, cleaners, QA staff, electricians, laboratory personnel, warehouse staff,
79
forklift truck drivers, etc. Overall, exposure to MDI is well controlled, with only two values
from 1327 personal samples resulting in values > 0.05mg/m3 (8 hour time-weight average).
Adopting monitoring methods capable of detecting and quantifying all isocyanate containing
species allows assessment of total isocyanate exposure as well as providing an insight to the
physical form of the MDI.
In summary, human exposure studies indicate that isocyanate exposures during work are
associated with occupational asthma. Such studies may provide insight into the relationship of
diisocyanate-induced disease and specific work practices and potential routes of exposure.
Isocyanates - Measurement methodology
Collection of samples can be through use of impingers/bubblers or filters, each involving
reagents. There can be internal losses of material in both impinger inlets and on the walls of
filter cassettes. There are also issues of the efficiency of reactions of particles with reagents
on filters. Impingers raise questions of particle sizes collected (for small particle sizes).
Instrumental (paper tape) methods are more suitable for exposure profiling over time than for
quantification.
Derivatives:
Each of the reagents has strengths and weaknesses. Older solutions are still in use, such as
Marcali, ethanol, nitro-reagents and 1-(2-methoxyphenyl)piperazine (2MP). On occasions
several detectors are required, for example a combination of electrochemical (EC) and
ultraviolet (UV) detection. The reagent 1-(2-pyridyl)piperazine (2PP) is effective in
separating isocyanates, but still finds polyisocyanates difficult. The reagent 9(methylaminomethyl)anthracene (MAMA) uses a detector-response ratio as a means of
quantification, but the ratio is not constant. Tryptamine also uses two detectors, but is more
constant than MAMA in fluorescent yield. MAP (1-(9-anthrecenylmethyl) piperazine)
combines the advantages of 2MP and MAMA, and gives the most constant yield. Di-nbutylamine (DBA) has the fastest reaction time, as high concentrations can be used. At
present this is an expensive and non-routine method, since it utilises liquid chromatographicmass spectrometric determination. The Iso-ChekTM sampler is a hybrid method, separating
the isocyanate particles and vapour and using both MAMA and 2MP derivatization.
In the UK the Health and Safety Laboratory method MDHS 25 is used, which utilises the
2MP derivative with EC+UV detection. There are potential problems with MDHS 25, i.e. the
reliance on the EC/UV ratio being consistent, and mis-identification can occur, with incorrect
quantification. However, good results were obtained in comparison with direct titrations of
polyisocyanates. The EC/UV ratios of several industrial isocyanate samples have been
investigated.
Six steps in sampling and analysis, each of which can have problems, can be identified:
Collection:
Efficiency problems of aspiration, internal losses and transmission losses are frequent.
Problems are addressed through inhalable sampler, filters and impingers. Vapour collection
depends on derivatization efficiency.
80
Derivatization:
Efficiency is affected by reagent reactivity, concentration and mixing. Flexibility is
recommended in sampling, covering collection and derivatization, given the limitations of
both filters and impingers, and taking into account the environments concerned and the
duration of the sampling. Filters should be extracted in the field. Use of high boiling solvents
is preferred.
Sample preparation:
The fewer things you do, the better. Losses are a potential problem with liquid-liquid
extraction as well as solid phase extraction.
Separation:
Separation has been dominated by reversed-phase high performance liquid chromatography
(HPLC). Several methods use a bulk product for calibration. Monomers can be used for
calibration in other methods. Isocratic elution has advantages: simple, stable and unvarying
baseline. Gradient elution is more powerful and faster, but may have an adverse effect on the
baseline. In the MAP method, pH gradient elution is used. It is also powerful, selective, and
gives a stable baseline.
Identification:
Retention time is important for monomers, while for oligomers selective detectors are needed,
multi-dimensional detectors or two detectors. For identification of MAP a UV/fluorescence
ratio is used. For safe and complete identification mass spectrometry is needed.
Quantification:
There can be direct calibration curves for monomers, while for oligomers it is a matter of bulk
calibration or monomer calibration.
Thermal degradation of PUR:
For thermal degradation a method based on the derivatization of aromatic and aliphatic
isocyanates using di-n-butylamine (DBA) followed by the derivatization of aromatic and
aliphatic amines with ethylchloroformate has been used. The DBA-method has been
demonstrated for isocyanate-adducts, -monomers and thermal degradation products of PUR,
for example when welding buses. Fast reaction rates between isocyanates and DBA were
observed and the method was found to be robust, with no influence of interfering compounds.
For a 0.01 mol 1-1 DBA concentration, the reaction rate was very fast and it was not possible
to study the time dependence of the reactions. The removal of the reagent during the work-up
procedure greatly facilitates the subsequent chromatographic determination and allows the use
of DBA at high concentrations.
81
Quality assurance of isocyanate measurements
National standardisation has been diverse. For example, the Swedish National Institute for
Working Life in 1997 recommended the DBA method. The UK Health and Safety Executive
recommends 2MP (which meets the performance requirements of EN 482) and Marcali.
NIOSH has three methods: 2MP, tryptamine, and the nitro reagent method.
Internationally the ISO standardisation committee ISO/TC146 has 5 methods under
consideration: 2MP; and four new work items; DBA, Iso-ChekTM, MAP and Guide on
selection of procedures.
In 1991 the European Commission decided that certified reference materials in the form of
2MP derivatives should be prepared for isocyanates. The specified certification studies have
been undertaken, and Certified Reference Materials (CRMs) have been prepared, and can be
obtained from the Community Bureau of Reference (BCR).
There are independent proficiency testing schemes like the UK WASP (Workplace Analysis
Scheme for Proficiency).
Conclusions, recommendations and needs for future research
-
-
-
-
-
-
Isocyanates result in more reported cases of occupational asthma and similar
respiratory disorders, than any other group of chemicals. Industrial uses of isocyanates
include manufacture of polyurethane foam, surface coatings, adhesives and textiles,
and occupational exposure can occur, particularly in processes involving heating and
spraying isocyanates.
Most countries have adopted occupational limit values based on monomeric
isocyanates. However, polyisocyanates (diisocyanate polymers or prepolymer adducts
with polyamines) and low molecular weight isocyanates (such as methylisocyanate)
are also used or can occur industrially. Toxicological evidence suggests that they
should also be included in setting appropriate harmonised limit values.
Methods exist for the determination of airborne isocyanates. These are mostly
complicated, expensive, and require a high degree of technical competence. There is a
need for simpler, more cost-effective methods. This would facilitate monitoring by
Small and Medium Sized Enterprises (SMEs).
There is a need for the further development of sampling and analytical methods for
isocyanates, particularly airborne, but also for dermal exposure and biological
monitoring. Where possible, such methods should be simple and cost effective, and
distinguish between vapour and particulate isocyanates.
Sampling and analysis methods should be supported by validation (such as according
to EN 482), quality control, quality assurance and certified reference materials.
The relative toxicity and metabolism associated with health effects of different
isocyanate species should be further investigated in particular connection with setting
limit values and improving biological monitoring. The parent compounds and
metabolites may be genotoxic or carcinogenic, in addition to having allergenic
potential. The metabolism of aromatic and aliphatic isocyanates has not been studied
in detail. There is also a lack of epidemiological studies on isocyanate workers.
Therefore, it is strongly recommended that such investigations are carried out.
Cases of occupational asthma have been observed where no measurable isocyanate in
air were identified, implying a deficiency in the sampling and analytical methods used
82
-
-
-
and/or an incorrect limit value and/or exposure via routes other than inhalation. For
this reason, air measurements should be seen as part of an occupational hygiene
assessment that might also include estimates of surface contamination, skin absorption
and/or biological monitoring and health surveillance.
In cases where isocyanate exposure cannot be prevented by substitution or minimised
by engineering controls, and is controlled by the use of personal protective equipment,
particular attention should be paid to the correct selection, maintenance and use of
such personal protective equipment.
There is debate about the current levels of exposure using available technologies and
methods. All too often measurements are infrequent, governed by the requirements of
law. Occupational hygienists should be encouraged to do more assessment.
There is a discussion of prevention, as opposed to monitoring. There is an opportunity
to address this issue for politicians. What is wanted is control of the environment,
rather than the requirement to dress up workers in special clothing. Regular
monitoring can reduce the incidence of exposure, accompanied by health surveillance.
There are difficulties in predicting particular problems in individual workplaces. There
is a need for improved education and communication.
International practice is already affected by requirements of environmental legislation,
such as requirements of the US Environmental Protection Agency, as it affects the
workplace; there can be obligations to report when particular materials are in use.
Workshop participants
Xaver Baur, Professional Associations' Research Institute for Occupational Medicine (BGFA)
Bochum, Germany
Karl S. Brenner, BASF, Germany.
Richard H. Brown, Health and Safety Laboratory, UK
V. Dharmarajan, Bayer Corporation, USA
Kurt Egemose, Miljö-Kemi, Denmark
Richard Ennals, Kingston University, UK
Lars-Erik Folkesson, The Swedish Trade Union Confederation, Sweden
Eddy Goelen, Flemish Institute for Technological Research, Belgium
Uwe Karst, Westfälische Wilhelms-Universität Münster, Germany
Roger Lindahl, National Institute for Working Life, Sweden
Paul Maddison, ICI Polyurethanes, Belgium
John McAlinden, Health and Safety Executive, UK
Jan-Olof Norén, National Board of Occupational Safety and Health, Sweden
Claude Ostiguy, Institut de Recherche en Santé du Travail, Canada
Paul D Siegel, National Institute for Occupational Safety and Health, USA
Gunnar Skarping, Lund University Hospital, Sweden
Bob Streicher, National Institute for Occupational Safety and Health, USA
Valerie Wilms, Berufsgenossenschaft der Strassen-, U-Bahnen und Eisenbahnen, Germany
Anders Östin, National Institute for Working Life, Sweden
Additional information
A full report from the workshop will be published by the Swedish National Institute for
Working Life in Work Life 2000, Yearbook 2, 2000 (Ed. R. Ennals), Springer, London.
83
Conclusions and recommendations from the workshop will be reported at the conference
ÒWorklife 2000Ò, January 22-25, 2001, in Malmö, Sweden. For information see
http://www.niwl.se/wl2000/ .
Information on ISO standardisation can be obtained from the convenor of ISO
TC146/SC2/WG4 Richard H Brown at the address given above.
10.3.4 The Swedish exposure assessment project – “Isocyanate 2000”. Abstract (Norén
2000)
(Norén JO, Arbetarskyddsstyrelsens mätprojekt 1997 – 1999 Isocyanater.
Arbetarskyddsstyrelsen, Solna 2000, Rapporten sammanställd av Arbetarskyddsstyrelsen i
samarbete med Yrkesinspektionerna i Malmö, Växjö, Göteborg, Linköping, Örebro,
Stockholm, Falun, Härnösand, Umeå och Luleå)
Between 1997 and 1999 the National Board of Occupational Safety and Health and the
Labour Inspectorate carried out a measurement project to chart isocyanate exposure in
industry and activities where products containing isocyanates are handled, where isocyanates
can occur as a result of thermal degradation of polyurethanes, or where formaldehyde-based
resins with nitrous additives are heated in such a way that low-molecular isocyanates are
liable to occur (Norén 2000). Parts of the project which were mainly concerned with methods
of measurement have already been presented in an interim report (Ref. 1).
In the course of the project, 105 undertakings were visited. During these visits the Labour
Inspectorate took measurements at 530 points, of which 118 were stationary, while the
remaining 412 exposure measurements related to individuals. In 115 measurements the
Isologger® were used as the only measuring-method. The occupational exposure limit value
was found to have been exceeded in 6% of the 415 measurements which were subsequently
followed by chemical analysis (i.e. measurements which were not directly indicative). Twothirds of these overshoots were related to personalised measurements, i.e. direct exposure of
the individual. In another 19% of the total number of measurements analysed, individual
exposure ranged from 10% to 100% of the exposure limit value for isocyanates.
The scope of the measurements was limited in sectors where comprehensive measurement
projects have been undertaken by other agencies, e.g. the vehicle repair trade, windscreen
gluing and foundries. Other activities excluded completely include, for example, the foaming
of mattresses and suchlike and vehicle-spraying, due to the exposure situations there being
well known.
The highest atmospheric concentrations of isocyanates were observed in various types of hot
work. In the degradation of polyurethane plastic (with isocyanates as the initial material), the
initial isocyanates are re-formed and other, new isocyanates, among them methyl isocyanate,
MIC, are formed as well. Heavy concentrations of isocyanates have been shown, for example,
in foundries casting by the Cold Box method and in connection with the welding of sheet
metal newly coated with isocyanate paint. We found high concentrations above all of methyl
isocyanate, MIC, in fragmentations of formaldehyde-based resins with nitrous additives.
Other operations where this was observed include laser-cutting of plywood and the
manufacture of pressed sawdust products and formaldehyde-urea adhesive. High
concentrations of methyl isocyanate were established in connection with the burning off of
industrial furnaces.
84
Most of the measurements in the project took place during traditional manufacture of
polyurethane products. In the majority of measurements, these operations yielded low
exposure values. Here again, the working temperatures make a difference. In connection with
the manufacture of polyurethane parts, high concentrations were observed during casting at
elevated temperatures of the isocyanates in several undertakings in the plastic and rubber
goods industry. These exposures are generally well known, and people protect themselves by
using various kinds of respiratory protection etc. One measurement at a sailmaker’s revealed
remarkably high MDI concentrations during high-temperature gluing, even though this was
made on a smaller area than a complete sail. Elevated isocyanate concentrations have not
generally been found in connection with cold work, with the exception of TDI. In cases where
high concentrations of isocyanates were observed, remedial measures have generally been
stipulated on the basis of existing rules for the working environment.
Various methods for measuring isocyanates in the field were compared during the project. For
this purpose we used the DBA impinger method, comparing it with a modified MDHS 25
method (ref 25) of measurement, based 2-MP reagent on a filter, developed by the National
Institute for Working Life in Umeå. We also employed an Isologger ® direct-reading
instrument and the earlier MAMA impinger method. Conclusions drawn from these
comparisons included the following.
Generally speaking, when impinger sampling is used, a filter should be used
downstream of the impinger, because small particles pass through the impinger itself.
Small particles (smoke) are above all generated by hot work. This problem does not
occur when reagent-coated filters (2-MP, for example) are used.
Agreement between the DBA and 2-MP measuring methods varies considerably. For
phenyl isocyanate, TDI and NDI the agreement is relatively good. For MDI and MIC
a wider spread is obtained. MIC probably requires an impinger or a reagent-coated
adsorbent for quantitative sampling.
Methods employing LC-UV analysis often yield different results from those using
LC-MS or LC-MS-MS. Methods of high specificity are required, especially in
complex environments (hot work), and mass-spectrometric analysis is therefore
recommended for all such isocyanate measurements.
Generally speaking, we find it regrettable that other than monomer isocyanates are
not analyzed in isocyanate measurement. True, the monomers are the most volatile,
but more complex isocyanates can also occur atmospherically, e.g. in connection
with thermal fragmentation and in connection with paint-spraying. These larger
isocyanates are not routinely analysed, and a low value stated for a mono-isocyanate
may conceal high values for oligomeric isocyanates.
Consequently, in spite of improved methods of analysis for monomer isocyanates,
we still cannot be certain about exposure in jobs where more complex isocyanates
are generated.
The Labour Inspectorate should in accordance with the "Plan of Activitiesis" for The Swedish
occupational Safety and Health Administration 2000/2002 carry out targeted supervision,
based on current rules for the working environment, of the workplaces where isocyanates are.
During the past three-year period, all inspection districts compiled inventories of current
workplaces where isocyanates were handled or formed. Those inventories will now form the
basis of inspections. A conspectus will be prepared by the National Board of Occupational
Safety and Health in order, if possible, to obtain as complete a picture as possible of
isocyanate handling and exposure.
85
10.3.5 German OELs regarding isocyanates
Ute Latza, Xaver Baur
German exposure limits for isocyanates
In Germany, the Commission for the Investigation of Health Hazards of Chemical
Compounds in the Work Area (MAK-Commission) has established health-based occupational
exposure limits (MAK-values) for monomeric isocyanates (Table 1). Similar to the definition
of the American Conference of Governmental Industrial Hygienists (ACGIH) for the
Threshold-Limit-Value-Time-Weighted-Average (TLV-TWA), the MAK-values are defined
as time-weighted average concentrations for a normal 8-hour workday and a 40-hour
workweek, to which nearly all workers may be repeatedly exposed day after day, without
adverse effect. In addition, there is a short term exposure limit (STEL) that is identical to the
8-hour TWA for some isocyanates (NDI, MDI, HDI, IPDI, MIC, PhI). Similar to the TLVSTEL of the ACGIH, this STEL is defined as a 15-minute TWA which should not be
exceeded at any time during a workday.
The existing MAK-values in Germany do not consider all –N=C=O groups relevant in
workplaces and which may influence the human health. Thus, they usually underestimate the
actual isocyanate exposure. In 1992 and 1996, the MAK-values for MDI and HDI,
respectively were reduced to 5 ppb due to animal-experimental and occupational medical
findings. The MAK-values for TDI and polymeric MDI were suspended because of suspected
carcinogenicity. At present there are no MAK-values for other monomeric isocyanates, and
polyisocyanates available.
Several of the MAK-values have been adopted by the federal agency in charge. In Germany,
the Committee for Hazardous Substances (AGS) under the hospice of the Ministry of Labor
and Social Affairs sets legally binding administrative norms. At present such norms exist for
some airborne monomeric diisocyanates, and two monoisocyanates but not for oligomeric or
polymeric isocyanates, and mixtures (Technical Directive on Hazardous Substances listed in
TRGS 900). There is a STEL for the isocyanates corresponding to the MAK classification,
and additionally for TDI. The AGS is planning to reduce the administrative norm for TDI to
0.035 mg/m3 but to allow a fourfold STEL (this means 15 minute TWA should not exceed
0.14 mg/m3). Lately, the AGS has approved descriptions of exposure scenarios for typical
workplace areas including a semi-quantitative estimation of the expected exposure as a basis
for a mandatory medical surveillance program for isocyanate workers.
Recently, the AGS (based on recommendations of the MAK-Commission) stipulated a
Biological Exposure Index (BEI) (BAT: biological tolerance value for occupational
exposures) for MDI (10 µg 4,4’-diaminodiphenylmethane / g creatinine; included in the
TRGS 903) that is not legally binding at present on account of several uncertainties. Whether
this threshold value is appropriate with regard to the problematic measurements issues has not
been scientifically evaluated yet.
86
Table 1: Health-Based Occupational Exposure (OELs: Maximal Workplace Concentration
(MAK)) and Legally Binding Norms, Carcinogenicity, and Sensitization Properties of
Isocyanates in Germany1
Abbreviation
EU-/ CAS-
Isocyanate
MAK1
number
Administrative
Category of
Sensitization/
norms2
carcinogenicity3
skin absorption3
Aromatic diisocyanates
TDI
209-544-5,
Toluylene 2,4 diisocyanate
4
Toluylene 2,6 diisocyanate
4
6
584-84-9
TDI
202-039-0,
6
91-08-7
airways
0.07 mg/m3,
3A
airways
5
3B
airways, skin/yes
3B
airways, skin
10 ppb
247-722-4,
MDI
202-9660,
4,4’-Methylene diphenyl
101-68-8
0.07 mg/m3,
m-Diisocyanatoluol (1,3-)
2641-62-5
9016-87-9
3A
10 ppb
TDI
PMDI
0.07 mg/m3,
10 ppb
0.05 mg/m3,
0.05 mg/m3,
disocyanate
5 ppb
5 ppb
Polymeric MDI
4
0.05 mg/m3,
5 ppb
NDI
221-641-4,
1,5’- Naphtylene diisocyanate
3173-72-6
5
0.09 mg/m3,
0.09 mg/m3,
10 ppb
10 ppb
0.035 mg/m3,
0.035 mg/m3,
5 ppb
5 ppb
airways
Aliphatic diisocyanates
HDI
212-485-8,
Hexamethylene 1,6 diisocyanate
TMDI
241-001-8,
2,2,4’ - Trimethylhexamethylen-
16938-22-0
1,6-diisocyanate
239-714-4,
2,2,4’ - Trimethylhexamethylen-
15646-96-5
1,6-diisocyanate
822-06-0
TMDI
airways, skin
0.04 mg/m3
0.04 mg/m3
Cycloaliphatic diisocyanates
IPDI
223-861-6,
Isophorone diisocyanate
HMDI, PICM
225-863-2,
Methylen-bis-(4-
5124-30-1
cyclohexylisocyanate)
210-866-3,
Methyl isocyanate
4098-71-9
5
0.09 mg/m3,
10 ppb
0.09 mg/m3,
airways, skin
10 ppb
0.054 mg/m3
Monoisocyanates
MIC
624-83-9
PhI
203-137-6,
Phenyl isocyanate
103-71-9
5
0.024mg/m3,
0.024 mg/m3,
10 ppb
10 ppb
0.05 mg/m3,
0.05 mg/m3,
10 ppb
10 ppb
skin
1 Deutsche Forschungsgemeinschaft (DFG). List of MAK and BAT values 2001. Commission for the Investigation of Health Hazards of
Chemical Compounds in the Work Area. Weinheim, Wiley-VCH, 2001.
2 TRGS 900 in connection with TRGS 901 (phenyl isocyanate), and TRGS 905 (MDI): Technische Regeln für Gefahrstoffe, TRGS 900,
Grenzwerte in der Luft am Arbeitsplatz, TRGS 901 Begründungen und Erläuterungen zu Grenzwerten in der Luft am Arbeitsplatz,
Allgemeiner Staubgrenzwert, TRGS 905, Verzeichnis krebserzeugender, erbgutverändernder oder fortpflanzungsgefährdender Stoffe. BArBl
(2001), 9, 86-96.
3 Established by the MAK-Commission. Category 3 of carcinogenic substances comprises substances suspected of causing cancer in humans
that cannot be assessed conclusively because of lack of data (category 3A substances without sufficient data; category 3B substances with
clues from animal and in vitro tests).
4 MAK-value suspended because of suspected carcinogenicity
5 Scheduled further evaluations of the MAK-Commission
6 Scheduled lowering of the OEL to 0.035 mg/m3 together with a higher peak limitation value by the AGS
87
10.3.6 Nordic network on isocyanates (NORDNI) DRAFT
Molander P Ed., Levin JO, Östin A, Rosenberg C, Henriks-Eckerman ML, Thorud S,
Fladseth G, Hetland S, Brødsgaard S, Thomassen Y. Harmonized Nordic Strategies for
Isocyanate Monitoring in Workroom Atmospheres, Consensus report, Nordic network on
isocyanates (NORDNI), Frøya, Norway, 31.08.-02.09.2001. In Press.
Consensus report from the 1st NORDNI meeting at Frøya, Norway, August 31st –
September 2nd 2001 on Harmonized Nordic Strategies for Isocyanate Monitoring in
Workroom Atmospheres
NORDNI delegates
Jan-Olof Levin, Natl. Inst. Working Life, P.O.Box 7654, SE-90713 Umeå, Sweden
Anders Östin, Natl. Inst. Working Life, P.O.Box 7654, SE-90713 Umeå, Sweden
Christina Rosenberg, Finnish Inst. Occup. Health, Topelieuksenkatu 41aA, FIN-00250,
Helsinki, Finland
Maj-Len Henriks-Eckerman, Turku Regional Inst. Occup. Health, Hämeenkatu 10, FIN20500 Turku, Finland
Søren Brødsgaard, MILJØ-KEMI, Dansk Miljø Center A/S, Smedeskovvej 38, DK-8464
Galten, Denmark
Siri Hetland, MILJØ-KJEMI, Norsk Miljø Senter A/S, Nils Hansens vei 13, N-0667 Oslo,
Norway
Yngvar Thomassen, Natl. Inst. Occup. Health, P.O.BOX 8149 Dep, N-0033 Oslo, Norway
Syvert Thorud, Natl. Inst. Occup. Health, P.O.BOX 8149 Dep, N-0033 Oslo, Norway
Geir Fladseth, Natl. Inst. Occup. Health, P.O.BOX 8149 Dep, N-0033 Oslo, Norway
Pål Molander, Natl. Inst. Occup. Health, P.O.BOX 8149 Dep, N-0033 Oslo, Norway
NORDNI background
The Nordic Network on Isocyanates (NORDNI) was initiated by Dr. Jytte Molin Christensen,
Natl. Inst. Occup. Health, Denmark, and is financed by the Nordic Council of Ministers. The
network was founded on the experiences from a Swedish workshop on isocyanates in Umeå,
February 2000, organized by Dr. Jan O. Levin, Natl. Inst. Working Life, Sweden [1]. Due to
Dr. Molin Christensen’s change of affiliation, the NORDNI administration was transferred to
Dr. Yngvar Thomassen and co-workers, Natl. Inst. Occup. Health, Norway.
The aim of NORDNI is to establish a broad network between nordic institutions working
within the field of occupational health with special emphasis on isocyanate exposure.
Contemporary, an international network is established regarding isocyanates and occupational
health, covering a wider field including characterization of exposure, risk assessment and
regulations [2]. Thus, it was decided that the activity of NORDNI should focus on
establishing consensus between the nordic national institutes of occupational health on
strategies for isocyanate sampling and determination.
The 1st NORDNI meeting was arranged at Frøya Hotell in the Trondheim area in Norway
August 1st – September 2nd 2001, and this report summarizes the conclusions and consensus
from this meeting. The report is written by Dr. Pål Molander, Natl. Inst. Occup. Health,
Norway.
88
Introduction
Isocyanates are major industrial chemicals containing the highly unsaturated N=C=O group,
and their widespread use is related to their important role as raw materials for the production
of polyurethanes (PUR) to form foams, paints, lacquers, inks, insulating materials, varnishes,
rubber modifiers and bonding- and vulcanizing agents. PUR is formed by the reaction of a
difunctional isocyanate and a polyfunctional alcohol, and a wide range of PURs can be
tailored by reacting different isocyanates and polyols or simply by varying the physical
conditions controlling the polymerization process. The chemical bond between an isocyanate
and a polyol in PUR products is not thermally stable, and can potentially be broken upon
treatment at elevated temperatures to release compounds containing isocyanate or amino
groups. Both aliphatic and aromatic isocyanates are used for the production of PUR, and
hexamethylene diisocyanate (HDI) toluene diisocyanate (TDI) and methylene diisocyanate
(MDI) are the most frequently used isocyanates for this purpose. In addition to release of
HDI, TDI and MDI during thermal degradation of PUR products, the aliphatic
monoisocyanate methyl isocyanate (MIC) is also potentially released from certain products
containing organic bonded nitrogen, as in PUR products.
Unfortunately, isocyanates are highly toxic substances that act as respiratory irritants and
skin- and respiratory sensitizers, with the possibility of causing diseases like bronchitis,
pulmonary emphysema and asthma [3-5] in addition to allergic reactions [4]. Furthermore,
isocyanates have a mutagenic potential through their ready reaction with proteins and DNA to
form adducts [6]. Thus, monitoring of isocyanates in workroom air is important to industrial
hygiene.
As distinct from MDI, the monomers of HDI and the TDI isomers, as well as MIC, are
volatile, but may still be present in workroom air as non-volatile dimers, trimers or prepolymers. Thus, highly reactive isocyanates in workroom air may exist as vapors, aerosols or
in mixed phases, making sampling of isocyanates in workroom air a complicated task. Due to
the high reactivity of the isocyanates, the most commonly used sampling methods for
isocyanates in workroom air include a derivatization step by pumping a volume of air through
an impinger solution containing an amine reagent and/or a filter impregnated with the amine
reagent, resulting in the formation of stable, non-volatile urea derivatives of any organic
isocyanate present. A number of different amine reagents have been explored for the sampling
of isocyanates, including 1-(2-methoxyphenyl)-piperazine (1-2MP), dibutylamine (DBA) and
9-(N-methylaminomethyl)-anthracene (MAMA), while numerous liquid chromatographic
(LC) methods with ultraviolet (UV) or mass spectrometric (MS) or electrochemical (ECD)
detection have been presented for the determination of the isocyanate derivatives.
Present strategies for isocyanate monitoring in the nordic countries and future
recommendations
The first session of the meeting was devoted to discussions regarding the basis of a
coordinated Nordic viewpoint in light of the occupational exposure limits (OEL) and the
present strategies for isocyanate monitoring in the different Nordic countries. The delegates
from each country accounted for the national OELs and which strategies that were in use in
the different countries for isocyanate monitoring. It was concluded that both the OELs and the
present monitoring strategies offered favorable conditions for a harmonized Nordic viewpoint.
89
It was generally consensus on the fact that there is a need for sampling strategies for both
short-term (peak exposure) and long-term isocyanate exposure of gas/vapor phases, aerosol
phases and mixed phases, and that personal sampling equipment is preferred over stationary
equipment. Furthermore, an ideal sampling method should collect isocyanates present as
gas/vapors, aerosols or in mixed phases simultaneously. An 8-h long term sampling interval is
adequate, alternatively a 2-h sampling interval (to be multiplied with 4) if the working
atmosphere is presupposed to be homogenous over the 8-h interval. With respect to exposure
from thermally released isocyanates, the sampling time should be as least 5 minutes in order
to sample a required total air volume of not less than 10 L. Finally, the limit of quantification
of the chromatographic method should be at least 1/10 of the OEL.
Two methods are mainly in use in the Nordic countries regarding isocyanate sampling; The
DBA impinger/filter method [7], and the 1-2MP filter method [8]. Both methods have certain
advantages and drawbacks, and neither of them provide performance characteristics making
them fully suitable for representative simultaneous sampling of a wide range of isocyanates
present in different phases. Nevertheless, both wet impinger methods and dry filter methods
have generally very high collection efficiencies of isocyanate gas/vapor. For the most volatile
isocyanates, e.g. MIC, a double filter with increased film thickness of the 1-2MP agent is
required [9], as compared to gaseous diisocyanate sampling only. Sampling of isocyanates
present in aerosols, however, is a more complicated task. Impregnated filters are in general
highly suited for sampling of particles of all sizes. However, the amount of reagent available
for the active isocyanates is limited as compared to impinger solutions. This is especially true
for larger particles and/or particles containing a reacting mixture, e.g. a curing paint, possibly
leading to losses of isocyanates due to continued curing in aerosol droplets trapped on the
filter. Furthermore, only the isocyanates that are directly in contact with the filter are available
for reaction with the impregnated amine reagent, possibly leading to underestimation of
isocyanates located inside large particles or on the side of the particle surface that is not in
contact with the filter. Nevertheless, such effects can be reduced by the use of filters with
thicker reagent films and/or depth filters, in addition to immediate transfer of the filters into
reagent solutions after completed air sampling. In general, filter methods are more userfriendly than impinger methods, making them especially suitable for personal sampling.
Impingers were not originally constructed for aerosol sampling, but are in theory also suited
for sampling of size-limited fractions of particles. Impingers are constructed to have an ideal
collecting effect when using a flow rate of 2 L/min. However, toluene is used as impinger
solvent in the DBA method, putting limits on the maximum allowed air sampling flow rate in
order for toluene not to evaporate. Thus, an air sampling flow rate of 1 L/min are generally
used with the DBA impinger method, leading to breakthrough and insufficient collection of
submicron particles, which often are present in e.g. thermal degradation processes. This effect
can however be reduced by attaching a filter downstream to the impinger solution. The filter
will then be continuously coated with DBA in toluene evaporating from the impinger
solution. However, impinger flasks are fragile, it is cumbersome for the workers to wear them
and their use as personal samplers is not compatible with several working procedures. The use
of toluene can create additional exposure or fire hazards, because it evaporates during
sampling, additionally limiting the maximum sampling time available. Finally, impingers
require manipulation of solvents by the industrial hygienist in the field and subsequent
transportation of solvents.
After careful consideration of the advantages and limitations of impinger and filter methods, it
was consensus between the NORDNI delegates to recommend a dry filter method, due to the
90
user-friendliness and the availability of unlimited sampling time, covering both short-term
and long-term exposure. A thick-film coated double filter method and immediate transfer of
the filters into a reagent solution after completed air sampling was recommended in order to
establish a general method suitable for sampling of a wide range of isocyanates with origin
from both gas/vapor, aerosol and mixed phases. Based on previous published research work
and established, validated methods, it was consensus on the recommendation of 1-2MP as
amine reagent on double thick-film filters, as described in a Finnish method [9]. However, the
delegates of NORDNI wish to stimulate to further R&D activity on the use of DBA as amine
reagent, due to the high reaction rates with isocyanates, and certainly anticipate development
and launching of a user-friendly DBA filter method. However, such a method should be
published and critically evaluated before the network can recommend it on a broad basis.
Required characteristics of the isocyanate sampling device
Particle size selective occupational exposure limits have already been established to address
the problems associated with specific health effects. Since the inhalable aerosol fraction may
contribute to possible health effects among workers exposed to isocyanates, the network
recommends that relevant air sampling instrumentation is applied for gaseous, aerosol and
mixed phase sampling of isocyanates.
Several inhalable air sampling devices are commercially available, but some may
undersample the inhalable aerosol fraction due to inner-wall losses of droplets or particles
inside the sampler before they reach the filter. Since the well-known IOM cassette is designed
to include the inner-wall deposited aerosol mass in the measurements of the inhalable
fraction, a quantitative recovery of this deposited mass may be very difficult as isocyanate
aerosol matrix are likely to be polymerized. If such inner-wall deposition of a sampling device
is considered to be an important issue, a sampler design where only the aerosol collected on
the filter is used to assess the inhalable fraction should be preferred. An example of such a
device is PAS-6 [10]. It is the opinion of the network that this sampler has an attractive design
for mixed-phase isocyanate collection, although this sampler not yet has been evaluated for
isocyanate sampling. The network has confirmed that the double filters employed in the
Finnish method [9] fit well into the PAS-6 sampler, and projects are initiated to critically
evaluate this sampler for isocyanate sampling of mixed phases.
Chromatographic determination of the isocyanate derivatives
It was generally consensus on the recommendation of a reversed phase LC approach for
determination of the isocyanate derivatives, in accordance with modern principles of
isocyanate measurement. The delegates do not wish to add further detailed directions
regarding specific choices of mobile and stationary phases or column dimensions to the
recommendation, as a wide variety of adequate combinations are available. However, the
network encourages further R&D exploration of microbore or capillary column dimensions
with high mass sensitivity in order to improve the concentration sensitivity of the methods
and to improve the coupling to mass spectrometers (MS) with electrospray ionization (ESI).
NORDNI recommends on a general basis a ESI-MS approach as detection principle, due to
the rapid evolvement and nice characteristics of LC-MS with ionization at atmospheric
pressures. Furthermore, the 1-2MP derivatives have excellent ESI capabilities leading to high
sensitivity, in addition to the availability of structure elucidation. The use of tandem MS or
iontrap MS instruments make available further specificity through fragmentation and
extraction of daughter ions, often leading to increased sensitivity. However, the network does
91
not recommend specific detailed ESI-MS strategies beyond the general recommendation of a
LC-ESI-MS approach.
Quantification of oligomer and prepolymer derivatives is troublesome due to the lack of
commercially available standards. In this regard the UV detector has certain advantages,
giving a signal that is proportional to the number of monomeric units, making available
utilization of the calibration curve of monomeric, commercially available isocyanate
derivatives for oligomer derivative quantification. Thus, an on-line LC-UV-ESI-MS approach
might be favorable in certain cases.
Biomonitoring
The network are generally positive to use of biomarkers for determination of isocyanate
exposure, but can not recommend utilization of specific biomonitoring methods on a wide
basis at the present stage, as these methods not are critically evaluated yet. However, the
network points out the importance of the use of biomarkers in order to obtain dose-response
models, and strongly encourage to further R&D development in this important field.
Quality control
The members of the network call attention to the great need for critically evaluation and
improved quality control of the laboratories working with isocyanate monitoring. Thus, the
network has initiated a quality control program where the participating groups are to analyze
the same set of 1-2MP isocyanate derivative standard solutions in their respective
laboratories. Later, generated standard filters are to be analyzed similarly. It is the intention
that Nordic laboratories working in the field but which are not members of NORDNI will be
invited to participate in the quality control program.
Sharing of knowledge and available isocyanate reference substances between the participating
groups of the network is initiated, and a complete list of reference substances possessed by the
members is in preparation.
Conclusions
NORDNI recommends that a dry filter method with two filters coated with thick films of 12MP, in accordance with a Finnish study [9], are to be used for isocyanate monitoring of
exposure from both gaseous/vapor, aerosol and mixed phases in workroom air. The filters
should immediately be transferred into reagent solutions after completed air sampling.
NORDNI recommends that the sampler used for isocyanate sampling should possess capture
characteristics suitable for collection of inhalable particles, and work has been initiated to
critically evaluate the PAS-6 sampler with double thick-film coated 1-2MP filters for
isocyanate sampling.
NORDNI recommends that reversed phase LC-ESI-MS should be used for chromatographic
determination of the 1-2MP isocyanate derivatives, in order to obtain both high sensitivity and
structure elucidation. However, on-line LC-UV-ESI-MS are preferred if available, due to the
availability of quantification of pre-polymers where standards are not available.
92
NORDNI will initiate a quality control program for nordic laboratories using the double-filter
1-2MP sampling method recommended by NORDNI. Sharing of knowledge and reference
substances between the members of the quality control program will be initiated.
NORDNI encourages to further R&D activity on biomonitoring methods for measurement of
isocyanate exposure and on development of DBA filter air sampling methods.
References
[1]
SWISOC meeting, Umeå, Sweden, 9-10 February 2000.
[2]
Consensus Conference on Isocyanates, Brummundal, Norway, 20-23 November 2001.
[3]
A.W. Musk, J.M. Peters, D.H Hegman, DH, Am. J. Ind. Med. 1988, 13, 331-349.
[4]
X. Baur, W. Marek, J. Ammon, A.B. Czuppon, B. Marczynski, M. Raulf-Heimsoth,
H. Roemmelt, G. Fruhmann, Int. Arc. Environ. Health, 1994, 66, 141-152.
[5]
C.A. Redlich, M.H. Karol, C. Graham, R.J. Homer, C.T. Holm, J.A. Wirth, M.R.
Cullen, Scand. J. Work Environ. Health 1997, 23, 227-231.
[6]
G. Sabbioni, R. Hartley, D. Henschler, A. Höllrigl-Rosta, R. Kober, S. Schneider,
Chem. Res. Toxicol. 2000, 13, 82-89.
[7]
M. Spanne. H. Tinnerberg, M. Dalene, G. Skarping, Analyst 1996, 121, 1095-1009.
[8]
Health and safety Executive, MDHS 25/3, Methods for the determination of
Hazardous substances; Organic isocyanates in air, Health and Safety
Executive/Occupational Safety and Hygiene Laboratory, Sheffield, UK, 1999.
[9]
M.-L. Henriks-Eckerman, J. Välimaa, C. Rosenberg, Analyst 2000, 125, 1949-1954.
[10] L.C. Kenny, R. Aitken, C. Chalmers, J.F. Fabriés, E. Gonzalez-Fernandez, H.
Kromhout, G. Lidén, D. Mark, G. Riediger, V. Prodi, Ann. Occup. Hyg. 1997, 41,
135-153.
93
10.3.7. Consensus Report for Toluene Diisocyanate (TDI), Diphenylmethane
Diisocyanate (MDI), Hexamethylene Diisocyanate (HDI) May 30, 2001.
In: Scientific Basis for Swedish Occupational Standards. XXII*. Arbete och
Hälsa 2001:20 (http://www2.niwl.se/forlag/en/samm_en.asp?ID=1057 )
Criteria Group for Occupational Standards. J Montelius (ed)
*Critical review and evaluation of those scientific data which are relevant as a background for discussion of
Swedish occupational exposure limits. This volume consists of the consensus reports given by the Criteria Group
at the Swedish National Institute for Working Life from July, 2000 through June, 2001.
There are a large number of isocyanates, and the present document covers three of the most
common ones: toluene diisocyanate (TDI), diphenylmethane-4,4´-diisocyanate (MDI), and
hexamethylene diisocyanate (HDI). It also serves as an update to the Consensus Reports
published in 1982 and 1988 (130, 74). Thermal breakdown products of polyurethane are not
discussed.
Chemical and physical characteristics. Uses
toluene-2,4-diisocyanate (2,4-TDI)
CAS No.:
584-84-9
Synonyms:
2,4-toluene diisocyanate
2,4-diisocyanatotoluene
4-methyl-1,3-phenylene diisocyanate
toluene diisocyanate
Structure:
CH3
NCO
NCO
Melting point:
Flash point:
21 °C
135 °C
toluene-2,6-diisocyanate (2,6-TDI)
CAS No.:
91-08-7
Synonyms:
2,6-toluene diisocyanate
2,6-diisocyanatotoluene
2-methyl-1,3-phenylene diisocyanate
toluene diisocyanate
94
Structure:
CH3
OCN
2,4-TDI:2,6-TDI (4:1)
CAS No.:
Melting point:
Flash point:
For all of the above:
Formula:
Molecular weight:
Density (liquid):
Density (vapor):
Boiling point:
Vapor pressure:
Saturation concentration:
Conversion factors:
NCO
26471-62-5
12.5-13.5 °C
132 °C
C9H6N2O2
174.16
1.22 g/cm3 (25 °C)
6.0 (air = 1)
251 °C
2.7 Pa (25 °C)
27 ppm
1 µg/m3 = 0.138 ppb
1 ppb = 7.239 µg/m3
diphenylmethane-4,4´-diisocyanate (MDI)
CAS No.:
101-68-8
Synonyms:
methylenebis(phenylisocyanate)
4,4´-diphenyl methane diisocyanate
bis(1,4-isocyanatophenyl)methane
4,4´-methylenediphenyl diisocyanate
4,4´-diisocyanato-diphenyl methane
diphenylmethane diisocyanate
4,4´-methylphenyl diisocyanate
Formula:
C15H10N2O2
Structure:
OCN
Molecular weight:
Density (liquid):
Density (vapor):
Boiling point:
Melting point:
Flash point:
Vapor pressure:
Saturation concentration:
CH2
250.3
1.23 g/cm3 (25 °C)
8.5 (air = 1)
314 °C
39.5 °C
196 °C
6.7 x 10-4 Pa (25 °C)
6.6 ppb
95
NCO
Conversion factors:
1 µg/m3 = 0.096 ppb
1 ppb = 10.40 µg/m3
hexamethylene-1,6-diisocyanate (HDI)
CAS No.:
822-06-0
Synonyms:
1,6-diisocyanatohexane
1,6-hexamethylene diisocyanate
Formula:
C8H12N2O2
Structure:
OCN–(CH2)6–NCO
Molecular weight:
168
Density (liquid):
1.04 g/cm3
Boiling point:
212.8 °C
Melting point:
- 67 °C
Flash point:
140 °C
Vapor pressure:
1.3 Pa (20 °C)
Saturation concentration:
13 ppm
Conversion factors:
1 µg/m3 = 0.143 ppb
1 ppb = 6.991 µg/m3
Isocyanates are characterized by their reactive -N=C=O group. Some diiso-cyanates (TDI,
HDI) are volatile at room temperature and others can not be inhaled unless they are heated or
in aerosol form (MDI). MDI and TDI usually occur industrially as mixtures of different
isomers and/or in prepolymerized form. Industrial grade TDI is usually a mixture of 2,4-TDI
and 2,6-TDI in a ratio of 4:1 or 65:35. MDI usually occurs as a mixture of several isomers and
oligomers: one common mixture is approximately 30-40% diphenylmethane-4,4´diisocyanate, 2.5-4.0% diphenylmethane-2,4´-diisocyanate, 0.1-0.2 % diphenylmethane-2,2´diisocyanate, and the remaining 50-60% oligomers. HDI rarely occurs in monomeric form
and is usually in adducts.
Isocyanates are used in the production of polyurethane, a common material for soft and
hard foam plastics, insulation materials, two-component adhesives, foam rubber, and various
types of paints and hardeners. TDI is used primarily in the production of low-viscosity
polyurethane foam, and MDI is used for the production of harder polyurethane items (in
catalyzers, for example). TDI and MDI are used in surface coatings (e.g. for chutes used in
mining and agriculture), in the shoe industry for shoe soles, in the automobile industry for
shock absorbers, and in a wide variety of other industries. MDI occurs in foundries in binders
for casting forms, and in orthopedic surgery in casts for broken bones.
The reported odor threshold for TDI is 360-920 µg/m3 (53). MDI is reported to be odorless
(52). There is no information regarding the odor theshold for HDI.
Measuring air concentrations of TDI, MDI and HDI
Measuring isocyanates in air is complicated by several factors (97, 129). Isocyanates are
extremely reactive compounds. They may occur as gases or as particles of various sizes in
aerosols. The monitoring method must be specific and extremely sensitive, since the threshold
values are low. Because of the high reactivity of isocyanates, samples must be taken using
chemosorption, i.e. by derivitization using a reagent in solution or a reagent-impregnated solid
96
medium, and this must be followed by chromatographic analysis. The method in general use
before the introduction of chromatography was the spectrophotometric Marcali method (86).
Measurements made with the Marcali method must be regarded with considerable reservation
today, since the sensitivity and specificity of the method do not meet present standards. In
simple exposure situations, however, the Marcali method may yield reliable values for TDI.
The reagents most widely used during the past 20 years for isocyanate derivatization in
conjunction with chromatographic analysis are the following:
N-[(4-nitrophenyl)methyl]propylamine (‘NITRO reagent’)
9-(N-methylamino methyl)-anthracene (MAMA)
1-(2-pyridyl)-piperazine (PP)
1-(2-methoxyphenyl)-piperazine (MP)
1-(9-anthracenylmethyl)-piperazine (MAP)
tryptamine (TRYP)
di-n-butylamine (DBA)
In monitoring TDI, MDI and HDI, the most important parameters are the gas:particle ratio
and the size and reactivity of any isocyanate particles that may be present. It is probable that
under certain conditions (such as spraying of quick-setting MDI products) the particles react
too slowly with the reagent when samples are taken on reagent-impregnated filters, and
samples must therefore be taken in an impinger (4). On the other hand, particles smaller than
2 µm are not captured effectively in an impinger. It is therefore recommended that, in
environments containing both quick-drying particles larger than 2 µm and particles smaller
than 2 µm, sampling in an impinger be followed by sampling on a reagent-coated fiberglass
filter (47, 128). In one of the methods commonly used in other countries, samples are taken in
an impinger containing MP in toluene or on a fiberglass filter coated with MP (47). MAMA in
toluene has been widely used in Sweden (11). For monitoring monomeric TDI, MDI and HDI
in environments where these substances are generated by polyurethane production, the choice
of reagent is generally not of critical importance. DBA in toluene has several advantages over
other reagents (135), but disadvantages have also been found (67). As a rule, reagent-coated
filters should be extracted in the field right after
the sample is taken. With regard to measuring TDI, MDI and HDI in complex environments –
around thermal breakdown of polyurethane materials, for example – our knowledge of the
efficiency of the various reagents and sampling methods is still quite limited.
Liquid chromatography is the only method used to separate isocyanates prior to analysis.
One or a combination of detectors – UV, fluorescence, electro-chemical – may be used for
identification and quantification (97, 129). To identify and quantify samples from complex
environments it is necessary to
use mass spectrometry. DBA is the reagent that has been most thoroughly investigated in
conjunction with mass spectrometric analysis (54, 57, 136). International standards are being
drawn up for methods based on MP, MAP, DBA, various combinations of reagents, and
different sampling methods (54).
In summary, we now know that earlier measurements of isocyanates, partic-ularly in
complex environments (with thermal breakdown, for example), can be off by a wide margin –
especially if they were made before the introduction of chromatography. Further, sampling in
an impinger may yield measurements that are too low because the particles smaller than 2 µm
were not captured. Chromatographic analysis of derivatized isocyanates without confirmation
by mass spectrometry may lead to concentration estimates that are too high. When the
derivatization reaction is slow, competing reactions may lead to estimates that are too low. In
97
assessing the results of epidemiological studies, therefore, the monitoring method must
always be assessed as well. If a study is to be accepted as reliable, the exposure levels must be
determined by modern chromatographic methods. An exception may be made for
measurements made in simple exposure situations, where determination with the Marcali
method may be acceptable.
Uptake, biotransformation, excretion
In studies with rats and guinea pigs it has been shown that inhaled TDI is absorbed in the
central respiratory passages and far out in the bronchioles (61).
In general, isocyanates bind to proteins quite rapidly (62). Skin uptake of TDI
has been demonstrated in rats after exposure 3 hours/day for 4 consecutive days (115).
Due to their –N=C=O group, isocyanates are extremely reactive substances that form
adducts. Urine samples taken after exposure to isocyanates contain the corresponding amines,
which can be identified if the sample is prepared by hydrolysis. Thus, toluene diamines
(TDA) can be found after exposure to TDI (115), 4,4´-methylenedianiline (MDA) and Nacetyl-4,4´-methylenedianiline (AcMDA) after exposure to MDI (124), and 1,6hexamethylene diamine (HDA) after exposure to HDI (15). It has been assumed on the
evidence of in vitro studies that the toxicity of isocyanates is largely due to the distribution of
isocyanate-glutathione conjugates to various organs via blood and the release of free
isocyanate in peripheral tissues. This occurs particularly with low local concen-trations of
glutathione (GSH) or elevated pH (14, 102). The distribution of isocyanates in the human
body, however, is largely unknown.
Data on metabolism of isocyanates are also sparse. In experiments in which rats were given
14C-TDI in diet, insoluble polymers were formed in the stomach at high doses (900 mg/kg
b.w./day) in feed, but not at lower doses (60 mg/kg b.w./day) (53). The metabolites of 2,6TDI are excreted primarily in feces. Oral administration of 2,6-TDI in oil (900 mg/kg b.w.)
resulted in formation of polymers in the digestive tract, and 2,6-TDI polymers were still in the
digestive tract 72 hours later. The half time for 2,6-TDI in aqueous solution is less than 2
minutes in the ventricle and less than 30 seconds in serum (53). MDI and TDI have been
found in and below the respiratory epithelium of exposed laboratory animals from the nose to
the terminal bronchioles. TDI-protein complexes have been found in pulmonary tissue of
guinea pigs after inhalation of TDI (60). Bronchoalveolar lavage fluid from TDI-exposed
guinea pigs contained five TDI-protein complexes, of which TDI-albumin was the most
prevalent (56). In humans exposed to airborne 2,4-TDI and 2,6-TDI, the substances are bound
mostly to albumin in plasma (70). TDI-hemoglobin complexes have been identified in guinea
pigs after inhalation of TDI (27). After rats had been exposed by inhalation to 14C-TDI, the
highest concentrations of radioactivity were found in respiratory passages, digestive tract and
blood, in that order. The radioactivity in plasma was linearly related to the dose of inhaled
14C-TDI, and the 14C-labeled compounds were almost entirely in the form of conjugates
(63).
Biological measures of exposure
Volunteers exposed to HDI in a test chamber (3.6 ppb for 7.5 hours) had the corresponding
amine (1,6-hexamethylene diamine, HDA) in hydrolyzed urine (15). The biological half time
98
was about 1 hour. In a similar study with lower exposures (1.7 to 3.1 ppb for 2 hours), HDA
levels in urine were proportional to HDI levels in air, and the half time was 2.5 hours (134).
HDA could not be found in unhydrolyzed urine, which suggests that this metabolite occurs as
an adduct. HDA was not detected in plasma in either of these studies (15, 134). HDA could be
identified in hydrolyzed urine from car painters exposed to prepolymerized HDI (116) and
production workers making HDI monomers (80). Of 22 car painters who used HDI-based
paint and wore face masks with air filters, 4 had HDA in hydrolyzed urine; none of seven
controls had detectable amounts (149).
Subjects exposed to 2,4-TDI and 2,6-TDI in a test chamber (5.5 ppb for 7.5 hours) had the
corresponding amines in plasma and urine – identified by gas chromatography-mass
spectrometry (GC-MS) after hydrolysis (125). Elimination from plasma was slow.
Elimination in urine had a slow and a fast phase, the latter with a biological half time of one
to two hours. Two persons were exposed to three concentrations in the range 3.4-9.7 ppb for 4
hours, and there was a correlation between TDI levels in air and TDA levels in plasma (16).
Elimination from plasma had two phases. The biological half time was two to five hours for
the fast phase and more than six days for the slow phase (16).
In a cross-sectional study of employees making automobile upholstery in a workplace
where there was low exposure to both aerosols from spraying of MDI and HDI adhesives and
thermal breakdown products from the adhesives and from TDI foam (air concentrations of
MDI <0.76 ppb, HDI <0.1 ppb, TDI <0.01 ppb), toluene-2,4-diamine (2,4-TDA) and toluene2,6-diamine (2,6-TDA) were detected in hydrolyzed plasma from respectively 16% and 7% of
the production workers, but none of the office workers (72). Some TDA isomer was found in
the urine of 48% of the production workers and 21% of the office workers.
A TDI metabolite (2,6-TDA), but not TDI, could be identified in hydrolyzed urine from
workers exposed to 2,6-TDI (79, 117). There was some correlation to air concentrations.
Workers exposed to TDI (≤ 0.5 ppb) in a foam plastic factory were monitored for 5 weeks:
the urine content of TDA fluctuated, as did the ratio between 2,4-TDA and 2,6-TDA (103).
There was some correlation with air concentrations. The amounts of TDA in plasma were
relatively constant, and not correlated to amounts in urine. In another study of workers in two
foam plastic factories where air concentrations of TDI were 0.05-0.5 ppb and 1.4-16.6 ppb
respectively, the TDA levels in plasma reflected the difference in air concen-trations (69).
While the workers were on vacation the levels in plasma declined with an average half time of
21 days. The levels of TDA in urine dropped also, with a half time of 5.8 to 11 days and some
indication of two phases.
Workers exposed to TDI (average 4.1 ppb) in a foam plastic factory had TDA in
hydrolyzed plasma and urine (135). TDA in plasma of some of the workers experimentally
exposed for a short time had a biological half time of about 10 days. The amount of TDA in
urine from the workers varied quite a bit, and was highest right after work. There was no clear
correlation between TDI levels in air and TDA levels in plasma or urine. The levels in plasma
and urine were higher and the half time in plasma longer than they were for the briefly
exposed subjects in the test chamber studies (16), which lends support to the hypothesis that
there is a slow compartment. In plasma from a worker in the same factory, most of the
metabolite was covalently bound to albumin (70).
Methylenedianiline (MDA) could be identified in pooled samples of hydrolyzed plasma and
urine from 10 workers exposed to MDI (it is unclear whether thermal breakdown was involved) (126). MDA could be identified in hydrolyzed hemoglobin from 10 of 26 workers
99
exposed to MDI (all but three <0.3 ppb; values for the other three were 1.0, 1.8 and 2.9 ppb)
(122). After alkaline extraction there were measurable amounts of acetyl-MDA (AcMDA)
and lesser amounts of MDA in urine from 18 of the 26, MDA alone in 4 samples, and neither
substance in 4. After acid hydrolysis the MDA levels were on average about 1/3 higher that
the total of AcMDA and MDA in the previous analysis. The levels of hemoglobin adducts had
no correlation to metabolites in urine (122).
In a polyurethane production facility where air concentrations of MDI were usually below
the detection limit, measurable amounts of 4,4´-MDA (0.035-0.83 pmol/ml) and AcMDA
(0.13-7.61 pmol/ml) could be found in urine in 15 of 20 workers after alkaline extraction, and
MDA values were 6.5 times higher after acid hydrolysis. MDA was found as hemoglobin
adducts in all the examined workers, and one worker also had adducts of AcMDA. Plasma
levels of 4,4´-MDA ranged from 0.25 to 5.4 pmol/ml, up to 120 fmol/mg of which was
covalently bound to albumin (124).
2,4-TDA, 2,6-TDA and 4,4´-MDA could be found in hydrolyzed urine from 15 workers at
a workplace where TDI- and MDI-based polyurethane was heated (26). The levels fluctuated
widely from day to day. Levels of these metabolites in plasma were much more stable. In four
of the monitored workers the levels of MDA declined during an exposure-free period, with
biological half times of 2.5-3.4 days in urine and 10-22 days in plasma.
It has long been known that some persons exposed to isocyanates form antibodies specific
to conjugates of the isocyanate and serum albumin (40, 147). These are of doubtful
pathogenic relevance, but may be used as biomarkers of exposure (for those persons who
develop antibodies). Three percent of workers exposed to spray aerosols of glue based on
MDI or HDI had specific IgE antibodies, while 33% had IgG specific to MDI, 32% to TDI
and 12% to HDI (72).
After exposure stops, the titer of specific antibodies declines (22, 81), but it may remain
elevated for as long as five years (71).
To sum up, it seems that in principle conditions exist for biological monitoring of exposure
to isocyanates. With regard to biomarkers for exposure, it is possible to analyze metabolites in
plasma and urine, although it involves considerable work with sample treatment,
determination by chromatography- mass spectro-metry, and quality control. Levels of
metabolites in urine samples taken soon after an exposure following a period without
exposure reflect the exposure of the previous hours, whereas levels in plasma reflect more
long-term exposure.
However, there is much that is not known – both generally and about the individual
monomers. In all cases the relative importance of gas and particles in exposures is far from
clear. The relevance of skin uptake is still largely unstudied. A special problem with
biomonitoring is the difficulty of differentiating exposure to a diisocyanate from exposure to
its amines and aminoisocyanates. For HDI the analytical problems are such that only high
exposures can be detected.
Specific IgG in serum increases with exposure to HDI, TDI and MDI, but in only some
exposed persons. The temporal relationship to exposure is not clear. The concentrations
persist for months and even years after exposure has stopped. Virtually nothing is known
about quantitative relationships between air concentrations and specific IgG. Similarly, very
little is known about the relation between antibody concentration and risk of health problems.
The only existing data pertain to respiratory symptoms and exposure to HDI, TDI and MDI in
100
environments with thermal breakdown. Specific IgE is probably of very limited value for
estimating exposure and risk.
Toxic effects
Animal data
For rats, the calculated LD50 for a single oral dose of TDI is 5.8 g/kg (152). The LC50 for
exposure via inhaled air, 4 hours/day for 2 weeks, was 9.7 ppm for mice, 12.4 ppm for guinea
pigs, and 13.8 ppm for rats. Watery eyes, salivation, agitation and hyperactivity were noted in
the animals during the exposures (31). Inhalation of up to 18 ppb 2,4-TDI for 3 hours caused
no change in the respiratory rate of mice, either after a single exposure or after the exposure
was repeated for several days. Inhalation of 23 ppb for 3 hours did reduce the respiratory rate,
however, and the effect was enhanced when the exposure was repeated the following day
(120). Acute inhalation exposure to high concentrations of TDI causes extensive damage and
necrosis in pulmonary epithelium, and leads to death of the animals by occlusion of
bronchioles with necrotic tissue, edema in mucous membranes, and the severe inflammatory
reaction (31). Mice that inhaled TDI (time-weighted average 400 ppb) 6 hours/day for 5 days
had squamous metaplasias, exfoliative changes, erosion and ulceration in nasal epithelium
(18). Exposure to 98 ppb TDI 6 hours/day for 4 days caused inflammation and necrosis in
respiratory epithelium of mice (51). MDI and TDI present about the same toxic picture in
experimental animals. In an inhalation toxicity study (113), the acute (4 hours) LC50 for rats
exposed to an aerosol mixture of respirable MDI monomers and polymers (with ≤ 0.005%
w/w phenyl isocyanate) was 490 mg/m3 (95% confidence interval 376-638 mg/m3). Two
weeks of exposure to a mixture of MDI polymers with 44.8-50.2% monomer at a
concentration of 13.6 mg/m3 resulted in severely retarded growth and some deaths, and 13
weeks of exposure to 12.3 mg/m3 also caused elevated mortality and retarded growth (113).
For mice, inhalation of 50 or 150 ppb TDI (2,4-TDI:2,6-TDI, 4:1) 6 hours/day for 104
weeks resulted in significantly lower body weights in the high-dose group and elevated
mortality among females in both exposure groups (survival in controls 40%, low-dose group
23%, high-dose group 26%). No such increase in mortality was seen for the males (49).
Interstitial pneumonitis and necrotic changes in nasal mucosa were observed at both exposure
levels (49). Rats were exposed to 50 or 150 ppb airborne TDI 6 hours/day, 5 days/week for
108 weeks (females) or 110 weeks (males): they initially lost weight, but weight development
was normal after 12 weeks of exposure. There were no effects on survival and no observed
changes in mucous membranes in the upper respiratory passages (49).
In rabbits and guinea pigs, toluene diisocyanate induces bronchial hyperreactivity to
acetylcholine, with a dose-response relationship (37, 38, 89, 120). Increased bronchial
response to acetylcholine was observed in guinea pigs after 4 x 1 hours of exposure to TDI
(unspecified isomer) in concentrations of 10 or 30 ppb, but not 5 ppb (90). In some
experiments the animals were pre-treated with capsaicin, and it was found that this
counteracted the isocyanate-induced increase in bronchial reactivity. This probably indicates
that neuropeptides are involved in the pathophysiological sequence (90, 109). Guinea pigs
developed respiratory tract hypersensitivity to TDI after dermal exposure (59).
Wistar rats were exposed to an MDI aerosol (a mixture of polymers with 44.8-50.2%
monomer) 6 hours/day, 5 days/week for up to two years: exposure to 576 ppb resulted in
101
hyperplasia of basal cells in olfactory epithelium and accumulation of alveolar macrophages
with surrounding fibroses in the lungs (112).
Bronchial reactivity in guinea pigs was increased more by dermal application of MDI
(intradermal 0.0003-0.3%; epidermal 10-100%) than by inhalation exposure (2775 or 3390
ppb) (110). Bronchoalveolar lavage fluid from guinea pigs with TDI-induced bronchial
hyperreactivity contained elevated numbers of eosinophilic granular leukocytes (eosinophils)
and elevated concentrations of cysteinyl leukotrienes, leukotriene B4 (LTB4) and
prostaglandin F2 (PGF2 ) (111).
Several polyisocyanate prepolymers were assessed for their potential to induce contact allergy
(delayed dermal hypersensitivity) in a study with guinea pigs, using the method described by
Buehler (154). TDI and HDI were among the substances tested, and both were strongly
allergenic. Eighteen of 20 animals were sensitized to TDI, which was ranked as a grade V
allergen on the Magnusson-Kligman scale (78); the induction concentration was 5% and the
test concentration was 1%. Fourteen of 20 animals were sensitized to HDI, which was ranked
as a grade IV allergen on the Magnusson-Kligman scale (78); the induction concentration was
1% and the test concentration was 0.1%. The control animals tested negative. Isocyanates
have also been tested on mice for skin sensitization, measured as ear swelling. TDI (131, 133,
137), MDI (131, 133) and HDI (133) were found to be contact allergens. HDI was observed to
be more potent than MDI, which in turn was more potent than TDI (133). The SD50 (the dose
that sensitized 50% of animals) was 0.088 mg/kg for HDI, 0.73 mg/kg for MDI and 5.3 mg/kg
for TDI. It was also demonstrated in this study that the different isocyanates cross-reacted and
that TDI, which was the least potent sensitizing agent, also had the lowest tendency to crossreact (133). A 5% (but not 1%) solution of TDI (2,4-TDI:2,6-TDI, 4:1) caused ear swelling in
previously unexposed mice. After sensitization, the 1% solution also caused ear swelling
(131). Sensitization was observed in 7 of 8 guinea pigs seven days after dermal application of
TDI (2,4-TDI:2,6-TDI, 4:1) (59). A number of other studies with guinea pigs, which were
made by methods other than those prescribed in the OECD Guideline (99), have also shown
that MDI and TDI are medium-strong to strong contact allergens (59, 66, 110).
Human data
Irritation of respiratory passages
Seven men exposed to TDI (the substance is usually not more closely specified in these
studies, but in most cases is probably a 4:1 mixture of 2,4-TDI and 2,6-TDI) concentrations
exceeding 100 ppb (724 g/m3) immediately showed symptoms of respiratory irritation
(cough, nasal congestion, throat irritation) (91). It has long been known that exposure to TDI
in concentrations exceeding 500 ppb results in irritation of the nose and throat (152). In a
study of 379 TDI-exposed workers at 14 workplaces, 30% (n = 115) had symptoms that could
with some confidence be attributed to their exposure (32). All 12 persons exposed to
(unspecified) isocyanates in the concentration range 30-70 ppb had symptoms in the form of
cough, dyspnea and/or irritation of mucous membranes in nose and throat (43).
In this study, at exposures below 30 ppb no immediate symptoms of respiratory irritation were
seen in persons who were not hypersensitive to isocyanate (43). A WHO report published in
1987 states that exposure to TDI concentrations exceeding 50 ppb causes irritation of eyes
and upper and lower respiratory passages (53). This report does not mention the source of the
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original data. The exposure measurements in most of the studies reviewed here were made by
methods that do not meet present standards.
Exposure to MDI is irritating to skin, eyes and respiratory passages (52). For MDI, the
relationship between symptoms and exposure levels is still insufficiently known. In one study,
nose and throat irritation was observed in about half of 13 employees who had been
transferred because of their reactions to isocyanate exposure and in a few of the 20 who had
stayed in the same jobs and were still being exposed. Precise exposure levels are not given in
this study, but it is reported that the exposure limit for MDI (96 ppb) was reached during
some operations and that higher peaks may have occurred (65).
Asthma and asthma-like symptoms
People who become hypersensitive to isocyanates develop symptoms such as coughing, rales
and dyspnea at exposures below 20 ppb (10, 13, 98, 151). Isocyanate-induced asthma often
begins with coughing and breathing difficulty in conjunction with exposure, but sometimes
bronchial obstruction with exertion or on exposure to other bronchoconstricting stimuli is the
only symptom of incipient isocyanate asthma. The asthmatic reaction may be of either the
immediate (within 30 minutes of exposure) or delayed type (3 to 6 hours after exposure), and
may also be biphasic. Persons with isocyanate asthma sometimes have rhinitis and/or
conjunctivitis, and may have urticarial reactions as well (8).
In a prospective cohort study, 89 previously unexposed workers who were employed in the
manufacture of TDI were followed for 2.5 years (20). TDI levels registered by stationary
monitors (8-hour time-weighted averages, 10 occasions) were in the range 3-54 ppb, median
6.5 ppb; personal monitors showed 1-25 ppb, median 5 ppb. The TDI-exposed workers had a
significantly higher occurrence of symptoms involving the lower respiratory passages (cough,
wheezing, chest tightness, dyspnea etc.) than unexposed controls (20).
A review article by Musk et al. addresses the problems of defining a relationship between
isocyanate exposure and effects on health and determining the relative importance of brief
exposures to high concentrations and continuous exposure to low concentrations (96). It has
been proposed that, for healthy persons, brief episodes of high exposure are more likely to
lead to isocyanate asthma than long-term exposure to lower concentrations. The relative
importance of high, short-term exposures and low, long-term exposures in the development of
isocyanate asthma is still unclear, however.
White et al. (148) examined 203 women who were occupationally exposed to TDI while
sewing automobile seat covers of polyurethane plastic. In some parts
of the factory there was exposure to both TDI and fibrous dust. In an initial sub-study of 68
women who worked in the factory, 48 of whom worked with the polyurethane material, 17
(25%) were found to have respiratory symptoms. Ten of these had developed symptoms and
three had become worse after they began work (and thus exposure) at the factory. It is not
clear from the report how many of the 48 upholstery workers reported periods of breathing
difficulty and wheezing on the questionnaire the subjects filled in for a medical interview.
Another sub-study reports periods of dyspnea and wheezing in 30% of the women: 24%
worked with the upholstery material and 11% had other jobs where they were not exposed to
TDI. The difference between these groups was not statistically significant, however.
Furthermore, the group exposed to isocyanates contained more smokers (55%; 42% in
controls), and there was no attempt to adjust for this difference. The levels of TDI were
monitored in the breathing zone of the women while they were working, and also near the
103
needles of the sewing machines and the scissors used to cut the plastic. Air samples were
collected for 5 to 29 minutes (= 5 to 29 liters of air) and analyzed with HPLC. One shortcoming of this study is that it is not clear how many measurements were used to calculate the
exposure levels. The measured air concentrations of TDI were between 0.3 and 3 ppb, and in
the opinion of the authors there were no exposure peaks that deviated significantly from these
values. Dust concentrations reportedly did not exceed 1 mg/l (1000 mg/m3) (148). The most
serious shortcomings of this study are inadequately reported exposure data and flawed data
analysis.
In an English study (93), exposure conditions for 27 workers whose isocyanate asthma had
been reported to a register were compared with conditions for 51 persons in the same factory
who did not have asthma. Individual exposures to TDI were measured with the paper tape
method (described in Reference 29) during the entire workshift, and reported as 8-hour timeweighted averages (TWA) and exposure peaks. The 8-hour TWA was somewhat higher for
the asthma cases (1.5 ppb; 95% confidence interval 1.2-1.8 ppb) than for controls (1.2 ppb;
95% confidence interval 1.0-1.4 ppb). Individual top exposures were between 1 and 50 ppb,
the same for cases and controls. For persons whose exposure was higher than the median
value for the control group (1.125 ppb), the odds ratio for developing asthma was 3.2 (95%
confidence interval 0.96-10.6). An exposure increase of 0.1 ppb corresponded to an 8%
increase in risk of developing asthma. Time from hiring to the onset of asthma symptoms
ranged from less than 1 month to 23 years (median 21 months). The authors describe the
study as a case-referent study, but it is a dubious description since the cases are defined by
both their illness and their exposure. Exposure conditions for the asthma cases and for
controls were estimated later by monitoring workers doing similar jobs. A prerequisite for the
study to be valid is that workers with low and high exposure within in the same area had the
same chance to be diagnosed as having asthma. The authors do not make clear whether this
requirement was met. The study, for this reason and others, provides no solid basis for any
conclusions on dose-response or dose-effect relationships.
In the cohort study reviewed above (20), a few of the workers hypersensitive to TDI
developed severe bronchial obstruction after bronchial provocation with 5 ppb TDI. Bronchial
provocation with different concentrations of isocyanates elicited asthma-like reactions in
workers who had previously experienced coughing and chest tightness in conjunction with
exposure to isocyanates (6), see Table 1. In brief, concentrations of ≤ 20 ppb triggered asthma
symptoms in 16 of 59 workers exposed to MDI, 12 of 40 exposed to TDI and 3 of 42 exposed
to HDI (6). Bronchial obstruction was observed in four workers hypersensitive to isocyanates
at TDI exposures estimated by the authors of one study to be about 1 ppb, though it is not
clear how this exposure level was determined (24). In another study, specific
bronchoprovocation tests were given to persons with suspected occupational asthma and
exposure to TDI, MDI or HDI at work (average exposure time 8.8 years). They were exposed
in a test chamber to the individual isocyanates in concentrations of 5 to 20 ppb for up to 2
hours. Four of six subjects had positive reactions to TDI, 10 of 17 to MDI, and 15 of 39 to
HDI (25). For persons who have developed TDI asthma, it seems to be the cumulative dose
that determines whether symptoms appear. In a study by Vandenplas et al. 4 persons with
isocyanate asthma were each exposed to TDI on 3 or 4 occasions. The total dose on each
occasion was equivalent to the dose that had previously been shown to cause a 20% reduction
of FEV1 for that subject, but the concentration ranged from 5 to 20 ppb and the exposure time
ranged from 1 to 90 minutes. It was found in this study that exposure to low concentrations of
104
TDI for longer periods triggered the same reaction as exposure to higher concentrations for
shorter periods, provided that the total dose was the same (140).
Table 1. Results of experimental provocation exposure of 141 workers who were occupationally
exposed to isocyanates and had work-related dyspnea. Subjects were exposed to 5 ppb for 15 minutes,
followed by 10 ppb for 30 minutes, followed by 20 ppb for 5 minutes. The table shows, for each tested
diisocyanate, the number of persons having asthma-like reactions at each concentration (6).
MDI (n=59)
TDI (n=40)
HDI (n=42)
5 ppb
10 ppb
20 ppb
6
1
0
2
3
2
8
8
1
Six cases of occupational asthma were identified in a group of 48 spray painters who were
exposed to TDI, MDI and HDI at work. Exposure levels were not determined in this study
(123). Foundry workers who had developed asthma with hypersensitivity to isocyanates had
positive reactions to one hour of exposure to MDI (bronchial provocation in a test chamber).
The exposure levels in this study were on average 12 ppb and never higher than 20 ppb (151).
Bronchial inflammation due to isocyanate asthma, regardless of which isocyanate is the
cause, resembles that observed with other types of asthma. Bronchial biopsies from patients
with isocyanate asthma have elevated levels of activated eosinophils in mucosa and
submucosa and higher numbers of mast cells in epithelium (35). Bronchoalveolar lavage fluid
and biopsies of respiratory mucosa from persons with isocyanate asthma contain elevated
numbers of eosinophils and activated lymphocytes (83, 84, 119). Induced sputum from
patients with isocyanate asthma contains elevated numbers of eosinophils (76). Indications of
eosinophil activation (eosinophil cationic protein (ECP)) in blood increase after provocation
with isocyanate (85). In patients with isocyanate asthma, acute exposure to TDI (unspecified
isomer) leads to a temporary increase in the number of lymphocytes containing interleukin 4
in respiratory mucosa, possibly indicating a preponderance of Th2 lymphocytes (77). Early in
the reaction to TDI there is a migration of neutrophilic granular leukocytes (neutrophils) to
the respiratory passages. This has been observed with TDI provocation in persons
occupationally exposed to TDI (34) and also in animal studies (46, 111). It resembles the
early phase of the allergic asthma reaction, when an invasion of neutrophils can be observed
in airways (28, 30, 94). Asthmatics with delayed reactions triggered by TDI (unspecified
isomer) also have elevated numbers of eosinophils and CD8-positive lymphocytes in blood
(36). Stimulating mononuclear blood cells with antigens to TDI-, MDI- and HDI-albumin
complexes liberates more histamine releasing factors in patients with isocyanate asthma than
in asymptomatic controls exposed to diisocyanate (45, 73). The authors suggest that liberation
of histamine releasing factors on specific provocation might serve as a biological marker for
isocyanate asthma.
Some studies report a correlation between certain HLA types and risk of developing TDIinduced asthma. There was an elevated risk of developing asthma as a result of TDI exposure
for persons who had the allele DQB1*0503 or the allele combination DQB1*0201-0301,
whereas the risk was reduced for persons with the allele pair DQB1*501 or the combination
DQA1*0101-DQB1*0501 (12). Other researchers, however, have not been able to confirm
105
that special HLA class II alleles are relevant in this context (114) and no definite conclusions
can yet be drawn regarding a relationship between HLA type and risk of isocyanate asthma.
In a retrospective study (17-year follow-up) of 300 exposed workers, a correlation was
found between hypersensitivity to TDI and exposure to high concentrations of TDI (above 50
ppb, usually a 4:1 mixture of 2,4-TDI and 2,6-TDI ) (108). The exposure was brought down
below 20 ppb, and no new cases of TDI hypersensitivity were subsequently seen in a 3-year
retrospective follow-up of workers who worked with TDI daily (108). In another study, IgE
antibodies specific to isocyanates – TDI (unspecified isomer), MDI, HDI – were found in 20
of 94 exposed workers. There was no significant correlation between specific and total IgE
(92). This study includes no analysis of a relationship between symptoms and the presence of
IgE antibodies. In various other studies, 10 to 30% of those with isocyanate asthma have been
found to have circulating IgE antibodies specific to albumin-bound isocyanate and/or positive
reactions to isocyanates in prick tests. (21, 25, 58, 64, 143, 151). Despite the fact that the
isocyanates are quite dissimilar in chemical structure, cross-reactions have often been
observed both in vitro (IgE, IgG) and in tests of specific bronchial reactivity (5, 25, 132). This
is believed to be due to the high reactivity of isocyanates and their rapid formation of
complexes with more high-molecular substances, with resulting sensitization to these new
complexes rather than to the isocyanate itself (39). The correlation between the presence of
isocyanate-specific IgE antibodies in blood and positive reactions to specific bronchial
provocation (25) or respiratory symptoms (9) is weak, which may indicate that isocyanatespecific IgE antibodies have only a minor role in isocyanate asthma. In most persons who
have isocyanate asthma it is impossible to find circulating IgE antibodies specific to
isocyanate.
In car painters exposed to vapors and aerosols containing HDI (prepolymers and monomer),
titers of IgG specific to HDI prepolymers (but not the monomer) were significantly higher
than in unexposed controls (147). No HDI-specific IgE antibodies were found in this study.
For many people, the asthma persists despite breaking off the exposure, with both
symptoms and elevated bronchial reactivity to direct stimuli (82, 101). It is important to
diagnose isocyanate asthma early and stop the exposure of persons who develop it, since early
intervention will alleviate the asthma symptoms and may eliminate the asthma completely
(107).
Alveolitis
There are a few reported cases of alveolitis caused by exposure to airborne TDI, MDI and
HDI. This alveolitis is characterized by restrictive reduction in lung function, interstitial
fibrosis, increase of CD8-positive cells in bronchoalveolar lavage fluid (CD4/CD8 < 1.0) and
IgG antibodies specific to albumin-bound isocyanate (7, 139, 150, 153). In a total of 1,780
isocyanate-exposed workers, Baur (7) identified 14 cases of dyspnea and fever associated
with exposure to isocyanates. These persons had signs of alveolitis on lung x-rays and/or
restrictive reduction in lung function and/or reduced diffusion capacity and/or IgG antibodies
against albumin-bound TDI, MDI or HDI in serum. Bronchoalveolar lavage and biopsies
from the respiratory tract showed inflammatory changes, but no isocyanate-specific IgE
antibodies were found in serum. The average exposure time was 6 years (0.5-20 years) but
cumulative exposures were neither calculated nor estimated. Baur (7) found the occurrence of
alveolitis to be about 1%, whereas Vandenplas et al. (141) found a prevalence of 4.7% among
workers occupationally exposed to resins containing MDI or MDI prepolymers. In both these
106
studies it was remarked that exposure to MDI was more commonly associated with
isocyanate-induced alveolitis than exposure to TDI or HDI. Most of the alveolitis cases in the
Vandenplas study (141) had symptoms so severe that they had been forced to quit their jobs
soon after the symptoms appeared, leading the authors to postulate that the ‘healthy worker’
effect for isocyanate-induced alveolitis may be quite large, and that alveolitis caused by
isocyanate exposure is probably more common than these studies indicate. Isocyanateinduced alveolitis seems to affect non-smokers more than smokers (7).
Other effects on lung function
Long-term exposure to TDI in concentrations below 20 ppb usually causes no acute
symptoms, but it has been argued that it may lead to reduced lung function (105, 144, 145). A
cross-sectional study of workers exposed to MDI (usually below 20 ppb; a few measurements
showing concentrations up to 87 ppb) revealed that their lung function was lower than that of
an unexposed control group (106). Workers (n = 65) occupationally exposed to air
concentrations of HDI too low to cause symptoms (below the detection limit in 92% of
measurements), as well as various organic solvents, showed a small but statistically
significant decline of lung function (FEV1 , FVC) in comparisons with unexposed controls (n
= 68) and workers occupationally exposed to organic solvents alone
(n = 40). This 2.5-year prospective study, however, does not include a group exposed to HDI
alone (2).
The above findings are contradicted by the results of several other studies. In a 9-year study
of asymptomatic workers exposed to TDI, their decline in lung function was no different from
that in an unexposed control group (1). TDI-exposed workers with symptoms, however,
showed a more rapid decline in lung function than the unexposed controls (1). A study by
Butcher et al. (20) revealed no effect on lung function after 2 years of exposure to TDI in the
concentration range 3-54 ppb (average values for 8-hour samples). In a study by Musk et al.
(95), 107 workers in a factory producing polyurethane foam were followed for 5 years.
During this period a total of 2,573 monitoring measurements (20 to 60 minutes) of TDI and
MDI were made in the breathing zone of the workers. The average TDI concentration was 1.2
ppb, and 90% of the measurements were below 5 ppb. The average MDI concentration was
0.6 ppb, with 90% of measurements below 2.2 ppb. No information on exposure peaks is
given. Changes in lung function during the 5 years of the study were the same for exposed
individuals as for controls. No increase in respiratory symptoms and no decline in lung
function were found in the exposed group (95). In a 4-year follow-up of TDI-exposed
workers, lung function changes in 57 exposed workers were the same as those in 24 workers
in a control group. When the exposed workers were divided into three exposure groups,
however, it was found that the 15 workers in the high-exposure group (TWA 8.2 ppb, with
individual top exposures briefly exceeding 30 ppb) had a more rapid decline in lung function
(measured as average mid-expiratory flow, FEV1/FVC, and end-expiratory flow) during the
period than the 14 workers in the medium-exposure group (average TDI exposure 1.7 ppb,
individual top exposures 3-14 ppb), the 28 workers in the low-exposure group (average 0.1
ppb, top exposures below 1 ppb), and the control group (100).
In a study by Hathaway et al., no effect on lung function was found in 43 workers after 6
years of occupational exposure to HDI, HDI biuret and HDI trimer (HDI adducts), when they
were compared with 42 controls. HDI concentrations in this study were about 0.5 ppb (2
107
hours of exposure), and the calculated 12-hour TWA was 0.1 ppb. Daily top exposures
averaged 2.9 ppb (44).
Tornling et al. found no difference in lung function changes in a 6-year follow-up study of
non-smoking car painters exposed to HDI and HDI biurettrimer when they were compared
with non-smoking controls who were repair shop metalworkers and mechanics (138).
Exposed smokers, however, had a greater annual loss of lung function (FVC, VC, FEV1) than
smokers in the control group. The meaning of this is difficult to interpret, since total tobacco
exposure is not taken into account – the only information is whether the subject was a smoker,
ex-smoker or non-smoker. Average exposure in this study was 0.2 ppb, but concen-trations
exceeding 286 ppb were not rare. A significant correlation was found between decline in FEV
over time and the number of occasions with high peak exposure. This may possibly indicate
that, for smokers, decline of lung function resulting from HDI exposure depends more on
brief episodes of high exposure than on the average long-term exposure. The number of nonsmokers in this study was too small to support any general conclusions drawn from observed
effects in this group. Further, there may have been some exposure of the controls (especially
the metalworkers).
Pham et al. examined 318 workers: 83 not exposed to isocyanates, 117 indirectly exposed
and 118 directly exposed to MDI (106). The concentration of airborne MDI was on most
occasions below 20 ppb, but there were a few exposure peaks up to 87 ppb. The exposed
groups had a slight restrictive reduction in ventilation capacity when compared with
unexposed controls.
Effects on skin
In several case reports of isocyanate-exposed workers with allergic contact eczema on hands,
arms and face, contact allergy (delayed dermal hypersensitivity) to MDI, TDI and/or HDI has
been diagnosed by patch tests (17, 23, 33). Of 15 workers exposed to TDI in the range 70-170
ppb, 5 had a positive patch test for TDI and 3 had contact eczema caused by TDI (48). Rothe
described 12 cases of contact allergy and allergic contact eczema caused by occupational
exposure to MDI (118). In some cases patients have positive test reactions to several isocyanates, and occasionally to methylene dianiline (MDA) as well – often despite the fact that
they had not previously been exposed to the particular substance that induced the reaction (33,
68). This has been interpreted as evidence of cross-reactivity. The patients had been sensitized
in jobs such as mold sprayer, car painter, spray painter and medical technician. Several of
them had become sensitized because of inadequate protection against skin exposure (work
with worn-out gloves or no gloves, for example), although working conditions were otherwise
good (33, 68). In several cases sensitization occurred after a few weeks or months of exposure
at work (33). In some reported cases the patient had MDI- or HDI-induced asthma in addition
to the contact eczema (33).
Teratogenicity, mutagenicity, carcinogenicity
Animal data, in vitro studies
TDI (2,4-TDI:2,6-TDI, 4:1) and MDI, but not HDI, were mutagenic in Salmonella
typhimurium strains TA1538, TA98 and TA100 with metabolic activation (3). Changes in
DNA conformation were observed in DNA from calf thymus after in vitro exposure to TDI
(2,4-TDI:2,6-TDI, 4:1), but no such effect was obtained with exposure to MDI or HDI (104).
108
Diisocyanates and their metabolites (including diamines) form adducts with DNA (142). In
vitro incubation with TDI (2,4-TDI:2,6-TDI, 4:1) caused double strand breaks in leukocytes
(88), although in vitro exposure to pure TDI caused no DNA damage. It was concluded that
the damage is caused by metabolites. On contact with water isocyanates form aromatic
amines, many of which are carcinogenic. TDI (2,4-TDI:2,6-TDI, 4:1) and a mixture of 45%
MDI, 25% 4,4´-methylenediphenyl triisocyanate and 30% unspecified agent caused
chromosome aberrations in human lymphocytes after 24 hours of incubation, without
metabolic activation (75).
TDI (86% 2,4-TDI, 14% 2,6-TDI) given orally to mice 5 days/week for
105 weeks (120 or 240 mg/kg/day to males, 60 or 120 mg/kg/day to females) increased the
occurrence (significant dose-response trend) of hemangiomas, hemangiosarcomas and hepatic
adenomas in the females, but not in the males (49). Oral doses of the same substance given to
rats 5 days/week for 106 weeks (30 or 60 mg/kg/day to males, 60 or 120 mg/kg/day to
females) led to significant increases in the occurrence of subcutaneous fibromas and fibrosarcomas in the males. The males in the high-dose group also had significantly more
pancreatic adenomas than controls (p = 0.034) (49).
Long-term inhalation exposure to 50 or 150 ppb TDI (2,4-TDI:2,6-TDI, 4:1) 6 hours/day
did not increase the occurrence of tumors in either mice (104 weeks of exposure) or rats (108110 weeks of exposure) (49).
In a long-term toxicity and carcinogenicity study with Wistar rats, inhalation of 19, 96 or
576 ppb MDI (a mixture of polymers with 44.8-50.2% MDI monomer), 6 hours/day, 5
days/week for 2 years, resulted in lung adenomas in 10% of the males and 3% of the females
in the highest exposure group. One of 60 males in the high-exposure group also had a lung
adenocarcinoma. No lung tumors were found in controls. In this study, two years of exposure
to 576 ppb MDI was associated with an elevated occurrence of lung tumors, whereas
concentrations of 96 ppb or less did not increase the frequency of tumors (112).
2,4-TDA given to mice in feed (100 or 200 mg/kg feed) for 101 weeks increased the
occurrence of hepatocellular carcinomas and lymphomas in the females (49). 2,4-TDA given
to rats in feed (0.1%) for 36 weeks resulted in liver carcinomas (55). Rats were given (ad
libitum) 2,4-TDA in diet, 125 or 250 mg/kg feed for 40 weeks followed by 50 or 100 mg/kg
feed for 63 weeks. An elevated occurrence of hepatocellular cancers was seen in both sexes
(49). No such effects were seen with oral administration of 2,6-diaminotoluene. 2,6-TDA in
feed given to mice (50 or 100 mg/kg feed) and rats (250 or 500 mg/kg feed) for 103 weeks did
not increase the frequency of tumors (49).
MDA (4,4´-methylenedianiline ) was tested for carcinogenicity in an NTP study (146).
There was a dose-dependent increase of hepatocellular nodules in exposed rats. Mice
developed hepatocellular cancer. Thyroid adenomas and carcinomas were seen in the highest
dose groups in both species. Smaller or poorly documented studies also indicate a
carcinogenic effect. According to the IARC, there is ‘sufficient evidence’ that MDA is
carcinogenic to experimental animals (50).
According to the IARC, there is ‘sufficient evidence’ that TDI is carcinogenic to
experimental animals (51), and ‘limited evidence’ that MDI is carcinogenic to experimental
animals (52).
Wistar rats were exposed to MDI 6 hours/day on days 6 to 15 of gestation.
A slight increase in the occurrence of asymmetrical sternums was observed in fetuses at 864
ppb, but not at 288 ppb, and no other anomalies were noted in fetuses (19). Food intake by the
109
mothers dropped during the exposures, but no indications of toxicity were observed and their
weight development was no different from that of controls (19).
Human data
Inhalation of a mixture of MDI (60%), various triisocyanates (30%) and undefined
isocyanates (10%) in concentrations of 5 to 20 ppb increased the occurrence of double strand
breaks in the leukocytes of a 51-year-old worker occupationally exposed to MDI and MDI
oligomers (87). Analyses were made both before and two hours after an exposure, after the
subject had been away from work for 5 days. As a further control, the blood of a healthy
unexposed person was also examined (87).
Epidemiological studies have revealed no increase in cancer risk for people exposed to
isocyanates. Hagmar et al. made a study of cancer incidence among 4,145 employees who
were occupationally exposed to TDI (unspecified isomer) and MDI at nine polyurethane
production facilities. No increase in cancer incidence could be related to the exposure (42).
No increase in the occurrence of malignant tumors was found in a case-referent study of 7,023
employees at these workplaces (an expansion of the group covered in Reference 42). In this
study exposure levels were 3.6-414 ppb for TDI and less than 1 ppb for MDI, and exposures
ranged from a few days to more than 10 years (41). Sorahan et al., in a cohort study of 8,288
workers at 11 polyurethane production facilities in the U.K., found no increase in occurrence
of malignant tumors (127). In this study the exposure time was at least 6 months and the
exposures were estimated from historic data on the jobs done and the associated exposure
level. A slight elevation in the occurrence of pancreatic and lung cancers could be observed
among the women, and was interpreted by the authors as an effect of smoking, possibly in
combination with the occupational exposure (127). No increase in the incidence of malignant
tumors was seen in a cohort study of 4,611 employees at four different polyurethane
production plants in the U.S.A. In this study, estimated exposure to TDI was below 5.5 ppb
during the later part of the observation period but had previously been higher. The studied
cohort had a low average age, and average duration of employment was only 2.4 years –
circumstances which, in the expressed opinion of the authors, make the results of the study
inconclusive (121).
In its updated summary evaluations of carcinogenic risks to humans, the IARC has placed
TDI in Group 2B: ‘possibly carcinogenic to humans,’ and MDI in Group 3: ‘not classifiable
with regard to carcinogenicity to humans’ (51, 52). For TDI, MDI and HDI, no studies were
found of toxic effects on human reproduction or embryotoxic effects on humans (51, 52)
Dose-response / dose-effect relationships
More pronounced bronchial reactivity to acetylcholine was noted in guinea pigs after repeated
exposure (4 x 1 hour) to TDI in concentrations of 10 or 30 ppb, but not 5 ppb. Mice exposed
by inhalation to 23 ppb 2,4-TDI for 3 hours had a slower respiratory rate, and the effect was
enhanced when exposure was repeated the following day.
In the studies in which irritation of eyes and respiratory passages was ex-amined, persons
hypersensitive to isocyanates could not be differentiated from those with normal sensitivity. It
was also impossible to differentiate the effects of irritation, often accompanied by a cough,
from the asthma symptoms of those who had isocyanate asthma.
110
Asthma-like symptoms (periods of dyspnea and wheezing) were observed in
a rather poorly controlled study in which it was concluded that 2.5 years of occupational
exposure to 0.3-3 ppb TDI increased the risk of developing such symptoms. This study is
flawed by inadequate data presentation and data analysis. In another study with higher
exposures, it was found that long-term exposure to TDI concentrations in the range 1-25 ppb
(median 5 ppb) may lead to asthma symptoms in previously healthy persons. Persons
hypersensitive to isocyanates may develop asthma symptoms on provocation with a TDI
concentration estimated at 1 ppb.
Too little is known of the relationship between exposure levels and the development of
alveolitis. Six years of occupational exposure to HDI (TWA 0.5 ppb, daily top exposures on
average 2.9 ppb) had no effect on lung function changes, which were the same in exposed
workers and controls.
Several studies were excluded from this description of dose-response relationships because
they contain exposure measurements made with methods that do not meet present standards.
Conclusion
The critical effect of exposure to diisocyanates is development of asthma. Isocyanate asthma
has been observed in persons occupationally exposed to TDI at workplaces where air
concentrations ranged from 1 to 25 ppb (median 5 ppb). In one study of substandard quality,
the development of asthma-like symptoms such as dyspnea and wheezing was correlated to
exposure levels of 0.3 to 3 ppb TDI.
Asthma symptoms have been observed in individuals hypersensitive to isocyanates in
conjunction with TDI levels of 5 ppb and estimated TDI levels of 1 ppb.
TDI, MDI and HDI have been shown to be sensitizing to skin.
TDI and a mixture of MDI and its polymers have been shown to induce cancer in
experimental animals. Both substances are considered genotoxic. For HDI, there are no data
on cancer or genotoxicity.
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10.3.8. Consensus Report for Methylisocyanate (MIC) and Isocyanic Acid (ICA)
December 5, 2001
Drafted by Kerstin Engström and Jyrki Liesivuori. To be published in Arbete och Hälsa:
Scientific Basis for Swedish Occupational Standards. XXIII*.
Criteria Group for Occupational Standards. J Montelius (ed).
*Critical review and evaluation of those scientific data which are relevant as a background for discussion of
Swedish occupational exposure limits. This volume will consists of the consensus reports given by the Criteria
Group at the Swedish National Institute for Working Life from July, 2001 through June, 2002.
Chemical and physical data. Occurrence
methylisocyanate (MIC)
isocyanic acid (ICA)
CAS No.:
Synonyms:
624-83-9
isocyanic acid methylester
75-13-8
hydrogen isocyanate
Structure:
H3C-N=C=O
HN=C=O
Molecular weight:
Boiling point:
Melting point:
Vapor pressure:
Conversion factors:
57.06
39°C
- 45°C
46.4 kPa (20°C)
1 ppm = 2.4 mg/m3
1 mg/m3 = 0.4 ppm
43.02
23°C
- 80°C
13.3 kPa (- 19°C)
1 ppm = 1.8 mg/m3
1 mg/m3 = 0.6 ppm
Methylisocyanate (MIC) is a monoisocyanate. At room temperature it is a clear liquid. MIC is
sparingly soluble in water, although on contact with water it reacts violently, producing a
large amount of heat. The speed of the reaction depends a great deal on temperature, and is
accelerated by acids, bases and amines (50). MIC has a sharp odor and an odor threshold
above 2 ppm (13). Isocyanic acid (ICA) above 0 °C is an unstable liquid with a tendency to
polymerize. The primary polymerization product – which is also generated in gas form – is
the trimer, cyanuric acid. Isocyanic acid is soluble in water, but disintegrates both via
ionization and by formation of ammonia and carbon dioxide (10). In gas form has a sharp
odor (54).
Methylisocyanate occurs primarily as an intermediate in the production of carbamate
pesticides. It has also been used in the production of polymers (32). Photolytic breakdown of
N-methyldithiocarbamate releases some MIC, and it can therefore occur in the air around
application of the pesticides (26). MIC is found in tobacco smoke: the measured content in the
main stream ranges from 1.5 to 5 µg per cigarette (33). In the laboratory, MIC has also been
identified in emissions from heating of core sand and mineral wool, where it results from
breakdown or chemical transformation of the carbamide resin binder (42, 46). Exposure
measurements made in foundries indicate that MIC occurs primarily where “hot box” cores
are used in chill casting (47). MIC occurs in the isocyanate mixture created by thermal
breakdown of TDI- or HDI-based polyurethane lacquers during welding, cutting and grinding
operations in automobile repair shops (7, 59). ICA is usually found along with MIC in
welding plumes (and also around chill casting), often in concentrations as much as ten times
119
as high. Most information on the occurrence of MIC and ICA is relatively new, since it has
only recently become possible to analyze low-molecular monoisocyanates in mixed chemical
exposures such as those resulting from thermal breakdown. A method based on sampling in
dibutyl amine followed by analysis with liquid chromatography-mass spectrometry (LC-MS)
(42) was published in 1998. Several laboratories have since developed methods for analyzing
MIC. In another method that has been found applicable, samples are derivatized with 1-(2methoxyphenyl)piperazine and analyzed using GC-MS; LC and other detectors have also
been used successfully (20). A recently published abstract presents a diffusion sampling
method for MIC (48). These methods can also be used for analysis of ICA. Because of its
instability, however, ICA is not commercially available – a circumstance that makes its
quantification difficult.
Uptake, biotransformation, excretion
Massive exposure to MIC was one of the consequences of the disaster in Bhopal, India, in
1984, when about 27 tons of MIC dispersed into a populated area around a Union Carbide
plant. There are no precise air measurements, but concentrations were later estimated to have
been in the range 0.12 to 85 ppm (17). In subsequent assessments of the injuries, it has been
debated whether they were caused indirectly as a result of reduced respiratory function or
directly via respiratory uptake and distribution to other organs (13). The question arises from
the fact that MIC is a powerful irritant: it is postulated that this may have inhibited normal
respiratory uptake and systemic distribution. After Bhopal, animal experiments with
radiocarbon-labeled MIC were conducted to clarify this point.
Mice were exposed by inhalation to 0.5, 5 or 15 ppm 14C-MIC for 1 to 6 hours, and uptake
and distribution were studied (24). The radioactivity appeared in the blood within a few
minutes, but did not show a linear increase with concentration. This was attributed to the
greater irritation of higher doses and the resulting formation of mucus in the respiratory
passages, which was assumed to affect the respiratory rate and thus inhibit inhalation and
uptake in the blood. The highest radioactivity in blood in relation to air concentration was
measured after the exposure to 0.5 ppm. Radioactivity in blood dropped gradually after the
exposures and was nearly gone within three days. Radioactivity fell more rapidly in urine than
in bile. In male mice, the highest levels of radioactivity after 2 hours were found in the lungs,
sternum, digestive tract, spleen and kidneys, and after 24 hours in blood and lungs. In female
mice, the highest levels of radioactivity after 2 hours were in lungs, fetuses, spleen, uterus and
kidneys, and after 24 hours in lungs, spleen and fetuses (24). The effective uptake and
distribution is probably due to the in vivo binding of MIC to proteins in tissues, blood plasma
and erythrocyte membranes. Protein binding has been experimentally verified in mice after
both inhalation and intraperitoneal administration of 14C-labeled MIC (11, 12).
Sax (55) mentions, without going into detail, that MIC is absorbed by the skin. No other
data on skin uptake were found.
MIC has been observed to cause carbamoylation of N-terminal valine in the hemoglobin of
rats and rabbits both in vivo and in vitro (53), and 3-methyl-5-isopropyl hydantoin (MIH), the
cyclic transformation product of MIC and valine, could then be identified in blood. MIH has
also been identified in blood from the Bhopal victims (61). S-(Nmethylcarbamoyl)glutathione, another reactive conjugate, has been identified in bile from rats
given MIC via a catheter in the portal vein (52). In another experiment, the glutathione
120
conjugate in the form of S-(N-methylcarbamoyl)-N-acetylcysteine was identified in urine of
rats given MIC intraperitoneally (60).
MIC reacts readily with water, forming methylamine, which further reacts to dimethylurea
(72). It is quite likely that some MIC is also transformed in vivo to methylamine. No studies
were found in which methylamine or dimethyl urea were measured in blood or urine,
however.
There is no information on uptake, biotransformation or excretion of ICA. Patients with
uremia have elevated concentrations of carbamoylated hemoglobin, which is the reaction
product of hemoglobin and isocyanic acid (45, 73). The isocyanic acid is assumed to result
from the endogenous breakdown of urea occurring in cases of acute kidney failure.
Toxic effects
Human data
A study made at an industry producing and using MIC presents an examination of lung
function data in employee medical records covering a 10-year period (the dates are not given)
(8). The employees were divided by their supervisors into four categories based on their
estimated exposure to MIC: none (N = 123), low (N = 103), moderate (N = 138) and high (N
= 67). The records also contained information on smoking habits. About 800 monitoring
measurements of MIC (the method used is not reported) had been made in the 1977 – 1990
period. In 1977 more than 80% of the measurements had exceeded 0.02 ppm, whereas only
one of 33 measurements made in 1990 were above this level. The groups were compared,
using lung function values from the most recent examination and taking smoking habits into
account, and no effect of MIC on lung function could be discerned. Nor was any effect seen
when a worker’s first examination was compared with his most recent one. Conclusions
should be drawn with caution, however, since individuals who developed health problems
may have quit (and thus not been examined after the problem arose) and also because there is
considerable room for error in the exposure classifications. The medical records also
contained information on exposures due to spills or leakage. The authors do not give the
number of these cases, but report that the most common symptoms were eye and skin
irritation, and in a few cases respiratory problems. No clear effect on lung function was seen
in these cases.
Four volunteers were briefly exposed (1 to 5 minutes) to MIC (44) (see Table 1). No effect
was noted at an exposure level of 0.4 ppm, but 2 ppm caused irritation of eyes (notably tear
flow) and mucous membranes in nose and throat, although no odor was perceived. At 4 ppm
the symptoms of irritation were more pronounced, and at 21 ppm they were unbearable.
There are several studies providing information on the 1984 disaster in Bhopal. About
200,000 persons were acutely exposed to high (> 27 ppm) concentrations of MIC, as well as
to other substances including phosgene, methylamine and hydrogen cyanide (50). There is
thus some doubt as to whether all the observed effects can be attributed to MIC. Because of
the nature of the exposure conditions, and because effects on the lungs may have produced
secondary effects on other organs, most of the toxicological information from the disaster is
of little value in establishing an occupational exposure limit. A brief review of some of the
studies is nevertheless presented below.
The acute effects of the Bhopal disaster have been compiled. It is estimated that about 2000
people died within the first few hours. The reported cause of death is alveolar necroses
121
combined with ulcerations in bronchial mucosa and pulmonary edema (71). In one study, 379
survivors were divided into eight groups on the basis of their degree of exposure, as estimated
from the numbers of dead (both humans and animals) near their homes and the hypothetical
spread of the toxic cloud. There were 119 controls with similar socioeconomic backgrounds.
The number of dead was estimated to be 1850 in an area that was assumed to represent 70%
of the total area contaminated by the gas. The symptom most commonly reported on the
questionnaire given to the surviving victims was smarting eyes, followed by coughing,
persistent tear flow and nausea. The prevalence of eye symptoms showed no correlation to the
proportion of deaths nearby, but the reports of coughing did show such a correlation. Redness
and superficial sores on corneas and conjunctiva were observed in eye examinations (5).
Since amines can cause eye damage (35), the relevance of MIC here can not be assessed with
certainty.
Kamat et al. (41) followed 113 patients who had been referred to their pulmonary medicine
and psychiatric clinics for persistent respiratory symptoms in the three months following the
disaster. The patients (with 23 - 50% attrition from the original cohort) were followed up at 3,
6, 12, 18 and 24 months, using a standardized questionnaire, physical examinations, lung xrays, spirometry etc. The report is difficult to interpret, but it appears that a patient’s condition
was initially classified on the basis of the number and severity of respiratory symptoms: mild
for 30 patients, moderate for 57, and severe for 26. The respiratory symptoms had regressed
somewhat at 3, 6, and 12 months, but increased again at 18 and 24 months. Shortness of
breath with physical exertion was the most persistent. Neurological symptoms such as
muscular weakness and memory loss increased. The proportion of patients with depression
had increased at 6 months and the proportion with anxiety at 12 months. Other symptoms,
such as irritability and concentration difficulty, showed declining trends. Only 2 to 4 percent
of the lung x-rays were judged to be completely normal. The others showed changes in
interstitial lung tissue and in the pleural sac. Lung function tests revealed possible reductions
in lung function, primarily of a restrictive type.
The above study also presents an analysis of antibodies in serum samples from 99 cases
(41). These results are more fully described in an earlier report from the same study (43). The
initial samples were taken a few months after the disaster, and MIC-specific antibodies were
found in 11 subjects: IgM in 7, IgG in 6 and IgE in 4. The antibody titers of some of the
subjects were followed for up to a year after the disaster. The rises in antibodies were small,
and in most cases later samples were negative. The small elevations in IgE antibodies were
seen only on the first sampling occasion (41, 43). The data on antibodies are difficult to
assess, since the documentation is poor and the articles contain inconsistencies.
Another research group made similar examinations of lung function in Bhopal victims one
to seven years after the disaster (70). The material consisted of 60 persons, 6 of whom were
judged to have had low exposure (slight irritation of eyes and respiratory passages on the day
of the disaster), 13 moderate exposure (respiratory symptoms, eye irritation that did not
require hospitalization), and 41 high exposure (respiratory and eye symptoms severe enough
to require hospitalization and/or death of a family member as a result of the exposure). There
was also an unexposed control group. The most commonly reported symptoms were shortness
of breath on physical exertion and coughs. BAL samples taken one to seven years (average
2.8 years) after the disaster showed elevations of total cell counts, macrophages and
lymphocytes in the high-exposure group, statistically significant when compared with the
low-exposure group and controls.
122
Permanent damage to the respiratory passages was reported in a follow-up study made 10
years after the disaster (16). Questionnaires were distributed to 454 persons chosen on the
basis of residence within a radius of 2, 4, 6, 8 or 10 kilometers from the plant. The control
group comprised persons of the same socioeconomic background who lived in an area outside
the city. From the cohort, 20% were randomly chosen for spirometry tests; this group
ultimately contained 74 persons. The occurrence of specific respiratory symptoms – mucus
formation, cough, rales etc. – could be clearly related to the exposure level derived from the
distance between the victim’s home and the site of the disaster (from 0-2 km to >10 km). The
symptoms were equally prevalent among men and women, and more common among persons
below 35 years of age (median value for the entire group) and among smokers than nonsmokers. The same trend could be discerned in the results of lung function tests, which
showed mild obstructive reductions in lung function that increased with proximity to the
plant. This trend became a bit less clear when smoking habits and socioeconomic factors were
included in the calculations.
In a follow-up study of effects on eyes, no cases of blindness or impaired vision were found
2 months after the event (6). Of a total of 131 examined cases, six had unilateral scars on the
cornea, three had corneal edema and one complained of constantly running eyes. After 3
years, 463 were examined, 99 of whom were controls. Compared with controls, the victims of
the Bhopal disaster had higher frequencies of eye irritation, eyelid infections, cataracts,
trachoma and loss of visual acuity, which increased with increasing exposure (4).
One year after the disaster, a study of cognitive function was made on a group of 52 victims
(51). They were grouped into three exposure classes on the basis of symptoms and distance
from the plant. Compared with controls, normal performance values were seen in the leastexposed group, whereas in the other two groups the values deviated significantly for
“associate learning” and motor ability. In the most exposed group there were also lower
values on the Standard Progressive Matrix (SPM), a test that measures ability to think
logically. Clinical indications of central, peripheral and vestibular neurological damage, as
well as impaired short-term memory, were also seen in another study of the Bhopal victims
(15). In interviews, they reported more psychological symptoms such as headaches, fatigue,
concentration difficulty and irritability than controls. The symptoms did not always increase
with exposure. The exposure estimates can be questioned in both these studies of CNS effects,
and in the latter article there is some discussion of the difficulty of taking socioeconomic
differences into account in assessing the results. The authors also suggest that persistent
depressions may be a factor contributing to the other symptoms.
Asthma resulting from exposure to MIC has not been reported.
For ICA, there are no data regarding toxic effects on humans.
Animal data
The calculated LD50 for rats given MIC subcutaneously is 329 mg/kg body weight. The LC 50
for 30 minutes of exposure was 465 ppm (1080 mg/m3) (38). The LC50 for 15 minutes of
exposure to MIC has been reported to be 171 ppm for rats and 112 ppm for guinea pigs (19).
The reported LC50 for 3 hours of exposure is 26.8 ppm for mice (68).
The RD50 for mice (the dose that causes a 50% decline in respiratory rate), a measure of
sensory irritation (effects on the trigeminus nerve via the upper respiratory passages), was
estimated to be 1.3 ppm in one study (23), and 2.9 ppm in another (34). The RD50 for
123
pulmonary irritation (stimulation of the vagus nerve cells via type J receptors in the alveoli)
was 1.9 ppm for mice exposed via tracheal catheters (23).
Irritation of the upper and lower respiratory passages is the most commonly reported effect
in all animal experiments. When rats were exposed to 0, 3, 10 or 30 ppm MIC for 2 hours,
effects on lung function increased with concentration. No abnormal changes of lung function
were observed at exposure to 3 ppm MIC, but exposure to 10 ppm caused obstructive changes
in respiratory passages which did not regress during the following 13 weeks (62). Lung
damage was seen in rats exposed to 3 or 10 ppm MIC for 2 hours and examined 4 and 6
months later. At 4 months there were ECG changes in both dose groups, and right ventricular
hypertrophy was also seen in the high-dose group (not examined at 6 months). The authors
suggest that the hypertrophy and the ECG changes were probably secondary effects of the
lung damage with pulmonary hypertension (63). A LOAEL (Lowest Observed Adverse Effect
Level) of 3.1 ppm for damage to respiratory epithelium was reported in a study in which rats
were exposed by inhalation to 0, 0.15, 0.6 or 3.1 ppm MIC 6 hours/day for 4 + 4 days. The
NOAEL (No Observed Adverse Effect Level) in this study was 0.6 ppm (18).
Six hours of high exposure – above 4.4 ppm for guinea pigs, above 4.6 ppm for rats and
above 8.4 ppm for mice – resulted in damage to the upper respiratory passages of all three
species: necrosis and erosion of epithelial cells in the larynx and trachea, and alveolitis,
hemorrhages and inflammation in lungs (25). The changes disappeared within a week. When
rats were exposed to 128 ppm (320 mg/m3) MIC 8 minutes/day for 10 days, the exposure
induced progressive cellular inflammation with increase of eosinophils, neutrophils and
mononuclear cells (28). Guinea pigs exposed for 3 hours to 19 or 37 ppm MIC had lung
changes of the same types reported earlier in the victims at Bhopal (22).
In one study (14), F344 rats and B6C3F1 mice were exposed by inhalation to 0, 1, 3 or 10
ppm MIC for 2 hours, and then observed for 2 years. Survival and weight gain were normal in
all exposure groups. Definite effects on the lungs, particularly proliferation of the connective
tissue layer below the respiratory epithelium and connective tissue invasion in the lumen of
the respiratory passages, were observed in the rats exposed to 10 ppm. Similar damage was
seen in another group of rats exposed to 10 ppm MIC and examined one year later.
Rats and mice exposed to 10 or 30 ppm MIC for 2 hours had severe necrosis and damage
on most of the nasal mucosa, including the olfactory cells. Both epithelial and olfactory cells
regenerated rapidly, however, and had returned to normal within 3 months (66).
In a National Toxicology Program (NTP) study (31), mice were exposed to 1 or 3 ppm MIC
6 hours/day for 4 days. Histopathological examination after the exposure to 3 ppm revealed
pronounced fibrosis in bronchi, with intraluminal fibrosis and damage to olfactory epithelium.
The 1 ppm exposure caused damage to respiratory epithelium (not more fully described).
Myelotoxic effects on stem cells were also observed at both exposure levels, but they were
judged to be a secondary effect of the damage to the respiratory system.
Immunological effects of MIC have been examined in some studies (43, 65). A slight
increase of immunoglobulin levels was measured in rats after exposure to MIC (56). MIC
demonstrated a slight immunosuppressive effect in an NTP study with mice (65). Mice were
exposed to 1 or 3 ppm MIC 6 hours/day for 4 days, and slightly reduced mitogen-stimulated
lymphocyte proliferation was observed at both doses; at the higher dose there was also a
significantly lower response on MLR (Mixed Leukocyte Response) tests. The reduction was
temporary and had disappeared after 120 days. The authors regard these effects as secondary,
124
resulting from toxic effects on the lungs or general toxicity, rather than a direct effect of MIC
on the immune system.
Systemic effects of MIC observed in exposed rats are severe hyperglycemia, metabolic
acidosis and uremia (11, 36, 38). Exposure of mice or rats to MIC concentrations in the range
3 to 30 ppm, either intraperitoneally or via inhalation, has caused temporary degenerative
changes in blood cells and cells in liver parenchyma (29). In a study with mice, intraperitoneal
injections of 293-1170 mg MIC/kg body weight had effects on amino acid concentrations
(stimulating on glutamate and aspartate, inhibiting on GABA) in the brain and plasma. This
was regarded as an indication of neurotoxic and systemic effects (30). In vitro studies have
shown that MIC affects both brain and muscle cells, but the clinical relevance of this finding
is not clear (2, 3).
There are only a few studies of the toxic mechanisms of MIC. In vitro and in vivo studies
with cells from hepatic and nervous tissue of rats indicate that MIC can inhibit the respiratory
chain in mitochondria, and thus induce histotoxic hypoxia (39, 40). This effect was also
observed in another study, in which guinea pigs were exposed to 25, 125 or 225 ppm and rats
to 100, 600 or 1000 ppm MIC for 15 minutes (64). MIC also exerts a dose-dependent
inhibition of acetylcholinesterase activity in vitro in erythrocytes from humans, rats and
guinea pigs (37, 64).
There are no data from animal studies on toxic effects of ICA.
Mutagenicity, carcinogenicity, teratogenicity
MIC showed no mutagenic activity in standard Ames’ tests (58). Negative results were also
obtained in Ames’ tests with urine from rats exposed to MIC (1) and in a sex-linked recessive
lethal test with Drosophila (58). In the same study, positive results were obtained for point
mutations in the mouse lymphoma test. The authors conclude that MIC may be genotoxic by
binding to nuclear proteins. MIC has induced chromosome aberrations and polyploidy in
hamster fibroblasts both with and without metabolizing systems (49). Persons exposed to
MIC and other substances during the Bhopal disaster had higher frequencies of chromosome
aberrations than unexposed controls (27).
No neoplastic changes in respiratory organs were observed in a study (14) in which F344
rats and B6C3F1 mice were exposed by inhalation to 0, 1, 3 or 10 ppm MIC for 2 hours and
subsequently observed for up to 2 years. In the male rats exposed to 3 or 10 ppm there were
elevated incidences of pheochromocytomas in adrenal cortex and acinous tumors in pancreas.
This study is not a conventional cancer study, and the authors point out that the correlation to
exposure is weak and that no conclusions should be drawn on the basis of their observations.
Judging from structure-activity correlations, the carcinogenic potency of MIC should be
low (21). There are no mutagenicity, carcinogenicity or teratogenicity studies with long-term
exposures to MIC.
A dose-dependent absorption of fetuses was observed in mice exposed to 2, 6, 9 or 15 ppm
MIC for 3 hours on the eighth day of gestation. There was total resorption in more than 75%
of the females exposed to the two highest doses, and reduced fetus and placenta weights were
observed at all dose levels. The authors suggest that the maternal toxicity (weight loss,
reduced weight gain) may have caused the observed effects (67). In a later study it was shown
that treatment with hormones that counteract certain effects of the maternal toxicity (but not
e.g. weight loss) did not counteract the effects on the fetuses (69). In another study, mice were
125
exposed to 1 or 3 ppm MIC 6 hours/day on days 14 to 17 of gestation. There were significant
increases in the numbers of dead fetuses in both groups, and lower neonatal survival in the
high-dose group. The authors caution against drawing conclusions on whether the fetotoxicity
was a direct effect of MIC or was secondary to the effects on the lungs of the mothers (57).
Studies of victims of the Bhopal disaster revealed that mothers exposed to MIC had higher
numbers of miscarriages, but not stillbirths, than unexposed controls (9). In a controlled study,
Cullinan et al. (15) reported an increase in stillbirths (exposed 9%, unexposed 4%) and
miscarriages (year of disaster 7%, later years 1%), but the study covered few cases.
There are no data on mutagenicity, carcinogenicity or teratogenicity for ICA.
Dose-effect / dose-response relationships
Despite the Bhopal disaster and the facts that MIC is chemically related to more thoroughly
studied substances such as toluene diisocyanate and is an extremely toxic substance, the
literature on which to base a critical effect or a dose-response relationship is scanty. No
reliable studies on the relationship between occupational exposure to MIC and effects on
health were found. There is only one study on dose-response relationships for humans.
Results from animal studies suggest that dose-effect and dose-response curves are steep.
Irritation of eyes and mucous membranes has been described in human subjects after shortterm exposures to MIC. In one study, volunteers were exposed to MIC for 1 to 5 minutes: at
0.4 ppm no irritation was reported, but irritation of eyes and mucous membranes increased
markedly at 2 and 4 ppm, and was unacceptable at 21 ppm (see Table 1).
Table 1. Effects on four volunteers exposed to MIC in an exposure chamber for 1 to 5 minutes (44).
MIC concentration
Effects
21 ppm
4 ppm
2 ppm
0.4 ppm
Unendurable irritation
Severe irritation of mucous membranes
Tear flow, irritation of eyes, nose and throat
No irritation
Irritation of upper and lower respiratory passages has been described in studies with rats,
mice and guinea pigs. Permanent lung damage has been reported at higher doses (Table 2).
The exposure-effect relationships observed in laboratory animals exposed by inhalation to
MIC are summarized in Table 2.
There are no data on which to base an estimate of dose-effect or dose-response
relationships for ICA.
Conclusions
Judging from the data from brief exposures of human subjects, the critical effect of exposure
to MIC is irritation of eyes and mucous membranes, which occurs at 2 ppm. In animal
experiments exposure to similar levels for up to 6 hours results in severe damage to mucous
membranes in respiratory passages. At somewhat higher levels there is a steep increase in
mortality.
There are no data which would serve to establish a critical effect for ICA.
126
Table 2. Effects on laboratory animals exposed by inhalation to MIC.
Exposure
Species
Effect
Ref.
171 ppm, 15 min
rat
LC50
19
121 ppm, 15 min.
guinea pig
LC50
19
12.2 ppm, 6 hours
mouse
LC50
25
10 ppm, 2 hours
rat
Proliferation of connective tissue
below respiratory epithelium with
intrusion into respiratory lumen
14
10 ppm, 2 hours
rat
Right ventricular
hypertrophy, ECG
changes secondary to lung damage
63
9 ppm, 3 hours
day 8 or 9 of gestation
mouse, rat
Over 80% of fetuses resorbed,
reduced placenta weights
67
6.1 ppm, 6 hours
rat
LC50
25
5.4 ppm, 6 hours
guinea pig
LC50
25
3.1 ppm, 6 hours/day,
4 + 4 days
rat
Damage to respiratory epithelium,
weight loss, pulmonary edema,
increase in hemoglobin (males)
18
3 ppm, 6 hours/day,
4 days
mouse
Bronchial fibrosis, damage to
olfactory epithelium
31
3 ppm, 2 hours
rat
ECG changes due to lung
damage
63
3 ppm, 2 hours
rat
No changes in lung function
62
2.9 ppm, 30 min.
mouse
RD50 (sensory irritation)
34
2.4 ppm, 6 hours
mouse, rat,
guinea pig
mouse
Retarded weight gain
25
RD50 (pulmonary irritation)
23
mouse
RD50 (sensory irritation)
23
1 ppm, 6 hours/day
4 days
mouse
Damage to respiratory epithelium
31
0.6 ppm, 6 hours/day
4 + 4 days
rat
No effect on respiratory passages,
weight or hemoglobin levels
18
1.9 ppm, 90 min.
(via tracheal catheter)
1.3 ppm, 90 min.
127
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