Priority Existing Chemical
Assessment Report No. 28
Formaldehyde
November 2006
National Industrial Chemicals Notification and Assessment Scheme
GPO Box 58, Sydney NSW 2001, Australia www.nicnas.gov.au
Commonwealth of Australia 2006
ISBN 0 9758470 9 0
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ii Priority Existing Chemical Assessment Report No. 28
Preface
This assessment was carried out under the National Industrial Chemicals Notification and
Assessment Scheme (NICNAS). This Scheme was established by the Industrial
Chemicals (Notification and Assessment) Act 1989 (Cwlth) (the Act), which came into
operation on 17 July 1990.
The principal aim of NICNAS is to aid in the protection of people at work, the public and
the environment from the harmful effects of industrial chemicals.
NICNAS assessments are carried out in conjunction with the Australian Government
Department of the Environment and Heritage, which carries out the environmental
assessment for NICNAS.
NICNAS has two major assessment programs: the assessment of human health and safety
and environmental effects of new industrial chemicals prior to importation or
manufacture; and the other focussing on the assessment of chemicals already in use in
Australia in response to specific concerns about their health and/or environmental effects.
There is an established mechanism within NICNAS for prioritising and assessing the
many thousands of existing chemicals in use in Australia. Chemicals selected for
assessment are referred to as Priority Existing Chemicals.
This Priority Existing Chemical report has been prepared by the Director, NICNAS, in
accordance with the Act. Under the Act manufacturers and importers of Priority Existing
Chemicals (applicants) are required to apply for assessment. Applicants for assessment
are given a copy of the draft report and 28 days to advise the Director of any errors.
Following the correction of any errors, the Director provides applicants and other
interested parties with a copy of the draft assessment report for consideration. This is a
period of public comment lasting for 28 days during which requests for variation of the
draft report may be made. Where variations are requested the Director's decision
concerning each request is made available to each respondent and to other interested
parties (for a further period of 28 days). Notices in relation to public comment and
decisions made appear in the Commonwealth Chemical Gazette. A person may apply
(within 28 days) to the Administrative Appeals Tribunal (AAT) for review of decision(s)
where the Director has refused to vary the draft report as requested.
The draft formaldehyde report was published in September 2005. Several parties
submitted applications to vary the draft report. Following the Director's decisions
concerning the variation requests, the Formaldehyde Council Inc., Australian Wood
Panels Association Inc and Plywood Association of Australasia lodged applications with
the Administrative Appeals Tribunal (AAT) in November 2005. All parties withdrew
their applications before the hearing and the final order to dismiss the applications was
made by the AAT in October 2006. This report is the final published report.
In accordance with the Act, publication of this report revokes the declaration of this
chemical as a Priority Existing Chemical, therefore manufacturers and importers wishing
to introduce this chemical in the future need not apply for assessment. However,
manufacturers and importers need to be aware of their duty to provide any new
information to NICNAS, as required under Section 64 of the Act.
iii
Formaldehyde
For the purposes of Section 78(1) of the Act, copies of assessment reports for New and
Existing Chemical assessments are freely available from the web (www.nicnas.gov.au)
and may be inspected by the public at the library of the Office of Australian Safety and
Compensation Council (OASCC). Summary Reports are published in the Commonwealth
Chemical Gazette (http://www.nicnas.gov.au/Publications/Chemical_Gazette.asp), which
are also available to the public at the ASCC library.
Copies of this and other Priority Existing Chemical reports are available on the NICNAS
website. Hard copies are available free of charge from NICNAS from the following
address:
GPO Box 58, Sydney, NSW 2001, AUSTRALIA
Tel: +61 (2) 8577 8800
Fax: +61 (2) 8577 8888
Free call: 1800 638 528
Other information about NICNAS (also available on request and on the NICNAS web
site) includes:
· NICNAS Service Charter;
· Information sheets on NICNAS Registration;
· Information sheets on the Priority Existing Chemicals and New Chemical
assessment programs;
· Safety information sheets on chemicals that have been assessed as Priority
Existing Chemicals;
· Details for the NICNAS Handbook for Notifiers; and
· Details for the Commonwealth Chemical Gazette.
More information on NICNAS can be found at the NICNAS web site:
http://www.nicnas.gov.au
Other information on the management of workplace chemicals can be found at the web
site of the Office of the Australian Safety and Compensation Council (OASCC):
http://www.ascc.gov.au
iv Priority Existing Chemical Assessment Report No. 28
Overview and Recommendations
Overview
Formaldehyde (CAS No. 50-00-0) was declared a Priority Existing Chemical on 5 March
2002 in response to occupational and public health concerns.
Formaldehyde occurs naturally in the atmosphere through a variety of biological and
chemical processes. As a result of various metabolic processes, formaldehyde is naturally
present in the human body at very low concentrations. It is also produced incidentally in
the course of natural processes and human activities that involve the combustion of
organic materials, such as bush fires and fuel.
Formaldehyde is manufactured in Australia as aqueous solutions known as `formalin', at
approximately 55 000 tonnes per annum (calculated as 100% formaldehyde). Formalin
and products/mixtures containing formaldehyde are also imported at approximately 90
tonnes (100% formaldehyde) per year. In addition, approximately 700 tonnes per year of
paraformaldehyde (a significant source of formaldehyde) is imported.
Uses
The main industrial use of formaldehyde and paraformaldehyde is for the manufacture of
formaldehyde-based resins, which are widely used in a variety of industries,
predominantly the wood industry. Formaldehyde is also used directly or in formulations
in a number of industries including medicine-related industries (such as forensic/hospital
mortuaries and pathology laboratories), embalming in funeral homes, film processing,
textile treatments, leather tanning, and a wide range of personal care and consumer
products. The concentrations of formaldehyde in these products range from 40%, such as
in embalming and film processing solutions, to < 0.2%, such as in the majority of
cosmetics and consumer products.
Environmental exposure, effects and risks
Formaldehyde is water soluble and biodegradable. Its major environmental release is to
the atmosphere, where it breaks down in a short period of time. Direct release to the
aquatic compartment and soil is expected to be minor and significant removal occurs
through biodegradation. The short atmospheric lifetime of formaldehyde and worst-case
predicted environmental concentrations indicate that no significant risks to non-human
organisms through atmospheric exposure to formaldehyde are expected. A low
environmental risk to terrestrial organisms is also predicted due to likely low
concentrations of formaldehyde in aquatic systems and soil.
Health effects
In humans and experimental animals, formaldehyde is readily absorbed by all exposure
routes. When inhaled, it reacts rapidly at the site of contact and is quickly metabolised in
the respiratory tissue.
Following acute exposure via inhalation, dermal and oral routes, formaldehyde is
moderately toxic in animals. Humans experience sensory irritation (eye, nose and
v
Formaldehyde
respiratory tract irritation) at levels in air of 0.5 ppm formaldehyde and above. Evidence
clearly indicates that formaldehyde solution is a skin irritant and a strong skin sensitiser.
The available human and animal data indicate gaseous formaldehyde is unlikely to induce
respiratory sensitisation. Lung function tests suggest that asthmatics are no more sensitive
to formaldehyde than healthy subjects. Limited evidence indicates that formaldehyde may
elicit a respiratory response in some very sensitive individuals with bronchial
hyperactivity, probably through irritation of the airways.
No systemic toxicity was observed following repeated exposure to formaldehyde in
animals and humans. Effects at the site of contact show clear dose-related histological
changes (cytotoxicity and hyperplasia). A no-observed adverse-effect level (NOAEL) of
1 ppm (1.2 mg/m3) by inhalation and a NOAEL of 15 mg/kg bw/day by oral
administration were identified for histopathological changes to the nasal tract and the
fore- and glandular stomach in the rat, respectively.
Formaldehyde is clearly genotoxic in vitro, and may be genotoxic at the site of contact in
vivo. Overall, formaldehyde is considered to have weak genotoxic potential.
The possible relationship between formaldehyde exposure and cancer has been studied
extensively in experimental animals and humans. There is clear evidence of nasal
squamous cell carcinomas from inhalation studies in the rat, but not in the mouse and
hamster. Although several epidemiological studies of occupational exposure to
formaldehyde have indicated an increased risk of nasopharyngeal cancers, the data are not
consistent. The postulated mode of action for nasal tumours in rats is biologically
plausible and considered likely to be relevant to humans.
There are also concerns of an increased risk for formaldehyde-induced myeloid
leukaemia, however, the data are not considered sufficient to establish a causal
association. In addition, there is currently no postulated mode of action to support such an
effect. NICNAS will maintain a watching brief on the issue of leukaemia and
formaldehyde exposure.
Based on the available nasopharyngeal cancer data, formaldehyde should be regarded as
if it may be carcinogenic to humans following inhalation exposure. Formaldehyde meets
the National Occupational Health and Safety Commission's (NOHSC) Approved Criteria
for Classifying Hazardous Substances (NOHSC, 2004) as a Category 2 carcinogen (Risk
phrase R49, may cause cancer by inhalation). This classification should replace the
current classification of Carcinogen, Category 3 (R40, limited evidence of a carcinogenic
effect) in the Hazardous Substances Information System (DEWR, 2004). Other
classifications that remain applicable are: toxic by inhalation, in contact with skin and if
swallowed (R23/24/25), causes burns (R34), and may cause sensitisation by skin contact
(R43).
Based on animal and limited epidemiology data, formaldehyde is unlikely to cause
reproductive and developmental effects at exposures relevant to humans.
The critical health effects of formaldehyde for risk characterisation are sensory irritation,
skin sensitisation and carcinogenicity. Although gaseous formaldehyde is a known eye
and upper respiratory tract irritant in humans, the limitations of the available data and
subjective nature of sensory irritation do not allow identification of a definitive no-
observed-effect level (NOEL). The lowest-observed-effect level (LOEL) for sensory
irritation in humans is 0.5 ppm. Formaldehyde solution is also a strong skin sensitiser.
vi Priority Existing Chemical Assessment Report No. 28
A 2-stage clonal growth model was developed by the Chemical Industry Institute of
Toxicology (CIIT) in the United States to assess the respiratory carcinogenic risk of
formaldehyde to humans. This is a biologically-based, dose-response model that
incorporates mechanistic data. The model takes into account respiratory tract physiology
and regional air flow in animals and humans. It is considered a more reliable estimate of
cancer risk than the use of standard default assumptions, due to the incorporation of all
available biological data.
The table below shows key estimates of the human carcinogenic risk for public and
occupational exposure (for non-smokers) using the CIIT model.
Predicted Additional Respiratory Cancer Risk
Exposure Concentration
Public Occupational
0.3 in 1 million 0.05 in 1 million
0.10 ppm (100 ppb)
1 in 1 million 0.2 in 1 million
0.30 ppm (300 ppb)
33 in 1 million 50 in 1 million
1.00 ppm (1000 ppb)
Public exposure and health risks
Formaldehyde is naturally present in the air we breathe and in the food and water we eat
and drink. In addition, a wide range of human domestic and industrial activities is
responsible for both direct and indirect release of formaldehyde into the atmosphere from
diffuse and point sources. The principal route of public exposure is by inhalation, via
indoor and outdoor (ambient) air.
The estimated environmental exposures to formaldehyde using modelling techniques
indicate that the maximum annual average concentration of formaldehyde in urban air is
5.5 ppb and the maximum 24-h average is 23.5 ppb. Based on the CIIT carcinogenic risk
estimates of formaldehyde to humans (see table above), the public health risk of
respiratory tract cancer after repeated exposure to formaldehyde levels in ambient air is
low (less than 1 in a million). The risk of sensory irritation to the public is also low based
on the comparison of the NICNAS proposed ambient air standard (80 ppb, see
Recommendation 17) and the estimated formaldehyde levels in ambient air.
Formaldehyde concentrations in indoor air are generally higher than outdoor levels.
Formaldehyde levels in established conventional homes and buildings are generally low
at average levels of 15-30 ppb. However, limited monitoring data indicate that mobile
homes and possibly relocatable buildings have higher levels of formaldehyde [average of
29 ppb with a range from 8 to 175 ppb in occupied caravans; average of 100 ppb with a
range from 10 to 855 ppb in unoccupied caravans; average of 710 ppb with a range from
420 to 830 ppb in relocatable offices (1992 data)]. This is primarily due to the higher
usage of products that emit formaldehyde in these buildings, relatively low ventilation
rate and /or small internal volume, and other potential sources of formaldehyde such as
from combustion of gas used in cooking and refrigeration. There is a potential risk of
sensory irritation for people living in these types of buildings, but the risk of nasal cancer
is estimated to be low.
Due to public concern of childhood chemical exposure and cancers, together with the
findings of relatively high levels of formaldehyde in mobile homes and relocatable
buildings, a worst-case scenario risk estimation incorporating higher exposures during
childhood has been conducted using the CIIT model. The worst-case scenario was
vii
Formaldehyde
identified to be children who live in mobile homes and spend all their schooling time in
relocatable classrooms up to 17 years of age. The predicted additional risk of respiratory
tract cancer for a full 80-year lifetime, including childhood exposure to formaldehyde
under the worst-case scenario is low, at 0.45 in a million.
The general population may also come into skin contact with formaldehyde solutions due
to its use in a wide range of cosmetics and consumer products. However, the majority of
the products contain formaldehyde at low concentrations (< 0.2%). Because
formaldehyde solutions may induce skin sensitisation and even very low concentrations
of formaldehyde in solution may elicit a dermatological reaction in individuals who have
been sensitised, dermal exposure should be minimised or prevented wherever possible.
Occupational exposure and health risks
Occupational exposure during importation, transportation and storage of formaldehyde is
limited, except in cases of accidental spills or leaks of the chemical. The principle
occupational exposure route for formaldehyde is inhalation. Workers may be exposed to
formaldehyde vapours during resin manufacture, product formulation, and end use.
During repackaging, formulation and end use of formaldehyde products, workers are
likely to be exposed by skin and eye contact during handling of formaldehyde solutions,
such as in manual operations and cleaning of equipment.
The risk characterisation identified concerns in a number of use scenarios based on
sensory irritation. The risk of sensory irritation in embalmers and workers in medicine-
related industries, such as forensic/hospital mortuaries and pathology laboratories, is high
due to high concentrations of formaldehyde products handled and relative long exposure
durations. The risk of sensory irritation also exists during formaldehyde and
formaldehyde resin manufacture (when formaldehyde vapour replacement occurs and
where there is a need to break open or enter the enclosed system), product formulation
(during raw material weighing and transfer, open mixing process, and equipment cleaning
and maintenance), and end use (when formaldehyde product is heated and/or in contact
with high humidity, use of formaldehyde resins that contain high levels of free
formaldehyde, and during certain modes of application that may generate formaldehyde
vapour e.g. spraying).
Skin sensitisation of workers can occur as a result of manual handling of formaldehyde
products during formaldehyde and resin manufacturing, formulation, repackaging, and
end uses. The likelihood of skin contact in some end use scenarios, such as spraying or
brushing, is high. Because formaldehyde solutions may induce skin sensitisation and even
very low concentrations of formaldehyde in solution may elicit a dermatological reaction
in individuals who have been sensitised, dermal exposure should be minimised or
prevented wherever possible.
The CIIT carcinogenic risk estimation of formaldehyde to humans indicates that the risk
for respiratory tract cancer is low (less than 1 in a million) after 40 years repeated
occupational exposure to 0.6 ppm formaldehyde. Limited monitoring data indicate that
formaldehyde levels at the majority of workplaces are < 0.2 ppm. Consequently, the
occupational risks for respiratory tract cancers after repeated exposure to formaldehyde
by inhalation is likely to be low.
The occupational risks can be managed by a number of control measures to reduce
workers' exposure to formaldehyde, such as elimination, process improvements (e.g. use
of an automated or enclosed system), effective ventilation, and proper use of personal
protective equipment.
viii Priority Existing Chemical Assessment Report No. 28
The current national exposure standard is 1 ppm 8h time-weighted average (TWA) and
2 ppm short-term exposure limit (STEL). It is recommended that the occupational
exposure standard be lowered to 0.3 ppm 8h TWA and 0.6 ppm STEL. This
recommended standard not only provides adequate protection against discomfort of
sensory irritation (the health endpoint on which the proposed standard is set), but also
provides a high level of protection for cancer.
Recommendations
The recommendations arising from the assessment of formaldehyde are made for
occupational health, public health, and environmental protection. The critical issues that
have been taken into consideration in formulating these recommendations are summarised
in the preamble for each of these areas.
Recommendations for Occupational Health and Safety
Preamble
It is best occupational health and safety (OHS) practice to follow the hierarchy of controls
when a risk assessment indicates a potential risk to workers' health due to use of
chemicals in the workplace.
The hierarchy of controls are:
1. Elimination
2. Substitution
3. Engineering controls
4. Safe work practices (Administrative practices)
5. Personal protective equipment
When deciding on the best way to control a risk, start at the top of the hierarchy of
controls, i.e. investigate if the risk can be eliminated first, for example, by changing the
way the work is done, or by using safer substances. This is the most effective way to
control a hazard. If these methods are not possible, use engineering or administrative
controls to reduce or minimise the risk. The final approach is to use appropriate personal
protective equipment if the risk needs further control.
In addition, personal monitoring should be conducted where a workplace assessment
indicates a potential risk to health due to exposure to hazardous chemicals, particularly,
workplaces with possible high exposure to the chemical.
Based on the known hazards and risks of formaldehyde, the hierarchy of controls should
be implemented to manage occupational exposure to formaldehyde.
Specifically for formaldehyde, it is noted that:
· The best available LOEL for non-cancer effects in humans is 0.5 ppm for sensory
irritation;
· Formaldehyde in solution is a strong skin sensitiser;
· Formaldehyde may cause nasal cancer by inhalation;
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Formaldehyde
· The predicted risk for respiratory tract cancers is less than 1 in a million workers at
occupational exposure levels 0.6 ppm;
· The occupational risk characterisation identified concerns in a number of use
scenarios, particularly in embalming and medicine-related industries;
· The current Australian occupational exposure standard is 1 ppm time-weighted
average (TWA), and 2 ppm short-term exposure limit (STEL);
The following recommendations are made:
Recommendation 1. Occupational hazard classification (OASCC)
a) Based on the hazard assessment, formaldehyde should be classified as:
R23/24/25 toxic by inhalation, in contact with skin and if swallowed
R34 causes burns
R43 may cause sensitisation by skin contact
R49 may cause cancer by inhalation (Carcinogen, Category 2)
Compared with the current hazard classification for formaldehyde in the Hazardous
Substances Information System of the Office of the Australian Safety and Compensation
Council (OASCC), only classification for carcinogenicity has been changed (from
Category 3).
b) Based on the NOHSC's Approved Criteria for Classifying Hazardous Substances
(NOHSC, 2004), the appropriate risk phrases for mixtures containing formaldehyde are:
Risk Phrase Concentration Cut-off
0.1% to <0.2%
R49
0.2% to <3%
R49, R43
3% to <10%
R49, R43, R36/38, R20/21/22
10% to <25%
R49, R43, R34, R20/21/22
25%
R49, R43, R34, R23/24/25
Key:
R20/21/22 Harmful by inhalation, in contact with skin and if swallowed
R23/24/25 Toxic by inhalation, in contact with skin and if swallowed
R34 Causes burns
R36/38 Irritating to eyes and skin
R43 May cause sensitisation by skin contact
R49 May cause cancer by inhalation
It is recommended that this classification be included in the Hazardous Substances
Information System (HSIS) as soon as possible.
Recommendation 2. National occupational exposure standard (OASCC)
2.1 It is recommended that OASCC (formerly NOHSC) lower the current
occupational exposure standard for formaldehyde. Based on the hazard assessment for
x Priority Existing Chemical Assessment Report No. 28
formaldehyde, NICNAS recommends that the new standard be 0.3 ppm (0.36 mg/m3) 8h
TWA and 0.6 ppm (0.72 mg/m3) STEL. The recommended new standard offers
adequate worker protection for extended shifts. The documentation to support the
recommended exposure standard is in Appendix 16, which will serve as an attachment in
the OASCC Regulatory Impact Statement when the proposed exposure standard is
released for public comment. The OASCC should consider the recommended exposure
standard as a matter of priority, with a view to declaration of a new standard within 12
months.
Australian monitoring studies, whilst limited, indicate that in some sectors, particularly
workplaces manufacturing pressed wood products and mortuary and forensic/hospital and
pathology laboratories, exposure levels are likely to regularly exceed the proposed new
health-based exposure standard. These data need to be considered by OASCC in their
development of a new occupational exposure standard and the timing of its
implementation, noting such issues will be subject to further consultation with
stakeholders under the OASSC exposure standard setting process.
2.2 Anecdotal information provided to NICNAS indicates that, in practice,
occupational exposure standards (TWAs and STELs) appear to be misinterpreted. For
example, industry has advised that it is their understanding that workplaces need to
operate at half the level of an exposure standard to ensure compliance with the standard.
To address this, it is recommended that the OASCC and state and territory workplace
safety authorities develop and disseminate clear guidance on the application of national
exposure standards in the workplace.
Recommendation 3. Use of formaldehyde in spray and aerosol products
(Industry)
It is recommended that activities involving spraying of formaldehyde or products
containing formaldehyde only be carried out in a controlled manner using adequate
engineering controls and other suitable protection. If such controls or protection cannot
be provided for an activity, spraying should not be permitted.
Recommendation 4. Hazard communication (Industry)
It is recommended that suppliers and employers take note of the new hazard classification
in regards to carcinogenicity (Category 2 - may cause cancer by inhalation) and amend
Material Safety Data Sheets (MSDS), labels and training materials accordingly.
It is recommended that all manufacturers, suppliers and employers review their hazard
communication, paying particular attention to the following points:
MSDS (see Sample MSDS, Appendix 14):
· correct identification of health hazards, especially skin sensitisation,
corrosiveness, and carcinogenicity;
· correct information on the concentration cut-offs for mixtures containing
formaldehyde;
· first aid advice, including the advice that vomiting should not be induced; and
· include the Australian occupational exposure standard.
Labels:
· correct signal word;
xi
Formaldehyde
· correct risk and safety phrases;
· include emergency procedures; and
· correct first aid statements.
Recommendation 5. Specific recommendations for the embalming industry
(Industry)
· It is recommended that the Australian Funeral Directors Association (AFDA)
and the Australian Institute of Embalming (AIE), together with the registered
training organisations for embalming industry, the Funeral Industry
Development Australia (FIDA) and Mortuary and Funeral Educators (MFE),
use the information in this report to 1) update information on formaldehyde in
their training materials for embalmers; 2) develop a specific guideline for
controlling non-infectious hazards such as hazardous chemicals (including
formaldehyde) for embalmers. The development of any materials and
guidelines should be in consultation with relevant stakeholders such as
state/territory authorities and organisations representing the workers;
· The following workplace controls are recommended:
- Employers of embalming industry should consider replacing high
concentration formalin products with low concentrations or less
hazardous or formaldehyde-free products, if available;
- Effective ventilation is a critical control measure for embalmers. It is
recommended that the embalming industry ensure that a ventilation
system is in place and is effective at maintaining exposure levels below
the recommended national exposure standard of 0.3 ppm (TWA) and
0.6 ppm (STEL); and
- Embalmers should pay particular attention to the type of personal
protective equipment (PPE) used during embalming. Relevant Australian
standards and/or guidance from manufacturers in selecting and use of
PPE should be followed. Respirators should be used in situations where
high formaldehyde levels and high frequency exposures may be
encountered which may be above the occupational exposure standard,
such as embalming post-mortem bodies;
· NICNAS will prepare a Safety Information Sheet in consultation with
industry, organisations representing the workers and relevant state/territory
government organisations, specifically for safe use of formalin products in
the embalming industry. It is recommended that employer industry
associations and unions distribute this information widely to their members
and workers.
Recommendation 6. Specific recommendations for forensic/hospital
mortuaries and pathology laboratories (Industry)
· It is recommended that the Royal College of Pathologists of Australasia
(RCPA), National Institute of Forensic Science (NIFS), Australian Forensic
Medicine Managers Association (AFMMA), and other relevant associations
and training organisations use the information in this report to 1) update
information on formaldehyde in training materials for these industries; 2)
develop a guideline for controlling hazardous workplace chemicals including
xii Priority Existing Chemical Assessment Report No. 28
formaldehyde. The development of any materials and guidelines should be in
consultation with relevant stakeholders such as state/territory authorities and
organisations representing the workers;
· The following workplace controls are recommended:
- Use of local exhaust ventilation at each specimen station;
- Relocate specimen vats to areas with isolated ventilation or use local
exhaust ventilation over the vats;
- Avoid the need for dilution of concentrated formalin products by
purchasing diluted formalin products;
- Ensure effective ventilation, especially in areas where formaldehyde
levels may be high, such as exhaust ventilation in storage areas, and
down draught arrangements at dissection areas; and
· NICNAS will prepare a Safety Information Sheet in consultation with
industry, organisations representing the workers and relevant state/territory
government, specifically for safe use of formalin in forensic/hospital
mortuaries and pathology laboratories. It is recommended that employer
industry associations and unions distribute this information widely to their
members and workers.
Recommendation 7. Compliance with state and territory legislation
(Government)
It is recommended that state and territory OHS authorities review the compliance of
workplaces with the workplace controls recommended in this report, including
occupational exposure standard, MSDS and labels. Reviews should be conducted at an
appropriate interval to allow for the adoption by industry of the recommended workplace
controls, and should target industries with potential for high formaldehyde exposure, such
as the embalming industry.
Recommendation 8. Communication (Government and industry)
NICNAS will prepare a Safety Information Sheet for formaldehyde in consultation with
industry, organisations representing the workers, and relevant state/territory government,
aimed primarily at workers in general who use formaldehyde products. It is recommended
that state/territory jurisdictions and organisations representing the workers distribute this
information widely.
Recommendations for Public Health
Preamble
Noting that:
· The best available LOEL for non-cancer effects in humans is 0.5 ppm for sensory
irritation;
· Formaldehyde in solution is a strong skin sensitiser;
· Formaldehyde may cause nasal cancer by inhalation;
· Respiratory tract cancer risk estimates for the general public (including children) are
low based on worst-case exposure scenarios;
xiii
Formaldehyde
· Formaldehyde concentrations in indoor air are generally higher than outdoor levels;
· Limited monitoring data indicate that mobile homes and possibly relocatable
buildings have higher levels of formaldehyde, primarily due to use of large quantities
of formaldehyde-emitting materials;
· Currently there is no national indoor air standard or guidance value for formaldehyde;
· The direct and indirect exposure of the general public via cosmetic and consumer
products is expected to be widespread and repeated. Overseas countries, such as the
European Union (EU), have restrictions on use of formaldehyde in cosmetic products;
and
· Based on the hazard profile of formaldehyde, it is prudent to eliminate or reduce
formaldehyde exposure to the public wherever possible.
The following recommendations are made:
Recommendation 9. Indoor air guidance value (Government)
NICNAS recommends an indoor air guidance value of 80 ppb (sampling over a short
duration). This guidance value is based on sensory irritation, an acute effect. Therefore,
the sampling duration should be short (such as hourly). This value will provide guidance
for the public and regulatory authorities so that the results of monitoring studies can be
considered and action taken where appropriate.
This recommendation, together with the full report, will be forwarded to the Australian
Government Department of the Environment and Heritage (DEH) and the Environment
Protection and Heritage Council (EPHC) for consideration in setting an indoor air
standard or guidance value for formaldehyde in the future.
Recommendation 10. Standards Australia (Non-government organisation)
It is recommended that Standards Australia
· adopt and/or develop a standard(s) for mobile homes and relocatable buildings
which includes guidance on ventilation and use of pressed wood products that
meet the revised Australian Standards in regards to formaldehyde emission limits;
· adopt and/or develop applicable method(s) for the sampling and analysis of
formaldehyde in indoor air; and
· adopt international testing and labelling practices for assessing emissions of
formaldehyde from materials, which allow for testing to low emission levels as
provided in other countries such as Japan.
Recommendation 11. Mobile home and relocatable building manufacturers
(Industry)
Manufacturers of mobile homes and relocatable buildings should aim to minimise levels
of formaldehyde in indoor air. Recommendations include:
· design the structure to ensure that the recommended indoor air guidance
value of 80 ppb is not exceeded;
· only use low formaldehyde-emitting pressed wood products, such as those
that meet the Australian Standards for formaldehyde emission limits;
xiv Priority Existing Chemical Assessment Report No. 28
· coat or laminate untreated surfaces with materials, such as vinyl or water-
resistant coatings to reduce formaldehyde emission; and
· ventilate the buildings well before delivery and use to ensure the
recommended indoor air guidance value of 80 ppb is met.
Recommendation 12. Residents/occupants of mobile homes and relocatable
buildings (The general public)
The following recommendations are for the general public and are particularly relevant to
current residents/occupants of mobile homes and relocatable buildings:
· ensure adequate ventilation (exhaust ventilation, fans or window ventilation);
· exhaust all combustion appliances directly to the outdoors;
· purchase low formaldehyde-emitting pressed wood products, such as those
that meet Australian Standards for formaldehyde emission limits;
· where possible/practicable, ensure that furniture and fittings are manufactured
from materials that are low formaldehyde emitters;
· avoid smoking indoors; and
· avoid high room temperatures and high relative humidity wherever possible,
such as through the use of air-conditioning.
Recommendation 13. Indoor air monitoring (Government, industry and
research organisations)
In order to more accurately estimate the risks to the public from indoor air exposure to
formaldehyde, indoor air monitoring data should be collected, focusing on the buildings
with potentially high formaldehyde levels, such as mobile homes and relocatable
buildings including classrooms.
Recommendation 14. Communication (Government and industry)
To raise consumer awareness, NICNAS will prepare an Information Sheet, in consultation
with industry and other government departments, for distribution to mobile building
owners/residents, state and private education departments/offices, and teaching unions. It
is recommended that industry, local governments, and other relevant authorities distribute
the information widely.
To facilitate consumer choice and use of safer products, low formaldehyde emitting
products should be labelled accordingly.
Recommendation 15. Poison Scheduling (Government)
It is recommended that the National Drugs and Poisons Schedule Committee (NDPSC)
consider amending the current scheduling for formaldehyde and paraformaldehyde taking
note of the following:
1) the need to consider more restrictive categories given its potency of causing skin
sensitisation and its classification for the workplace as a Category 2 carcinogen;
2) the need for more protective cut-off values for cosmetics and personal care
products containing formaldehyde. The EU cut-off values are highlighted below
as representing a potential best practice model and have the following
restrictions:
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Formaldehyde
Formaldehyde and paraformaldehyde (as a preservative) for cosmetic use:
· free formaldehyde at 0.2% or less in all cosmetic preparations [except oral
hygiene preparations, nail hardeners and aerosol dispensers (sprays)];
· free formaldehyde at 0.1% or less in oral hygiene preparations;
· free formaldehyde at 5% or less in nail hardeners; and
· use of formaldehyde and paraformaldehyde in aerosol dispensers (sprays) is
prohibited.
Recommendations 16. Utilisation of the health hazard assessment
(Government)
It is recommended that other government organisations, such as Agricultural Pesticides
and Veterinary Medicines Authority (APVMA) and Therapeutic Good Administration
(TGA), take the findings of the human health hazard assessment into consideration in
future work on formaldehyde or products containing formaldehyde, noting use of
formaldehyde in therapeutic and agricultural and veterinary products.
Recommendations for Environmental Protection
Preamble
Noting that:
· The major environmental release of formaldehyde is into the atmosphere;
· Formaldehyde is a hazardous air pollutant otherwise known as an `air toxic';
· The release and disposal of formaldehyde from industrial facilities are regulated by
licence agreements; and
· Formaldehyde in ambient air is currently being investigated by the National
Environment Protection Council (NEPC), as part of their Air Toxics National
Environment Protection Measure (NEPM).
The following recommendations are made:
Recommendation 17. Ambient air standard (Government)
It is recommended that NEPC take the data and findings of this report into consideration
when setting an ambient air standard for formaldehyde. Evaluation of the available data in
this report indicates that an ambient air standard in the order of 80 ppb (sampling over a
short duration) would be warranted.
Recommendation 18. Communication (Government)
It is recommended that the Australian Government Department of the Environment and
Heritage update the National Pollutant Inventory (NPI) Fact Sheet for formaldehyde in
accordance with the findings of this report.
xvi Priority Existing Chemical Assessment Report No. 28
Table of Contents
PREFACE III
OVERVIEW AND RECOMMENDATIONS V
TABLE OF CONTENTS XVII
ACRONYMS AND ABBREVIATIONS XXIV
GLOSSARY XXX
1. INTRODUCTION 1
1.1 Declaration 1
1.2 Objectives 1
1.3 Sources of information 1
1.4 Peer review 2
2. BACKGROUND 3
2.1 Introduction 3
2.2 Global production 3
2.3 Australian perspective 4
2.4 Assessments by other national or international bodies 4
3. APPLICANTS 5
4. CHEMICAL IDENTITY AND COMPOSITION 8
4.1 Chemical name (IUPAC) 8
4.2 Registry numbers 8
4.3 Other names 8
4.4 Molecular formula 8
4.5 Structural formula 9
4.6 Molecular weight 9
4.7 Composition of commercial grade product 9
5. PHYSICAL AND CHEMICAL PROPERTIES 10
5.1 Physical state 10
5.2 Physical and chemical properties 10
5.3 Conversion factors 12
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6. METHODS OF DETECTION AND ANALYSIS 13
6.1 Characterisation 13
6.2 Atmospheric monitoring methods 13
6.2.1 In the workplace 13
6.2.2 In the environment 14
6.2.3 Indoor air 15
6.2.4 Off-gas monitoring from wood products 16
6.3 Biological monitoring 17
6.4 Water 17
6.5 Soil 18
7. MANUFACTURE, IMPORTATION AND USE 19
7.1 Manufacture 19
7.2 Importation 22
7.3 Use 23
7.3.1 Formulation of formaldehyde products 24
7.3.2 Repackaging 29
7.3.3 End use of formaldehyde products 29
7.4 Export 42
8. ENVIRONMENTAL RELEASE, FATE AND EFFECTS 43
8.1 Release 43
8.1.1 Emissions to the atmosphere 43
8.1.2 Emissions to water and soil 45
8.2 Fate 45
8.2.1 Atmosphere 46
8.2.2 Water 47
8.2.3 Soil and sediment 48
8.2.4 Biota 48
8.3 Effects on organisms in the environment 48
8.3.1 Aquatic organisms 48
8.3.2 Terrestrial organisms 50
8.3.3 Micro-organisms 51
8.3.4 Summary 52
9. KINETICS AND METABOLISM 54
9.1 Absorption 54
9.2 Distribution 54
9.3 Metabolism 54
9.4 Elimination and excretion 55
xviii Priority Existing Chemical Assessment Report No. 28
10. EFFECTS ON LABORATORY MAMMALS AND OTHER TEST
SYSTEMS 56
10.1 Acute toxicity 56
10.2 Corrosivity/Irritation 56
10.2.1 Skin and eye irritation 56
10.2.2 Respiratory irritation 57
10.3 Sensitisation 58
10.3.1 Skin 58
10.3.2 Respiratory 58
10.4 Repeat dose toxicity 59
10.4.1 Inhalation 59
10.4.2 Oral 62
10.4.3 Dermal 63
10.5 Genotoxicity 63
10.5.1 In vitro studies 63
10.5.2 In vivo studies 64
10.6 Carcinogenicity 66
10.6.1 Inhalation 66
10.6.2 Oral 67
10.6.3 Dermal 68
10.7 Reproductive toxicity 68
10.8 Developmental toxicity 69
11. HUMAN HEALTH EFFECTS 71
11.1 Acute toxicity 71
11.2 Irritation/Corrosivity 71
11.2.1 Skin irritation 71
11.2.2 Sensory irritation 72
11.3 Sensitisation 74
11.3.1 Skin 74
11.3.2 Respiratory 82
11.4 Non-neoplastic effects 84
11.4.1 Respiratory-related effects 84
11.4.2 Neurological effects 86
11.5 Genotoxicity 87
11.6 Carcinogenicity 87
11.6.1 Nasal tract, pharynx and pulmonary tumours 88
11.6.2 Non-respiratory tract cancers 98
11.7 Reproductive toxicity 110
11.8 Developmental toxicity 111
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12. HAZARD CLASSIFICATION 113
12.1 Acute toxicity 113
12.2 Irritation 114
12.3 Sensitisation 114
12.4 Repeat dose toxicity 115
12.5 Genotoxicity 116
12.6 Carcinogenicity 117
12.7 Reproductive effects 119
12.8 Developmental toxicity 120
13. ENVIRONMENTAL EXPOSURE 121
13.1 Ambient air concentrations 121
13.1.1 Point source emissions from industry 121
13.1.2 Diffuse source emissions 127
13.1.3 Natural background concentrations 128
13.1.4 Combining PECs from all sources 129
13.1.5 Measured data 129
13.1.6 Summary 131
13.2 Indoor air concentrations 133
13.2.1 Residential buildings 133
13.2.2 Non-residential buildings 137
13.2.3 Estimation of indoor to outdoor ratio 140
13.3 Formaldehyde concentrations in water and soil 141
13.3.1 Concentrations in water 141
13.3.2 Concentrations in soil and sediment 143
14. PUBLIC EXPOSURE 144
14.1 Direct exposure 144
14.1.1 Cosmetic and consumer products 144
14.1.2 Smoking 144
14.2 Indirect exposure 145
14.2.1 Indoor air 145
14.2.2 Ambient air 146
14.2.3 Drinking water, food, and soil 146
15. OCCUPATIONAL EXPOSURE 147
15.1 Routes of exposure 147
15.2 Methodology for assessing occupational exposure 147
15.3 Formaldehyde manufacture 148
15.4 Importation and transportation 149
xx Priority Existing Chemical Assessment Report No. 28
Table 15.1: Air monitoring data during formaldehyde manufacture 150
15.5 Formulation and repackaging 151
15.5.1 Resin manufacture 151
15.5.2 Formulation of formaldehyde products other than resins 152
15.5.3 Repackaging 155
15.6 End uses of formaldehyde products 157
15.6.1 Formaldehyde resins 157
15.6.2 Forensic/hospital mortuaries and pathology laboratories 162
15.6.3 Embalming 163
15.6.4 Photographic film processing 171
15.6.5 Leather tanning using formalin solutions 171
15.6.6 Sanitising treatment 172
15.6.7 Lubricant products 172
15.6.8 Analytical laboratories 172
15.6.9 Fumigation 173
15.6.10 Monitoring data on other use of formaldehyde products 173
15.7 Summary 173
16. CRITICAL HEALTH EFFECTS FOR RISK CHARACTERISATION 175
16.1 Acute effects 175
16.2 Repeated dose effects (other than carcinogenicity) 176
16.3 Carcinogenicity 177
16.4 Dose-response analysis 178
16.4.1 Sensory irritation 178
16.4.2 Skin sensitisation 179
16.4.3 Cell proliferation 179
16.4.4 Carcinogenicity 180
17. RISK CHARACTERISATION 183
17.1 Environmental risks 183
17.1.1 Atmospheric compartment 183
17.1.2 Aquatic compartment 184
17.1.3 Terrestrial compartment 185
17.2 Public health risks 185
17.2.1 Public exposure 185
17.2.2 Health impacts 186
17.2.3 Uncertainties 187
17.2.4 Summary 188
17.3 Occupational health risks 188
17.3.1 Physicochemical hazards 188
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17.3.2 Occupational exposure and health impacts 188
17.3.3 Uncertainties in occupational risk characterisation 191
17.3.4 Areas of concern in occupational settings 191
17.4 Data gaps 191
18. RISK MANAGEMENT 193
18.1 Environmental risk management 193
18.1.1 Current ambient air quality controls 193
18.1.2 Other environmental controls 197
18.1.3 Further actions identified 198
18.2 Public health risk management 199
18.2.1 Current indoor air quality management 199
18.2.2 Formaldehyde emission controls from wood products 203
18.2.3 Product labelling schemes 207
18.2.4 Current risk management for consumer products 208
18.2.5 Further actions identified 209
18.3 Occupational health and safety risk management 211
18.3.1 Current regulatory controls 211
18.3.2 Current industry controls 215
18.3.3 Further actions identified 221
19. SECONDARY NOTIFICATION 222
REFERENCES 314
APPENDICES
APPENDIX 1 - List of organisations and individuals consulted during this assessment 223
APPENDIX 2 Questionnaire for formulators/manufacturers of formaldehyde products 227
APPENDIX 3 - Summary tables of human epidemiology data 233
APPENDIX 4 - GHS classification 238
APPENDIX 5 - Conceptual framework for considering mode-of-action of chemical
carcinogenesis of formaldehyde 239
APPENDIX 6 - Modelling for atmospheric concentrations of formaldehyde 246
APPENDIX 7 - Estimates of point source emissions from industry 254
APPENDIX 8 - EASE modelling for film processing 257
APPENDIX 9 - Biologically motivated case-specific model for cancer 259
APPENDIX 10 - Worst-case scenario cancer risk estimation 264
APPENDIX 11 - Sample labels for Australian-made plywood products 267
xxii Priority Existing Chemical Assessment Report No. 28
APPENDIX 12 - Australian-made wood panel products 268
APPENDIX 13 - MSDS assessment 273
APPENDIX 14 Sample Material Safety Data Sheet for formaldehyde solution, 37% 279
APPENDIX 15 - Label assessment 287
APPENDIX 16 - Proposed occupational exposure standard 290
APPENDIX 17 MDF Plant Formaldehyde Air Dispersion, Report No 79365,
by EML Air Ltd 297
APPENDIX 18 - Review of MDF Plant Formaldehyde Air Dispersion, EML Report 79365,
prepared for NICNAS, by M.F. Hibberd & M. E. Cope 308
xxiii
Formaldehyde
Acronyms and Abbreviations
American Conference of Governmental Industrial Hygienists
ACGIH
Australian Dangerous Goods Code
ADG Code
Australian Inventory of Chemical Substances (NICNAS)
AICS
American Psychiatric Association
APA
Australian Pesticides and Veterinary Medicines Authority
APVMA
Australian Standard
AS
Australian Safety and Compensation Council
ASCC
Air Toxics Program
ATP
Agency for Toxic Substances and Disease Registry (US)
ATSDR
Australian Wood Panel Association
AWPA
benchmark dose analysis
BMD
Building Code of Australia
BCA
bodyweight
bw
celsius
C
Clean Air Act (US)
CAA
Chemical Abstracts Service
CAS
complementary deoxyribonucleic acid
cDNA
Canadian Environmental Protection Act
CEPA
Chinese hamster ovary
CHO
Confidence interval
CI
Concise International Chemical Assessment Document
CICAD
Chemical Industry Institute of Toxicology
CIIT
central nervous system
CNS
Commonwealth Scientific and Industrial Research Organisation
CSIRO
xxiv Priority Existing Chemical Assessment Report No. 28
Australian Government Department of the Environment and Heritage
DEH
1,3-dihydroxymethyl-5, 5-dimethyl hydantoin
DMDM Hydantoin
deoxyribonucleic acid
DNA
dinitrophenylhydrazine
DNPH
DNA protein cross-linking
DPX
Environment Australia (former name of the Australian Government
EA
Department of the Environment and Heritage)
estimation and assessment of substance exposure
EASE
European Community, or European Commission
EC
median effective concentration
EC50
European Centre for Ecotoxicology and Toxicology of Chemicals
ECETOC
Environmental Health Criteria
EHC
European Inventory of Existing Commercial Chemical Substances
EINECS
effective loading rate resulting in 50% effect
EL50
European Union
EU
fecundability density ratio
FDR
Forced expiratory flowrate
FEFR
forced expiratory volume in one second
FEV1.0
Flame ionisation detection
FID
gram
g
gas-chromatography
GC
gas-chromatography/mass spectrometry
GC-MS
Globally Harmonised System for Health and Environmental Hazard
GHS
Classification and Communication
GLP good laboratory practice
hour
h
hazardous air pollutant
HAP
high-performance liquid chromatography
HPLC
high production volume
HPV
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Formaldehyde
Hazardous Substances Information System
HSIS
US Department of Housing and Urban Development
HUD
High Volume Industrial Chemical List
HVICL
International Agency for Research on Cancer
IARC
Industrial Chemicals (Notification and Assessment) Act 1989 (Cwlth)
IC(NA) Act
immediately dangerous to life and health
IDLH
immunoglobulin-E
IgE
Intraperitoneal
ip
International Programme on Chemical Safety
IPCS
International Union of Pure and Applied Chemistry
IUPAC
International Organization for Standardization
ISO
kilocalorie
kcal
kilogram
kg
organic carbon partition coefficient
Koc
octanol/water partition coefficient
Kow
kilo Pascal
kPa
litre
L
median lethal concentration
LC50
median lethal dose
LD50
local exhaust ventilation
LEV
lowest-observed-adverse-effect concentration
LOAEC
lowest-observed-adverse-effect level
LOAEL
lowest-observed-effect concentration
LOEC
lowest-observed-effect level
LOEL
laminated veneer lumber
LVL
metre
m
maximale arbeitsplatz-konzentration (maximum workplace concentration)
MAK
xxvi Priority Existing Chemical Assessment Report No. 28
multiple cause of death
MCOD
medium density fibreboard
MDF
Maximum exposure limit
MEL
milligram
mg
milligram per kilogram bodyweight per day
mg/kg bw/d
minute
min
millilitre
mL
micronucleation
MN
meta-relative risk
mRR
mass spectrometry
MS
material safety data sheet
MSDS
melamine urea formaldehyde
MUF
melamine urea phenol formaldehyde resins
MUPF
not available
NA
National Drugs and Poisons Schedule Committee
NDPSC
National Environmental Protection Measure
NEPM
National Health and Medical Research Council
NHMRC
National Industrial Chemicals Notification and Assessment Scheme
NICNAS
National Institute of Occupational Safety and Health
NIOSH
no-observed-adverse-effect concentration
NOAEC
no-observed-effect concentration
NOEC
no-observed-adverse-effect level
NOAEL
no-observed-effect level
NOEL
National Pollutant Inventory
NPI
New South Wales
NSW
National Toxicology Program
NTP
National Occupational Health and Safety Commission
NOHSC
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Formaldehyde
Office of the Australian Safety and Compensation Council
OASCC
Organisation for Economic Cooperation and Development
OECD
occupational health and safety
OHS
odds ratio
OR
oriented strand board
OSB
Occupational Safety and Health Administration (USA)
OSHA
p value
P
p value for trend analysis
Ptrend
Plywood Association of Australia
PAA
Plastics and Chemicals Industry Association
PACIA
particleboard
Pb
proportionate cancer mortality ratio
PCMR
predicted environmental concentration
PEC
permissible exposure limit
PEL
peak expiratory flow rate
PEFR
proportionate mortality ratio
PMR
predicted-no-effect concentration
PNEC
parts per billion
ppb
personal protective equipment
PPE
parts per million
ppm
Parts per trillion
ppt
Queensland
QLD
depression of the respiratory rate by 50%
RD50
reference exposure level
REL
relative risks
RR
Registry of Toxic Effects of Chemical Substances (US)
RTECS
sister chromatid exchange
SCE
xxviii Priority Existing Chemical Assessment Report No. 28
SIDS Initial Assessment Report
SIAR
Screening Information Data Set
SIDS
standardised mortality ratios
SMRs
short-term exposure limit
STEL
Standard for the Uniform Scheduling of Drugs and Poisons
SUSDP
Threshold Limit Value
TLV
time-weighted average
TWA
urea formaldehyde resin
UF
urea formaldehyde foam insulation
UFFI
United Kingdom Health and Safety Executive
UK HSE
United Nations
UN
United Nations Environment Program
UNEP
United States Environmental Protection Agency
US EPA
ultra-violet
UV
Victoria
VIC
volatile organic compound
VOC
World Health Organization
WHO
° degree
”g microgram
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Formaldehyde
Glossary
Acute exposure A contact between an agent and a target occurring over a short period of
time, generally less than a day. (Other terms such as "short-term
exposure" and "single dose" are also used.)
Adverse effect Change in the morphology, physiology, growth, development,
reproduction, or life span of an organism, system or (sub) population
that results in an impairment of functional capacity, an impairment of the
capacity to compensate for additional stress, or an increase in
susceptibility to other influences.
Agent A chemical, biological, or physical entity that contacts a target.
Analysis Detailed examination of anything complex, made in order to understand
its nature or to determine its essential features
Assessment Evaluation of appraisal of an analysis of facts and the inference of
possible consequences concerning a particular object or process.
Assessment Quantitative/qualitative expression of a specific factor with which a risk
endpoint may be associated as determined through an appropriate risk assessment.
Background level The amount of an agent in a medium (e.g., water, soil) that is not
attributed to the source(s) under investigation in an exposure assessment.
Background level(s) can be naturally occurring or the result of human
activities. (Note: natural background is the concentration of an agent in a
medium that occurs naturally or is not the result of human activities).
Biomarker/biolog Indicator of changes or events in biological systems. Biological markers
ical marker of exposure refer to cellular, biochemical, analytical, or molecular
measures that are obtained from biological media such as tissues, cells,
or fluids and are indicative of exposure to an agent.
Bounding An estimate of exposure, dose, or risk that is higher than that incurred by
Estimate the person with the highest exposure, dose, or risk in the population
being assessed. Bounding estimates are useful in developing statements
that exposures, doses, or risks are "not greater than" the estimated value.
Chronic exposure A continuous or intermittent long-term contact between an agent and a
target. (Other terms, such as "long-term exposure," are also used.)
Concentration Amount of a material or agent dissolved or contained in unit quantity in
a given medium or system.
Contact volume A volume containing the mass of agent that contacts the exposure
surface
xxx Priority Existing Chemical Assessment Report No. 28
Dose Total amount of an agent administered to, taken up or absorbed by an
organism, system or (sub) population.
Dose-effect Relationship between the total amount of an agent administered to, taken
relationship up or absorbed by an organism, system or (sub) population and the
magnitude of a continuously-graded effect to that organism, system or
(sub) population
Related terms: Effect Assessment, Dose-Response Relationship,
Concentration-Effect Relationship.
Dose-related Any effect to an organism, system or (sub) population as a result of the
effect quantity of an agent administered to, taken up or absorbed by that
organism, system or (sub) population.
Dose-response Relationship between the amount of an agent administered to, taken up
or absorbed by an organism, system or (sub) population and the change
developed in that organism, system or (sub) population in reaction to the
agent. Synonymous with Dose-response relationship.
Related Term: Dose-Effect Relationship, Effect Assessment,
Concentration-Effect Relationship.
Dose-response Analysis of the relationship between the total amount of an agent
assessment administered to, taken up or absorbed by an organism, system or
(sub)population and the changes developed in that organism, system or
(sub)population in reaction to that agent, and inferences derived from
such an analysis with respect to the entire population. Dose-Response
Assessment is the second of four steps in risk assessment.
Related terms: Hazard Characterisation, Dose-Effect Relationship,
Effect Assessment, Dose-Response Relationship, Concentration-Effect
Relationship.
Dose-response Graphical presentation of a dose-response relationship.
curve
Dose-Response Relationship between the amount of an agent administered to, taken up
Relationship or absorbed by an organism, system or (sub) population and the change
developed in that organism, system or (sub) population in reaction to the
agent.
Related Terms: Dose-Effect Relationship, Effect Assessment,
Concentration-Effect Relationship.
Effect Change in the state or dynamics of an organism, system or (sub)
population caused by the exposure to an agent.
Effect assessment Combination of analysis and inference of possible consequences of the
exposure to a particular agent based on knowledge of the dose-effect
relationship associated with that agent in a specific target organism,
system or (sub) population.
Expert judgement Opinion of an authoritative person on a particular subject.
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Formaldehyde
Exposure Concentration or amount of a particular agent that reaches a target
organism, system or (sub) population in a specific frequency for a
defined duration.
Exposure Evaluation of the exposure of an organism, system or (sub) population to
assessment an agent (and its derivatives). Exposure Assessment is the third step in
the process of Risk Assessment.
Exposure The exposure mass divided by the contact volume or the exposure mass
concentration divided by the mass of contact volume depending on the medium.
Exposure The length of time over which continuous or intermittent contacts occur
duration between an agent and a target. For example, if an individual is in contact
with an agent for 10 minutes a day, for 300 days over a one-year time
period, the exposure duration is one year.
Exposure The number of exposure events in an exposure duration.
frequency
Exposure mass The amount of agent present in the contact volume. For example, the
total mass of residue collected with a skin wipe sample over the entire
exposure surface is an exposure mass.
Exposure model A conceptual or mathematical representation of the exposure process.
Exposure The course an agent takes from the source to the target.
pathway
Exposure period The time of continuous contact between an agent and a target.
Exposure route The way an agent enters a target after contact (e.g., by ingestion,
inhalation, or dermal absorption).
Exposure A set of conditions or assumptions about sources, exposure pathways,
scenario amount or concentrations of agent(s)involved, and exposed organism,
system or (sub) population (i.e. numbers, characteristics, habits) used to
aid in the evaluation and quantification of exposure(s) in a given
situation.
Exposure surface A surface on a target where an agent is present. Examples of outer
exposure surfaces include the exterior of an eyeball, the skin surface,
and a conceptual surface over the nose and open mouth. Examples of
inner exposure surfaces include the gastro-intestinal tract, the respiratory
tract and the urinary tract lining. As an exposure surface gets smaller, the
limit is an exposure point.
Fate Pattern of distribution of an agent, its derivatives or metabolites in an
organism, system, compartment or (sub) population of concern as a
result of transport, partitioning, transformation or degradation.
xxxii Priority Existing Chemical Assessment Report No. 28
Guidance value Value, such as concentration in air or water, which is derived after
allocation of the reference dose among the different possible media
(routes) of exposure. The aim of the guidance value is to provide
quantitative information from risk assessment to the risk managers to
enable them to make decisions. (See also: reference dose)
Hazard Inherent property of an agent or situation having the potential to cause
adverse effects when an organism, system or (sub) population is exposed
to that agent.
Hazard A process designed to determine the possible adverse effects of an agent
assessment or situation to which an organism, system or (sub) population could be
exposed. The process includes hazard identification and hazard
characterization. The process focuses on the hazard in contrast to risk
assessment where exposure assessment is a distinct additional step.
Hazard The qualitative and, wherever possible, quantitative description of the
characterization inherent properties of an agent or situation having the potential to cause
adverse effects. This should, where possible, include a dose-response
assessment and its attendant uncertainties.
Hazard Characterisation is the second stage in the process of Hazard
Assessment, and the second step in Risk Assessment.
Related terms: Dose-Effect Relationship, Effect Assessment, Dose-
Response Relationship, Concentration -Effect Relationship.
Hazard The identification of the type and nature of adverse effects that an agent
identification has inherent capacity to cause in an organism, system or (sub)
population.
Hazard identification is the first stage in hazard assessment and the first
step in process of Risk Assessment
Intake The process by which an agent crosses an outer exposure surface of a
target without passing an absorption barrier, i.e. through ingestion or
inhalation.
Measurement of Measurable (ecological) characteristic that is related to the valued
end-point characteristic chosen as an assessment point.
Medium Material (e.g., air, water, soil, food, consumer products) surrounding or
containing an agent.
Microenvironme The rate at which the medium crosses the outer exposure surface of a
nt target, during ingestion or inhalation.
Reference dose An estimate of the daily exposure dose that is likely to be without
deleterious effect even if continued exposure occurs over a lifetime.
Related term: Acceptable Daily Intake.
Response Change developed in the state or dynamics of an organism, system or
(sub) population in reaction to exposure to an agent.
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Formaldehyde
Risk The probability of an adverse effect in an organism, system or (sub)
population caused under specified circumstances by exposure to an
agent.
Risk analysis A process for controlling situations where an organism, system or (sub)
population could be exposed to a hazard.
The Risk Analysis process consists of three components: risk
assessment, risk management and risk communication.
Risk assessment A process intended to calculate or estimate the risk to a given target
organism, system or (sub)population , including the identification of
attendant uncertainties, following exposure to a particular agent, taking
into account the inherent characteristics of the agent of concern as well
as the characteristics of the specific target system.
The Risk Assessment process includes four steps: hazard identification,
hazard characterization (related term: dose-response assessment),
exposure assessment, and risk characterization. It is the first component
in a risk analysis process.
Risk The qualitative and, wherever possible, quantitative determination,
characterization including attendant uncertainties, of the probability of occurrence of
known and potential adverse effects of an agent in a given organism,
system or (sub) population, under defined exposure conditions.
Risk Characterization is the fourth step in the Risk Assessment process.
Risk Interactive exchange of information about (health or environmental)
communication risks among risk assessors, managers, news media, interested groups and
the general public.
Risk estimation Quantification of the probability, including attendant uncertainties, that
specific adverse effects will occur in an organism, system or
(sub)population due to actual or predicted exposure.
Risk evaluation Establishment of a qualitative or quantitative relationship between risks
and benefits of exposure to an agent, involving the complex process of
determining the significance of the identified hazards and estimated risks
to the system concerned or affected by the exposure, as well as the
significance of the benefits brought about by the agent.
It is an element of risk management. Risk Evaluation is synonymous
with Risk-Benefit evaluation
Risk management Decision-making process involving considerations of political, social,
economic, and technical factors with relevant risk assessment
information relating to a hazard so as to develop, analyse, and compare
regulatory and non-regulatory options and to select and implement
appropriate regulatory response to that hazard.
Risk management comprises three elements: risk evaluation; emission
and exposure control; risk monitoring.
Risk monitoring Process of following up the decisions and actions within risk
management in order to ascertain that risk containment or reduction with
respect to a particular hazard is assured.
Risk monitoring is an element of risk management.
xxxiv Priority Existing Chemical Assessment Report No. 28
Safety Practical certainty that adverse effects will not result from exposure to
an agent under defined circumstances. It is the reciprocal of risk.
Safety factor Composite (reductive) factor by which an observed or estimated no-
observed-adverse effect level (NOAEL) is divided to arrive at a criterion
or standard that is considered safe or without appreciable risk.
Related terms: Assessment Factor, Uncertainty Factor.
Source The origin of an agent for the purposes of an exposure assessment.
Subchronic A contact between an agent and a target of intermediate duration
exposure between acute and chronic. (Other terms, such as "less-than-lifetime
exposure" are also used.)
Target Any biological entity that receives an exposure or a dose (e.g., a human,
human population or a human organ).
Threshold Dose or exposure concentration of an agent below that a stated effect is
not observed or expected to occur.
Time-averaged The time-integrated exposure divided by the exposure duration. An
exposure example is the daily average exposure of an individual to carbon
monoxide. (Also called time-weighted average exposure.)
Tolerable daily Analogous to Acceptable Daily Intake. The term Tolerable is used for
intake agents which are not deliberately added such as contaminants in food.
Toxicity Inherent property of an agent to cause an adverse biological effect.
Uncertainty Imperfect knowledge concerning the present or future state of an
organism, system or (sub) population under consideration.
Uncertainty Reductive factor by which an observed or estimated no-observed-
factor adverse-effect level (NOAEL) is divided to arrive at a criterion or
standard that is considered safe or without appreciable risk.
Related terms: Assessment Factor, Safety Factor.
xxxv
Formaldehyde
xxxvi Priority Existing Chemical Assessment Report No. 28
1. Introduction
1.1 Declaration
The chemical formaldehyde (CAS No 50-00-0) was declared a Priority Existing
Chemical for full assessment under the Industrial Chemicals (Notification and
Assessment) Act 1989 (the Act) on 5 March 2002. It was nominated by the public,
unions and non-government organisations for assessment due to its adverse
effects and widespread use. In addition, there were indications of a need to review
the occupational exposure standard and develop a National Environmental
Protection Measure (NEPM) for formaldehyde.
1.2 Objectives
The objectives of this assessment were to:
· characterise the properties of formaldehyde;
· determine the uses of formaldehyde in Australia;
· determine the extent of environmental, public and occupational exposure
to formaldehyde;
· characterise the intrinsic capacity of formaldehyde to cause adverse
effects on humans and the environment;
· characterise the risk to humans and the environment resulting from
exposure to formaldehyde; and
· determine the extent to which any risk can be minimised.
1.3 Sources of information
Information for the assessment was obtained from various sources including
industry, literature searches, site visits, all levels of governments, and other
organizations, such as research institutes and overseas regulatory authorities.
Industry
In accordance with the Act, manufacturers and importers of formaldehyde were
required to apply for assessment and supply relevant information. Data supplied
by applicants included:
· quantity of the chemical and/or products containing the chemical
manufactured and/or imported;
· quantity of the chemical formulated into products;
· uses of the chemical and products containing the chemical;
· methods used in handling, storing, manufacturing and disposal of the
chemical and products containing the chemical;
· information on human and environmental exposure to the chemical;
1
Formaldehyde
· Material Safety Data Sheet (MSDS) and labels; and
· contact details of their customers.
The National Industrial Chemical Notification and Assessment Scheme
(NICNAS) conducted a questionnaire survey (the NICNAS survey) in October
2002 to investigate the use patterns, occupational exposure levels, control
technologies and environmental exposure to formaldehyde. Randomly selected
formulators and end users of formaldehyde products participated in the NICNAS
survey. Further details are provided in Section 7.3.
A number of industry associations were also contacted and provided relevant
information. A list of all companies, associations and individuals consulted
during this assessment is provided in Appendix 1.
Literature review
A number of overseas peer-reviewed assessment reports on formaldehyde are
available (see Section 2.4). The major source of information on the health effects
of formaldehyde for this assessment was the Concise International Chemical
Assessment Document (CICAD) for formaldehyde, published under the
International Programme on Chemical Safety (IPCS, 2002). To enhance the
efficiency of the NICNAS assessment and provide transparency, not all primary
sources of data in the CICAD were evaluated. However, relevant studies
published since the cited reviews were identified (up to July 2004) and assessed
on an individual basis.
Site visits
Information on methods of use and potential for workers' exposure was also
obtained through a number of site visits. The site visits included formaldehyde
and formaldehyde resin manufacturers, a wood panel plant, funeral homes,
pathological laboratories and film processing plants.
1.4 Peer review
During all stages of preparation, the report has been subject to internal peer
review by NICNAS and the Australian Government Department of the
Environment and Heritage (DEH). Selected parts of the report were also
externally peer reviewed by independent experts from Australia and overseas.
2 Priority Existing Chemical Assessment Report No. 28
2. Background
2.1 Introduction
Formaldehyde is a naturally occurring, volatile organic compound which is
ubiquitous in the environment. It is formed primarily by the combustion of
organic materials and by a variety of natural and anthropogenic activities.
Formaldehyde is the product of many natural processes, such as forest and bush
fires, animal wastes, microbial products of biological systems, and plant volatiles.
In water, it is also formed by the irradiation of humic substances by sunlight. As a
metabolic intermediate, formaldehyde is present at low levels in most living
organisms. It is emitted by bacteria, algae, plankton, and vegetation as well.
Anthropogenic sources of formaldehyde from combustion processes account
directly or indirectly for most of the formaldehyde entering the environment.
Direct combustion sources include power plants, incinerators, refineries, wood
stoves, kerosene heaters, and cigarettes. Formaldehyde is also produced indirectly
by photochemical oxidation of hydrocarbons or other formaldehyde precursors
that are released from combustion processes. Other anthropogenic sources of
formaldehyde in the environment include industrial on-site uses and off-gassing
from building materials and consumer products.
Secondary formation of formaldehyde occurs in the atmosphere through the
photochemical oxidation of natural and anthropogenic volatile organic
compounds in the air, such as methane, isoprene, and pollutants from mobile and
stationary sources, such as alkanes, alkenes, aldehydes and alcohols.
2.2 Global production
Since 1889 in Germany, formaldehyde has been produced commercially by the
catalytic oxidation of methanol. Various manufacturing methods were used in the
past, but only two are widely used today: the silver catalyst and metal oxide
catalyst processes (IARC, 1995). Formaldehyde is used predominately in the
production of resins, followed by fertilizer production, and for various other
purposes, such as preservatives and disinfectants. Formaldehyde can be used in a
variety of industries, including the medical, detergent, cosmetics, food, rubber,
metal, wood, leather, petroleum, and agricultural industries, and as a hydrogen
sulfide scavenger in oil operations.
Because of its low cost and high purity, formaldehyde has become one of the
most important industrial and research chemicals in the world. The global
production of formaldehyde in 1999 (the most recent figure) was estimated 5 to 6
million tonnes (Asia: 1 to 1.5 million tonnes, North America: 1 to 1.5 million
tonnes, Western Europe: 2 to 2.5 million tonnes) (OECD, 2002). A global
production figure of 12 million tonnes in 1992 was reported by IARC (1995).
Formaldehyde is listed on the Organisation for Economic Cooperation and
Development's (OECD) List of High Production Volume (HPV) chemicals, i.e.
production volume of 1000 tonnes or more in at least one OECD country (OECD,
2004).
3
Formaldehyde
2.3 Australian perspective
In Australia, consistent with overseas use, formaldehyde is mainly used in the
manufacture of formaldehyde-based resins, which are widely used in a variety of
industries, predominately the wood industry. Formaldehyde is on the 2003
Australian High Volume Industrial Chemical List (HVICL) compiled by
NICNAS (NICNAS, 2002), which means it is an industrial chemical that had a
combined annual import and manufacturing quantity of 1000 tonnes or more
during 2001-2002. The total quantity of formaldehyde manufactured and
imported is detailed in Sections 7.1 and 7.2.
Concerns have been expressed by the public and several organisations over its
widespread use and adverse health effects, including its sensitisation potential and
carcinogenicity.
Formaldehyde is listed in the OASCC's Hazardous Substances Information
System (DEWR, 2004) and in Schedules 2 and 6 of the Standard for the Uniform
Scheduling of Drugs and Poisons (SUSDP) (NDPSC, 2005). It is also listed in the
Australian Code for the Transport of Dangerous Goods by Road and Rail (FORS,
1998) as a dangerous good. An Australian occupational exposure standard for
formaldehyde has been established (DEWR, 2004).
2.4 Assessments by other national or international bodies
Formaldehyde has been assessed by several national and international bodies,
who have reviewed and evaluated data pertaining to the health and/or
environmental hazards posed by the chemical. Of these, the most noteworthy are:
· International Agency for Research on Cancer examined a number of
recent epidemiology studies on carcinogenicity (IARC, 2004a). It
concluded that the carcinogen classification for formaldehyde be
upgraded from probable human carcinogen (Category 2A) to known
human carcinogen (Category 1) based on evidence that exposure to
formaldehyde may cause nasopharyngeal cancer in humans (more details
in Section 11.6). IARC has also reviewed formaldehyde on a number of
previous occasions (IARC, 1987, 1995);
· Concise International Chemical Assessment Document (CICAD) No. 40:
Formaldehyde, published by the International Programme on Chemical
Safety (IPCS, 2002);
· A Screening Information Data Set (SIDS) Initial Assessment Report
(SIAR) prepared by the German BMU (Bundesministerium für Umwelt,
Naturschutzund Reaktorsicherheit) was agreed at the Organization for
Economic Cooperation and Development (OECD) 14th SIDS Initial
Assessment Meeting (SIAM) in March 2002 (OECD, 2002). It concluded
that further work on the environmental exposure assessment was needed;
· US Agency for Toxic Substances and Disease Registry (ATSDR) report
(ATSDR, 1999); and
· Environmental Health Criteria (EHC) Number 89: Formaldehyde,
published by the IPCS (IPCS, 1989).
4 Priority Existing Chemical Assessment Report No. 28
3. Applicants
Following the declaration of formaldehyde as a Priority Existing Chemical, the
following companies or organisations applied for assessment of this chemical.
In accordance with the Industrial Chemicals (Notification and Assessment) Act
1989, NICNAS provided the applicants with a draft copy of the report for
comment during the correction and variation phases of the assessment. The
applicants were as follows:
Australian Plantation
A.S. Harrison & Co Pty Ltd
PO Box W2 Products and Paper Industry
Warringah Mall NSW 2100 Council
Level 3, Tourism House
Barton, ACT 2600
ACE Chemical Company
119A Mooringe Avenue
Camden Park SA 5038 Australian Wood Panels
Association
33 Bambury St
Agent Sales and Services Pty
Fingal Head, NSW 2487
Ltd
32 Charles St
South Perth, WA 6151 BASF Australia Ltd
Box 4705
Melbourne VIC 3001
AGFA-Gevaert Ltd
PO Box 48
Nunawading VIC 3131 Bayer Australia, SP/CH
Business Group
633-647 Springvale Rd
Akzo Nobel Pty Ltd
Mulgrave North VIC 3170
51 McIntyre Road
Sunshine VIC 3020
BetzDearbon Australia
69-77 Williamson Rd
Amtrade International Pty
Ingelburn NSW 2565
Ltd
PO Box 6421 St Kilda Road
Central Post Office VIC 8008 Biolab (Aust) Pty Ltd
2 Clayton Rd
Clayton, VIC 3168
Ashland Pacific Pty Ltd
PO Box 162
Chester Hill NSW 2162 Bio Scientific Pty Ltd
PO Box 78
Gymea NSW 2227
Asia Pacific Specialty
Chemicals Ltd
PO Box 232 Campbell Brothers Ltd
PO Box 118
Seven Hills NSW 1730
Newport VIC 3015
Australian Council of Trade
Campbell Cleantec Ltd
Unions
PO Box 490
393 Swanston Street
Sumner Park BC QLD 4074
Melbourne VIC 3000
5
Formaldehyde
H Trevail & Son Pty Ltd
Canpoint International Pty
157 Kingsgrove Rd
Ltd
Kingsgrove, NSW 2208
72 Tennyson Rd
Mortlake, NSW 2137
Halex Flooring Products Pty
Ltd
Carter Holt Harvey Panels
2/73 Zenith Rd
L6, Tower A, Zenith Centre
Dandenong VIC 3175
821 Pacific Highway
Chatswood, NSW 2067
Hexion Specialty Chemicals
Pty Ltd
CHT Australia Pty Ltd
2-8 James Street
33 Elliott Rd
Laverton North VIC 3026
Dandenong Vic 3175
ISP (Australasia) Pty Ltd
Ciba Specialty Chemicals
PO Box 6564
235 Settlement Road
Silverwater NSW 1811
Thomastown VIC 3074
International Sales and
Clariant (Australia) Pty Ltd
PO Box 23 Marketing Pty Ltd
262 Highett Road
Chadstone VIC 3148
Highett VIC 3190
Colgate Palmolive Pty Ltd
GPO Box 3964 International Trade Strategies
Sydney NSW 2001 Pty Ltd
Level 2, 60 Collins St
Melbourne, Vic 3000
Cytec Australia Holdings
PO Box 7215
Baulkham Hills BC NSW 2153 Jayco Corporation Pty Ltd
252-254 Frankston-Dandenong
Rd
Du Pont (Australia) Ltd
Dandenong, Vic 3175
49-59 Newtown Road
Wetherill Park NSW 2164
Kodak (Australasia) Pty Ltd
PO Box 90
Dynea WA Pty Ltd
Coburg VIC 3058
PO Box 1298
Bunbury WA 6231
Lomb Scientific (Aust) Pty Ltd
PO Box 2223
Ecolab Pty Ltd
Taren Point NSW 2229
6 Hudson Avenue
Castle Hill NSW 2154
Manildra Flour Mills
(Manufacturing) Pty Ltd
Gumfighters
PO Box 72
Suite 68, 89-97 Jones St
Auburn, NSW 2144
Ultimo, NSW 2007
Merck Pty Ltd
Gunnersen Timbermark Pty
207 Colchester Rd
Ltd
Kilsyth VIC 3137
112 Salmon St
Port Melbourne, VIC 3207
Novek Synthetics
102a Winbourne Rd
H B Fuller Company
Hazelbrook, NSW 2779
Australia Pty Ltd
PO Box 4202
Dandenong South, VIC 3164
6 Priority Existing Chemical Assessment Report No. 28
Swift and Company Ltd
Nowra Chemical
PO Box 689
Manufacturers Pty Ltd
Mulgrave VIC 3170
112 Albatross Rd
Nowra 2541
The Structural Adhesive
Company Pty Ltd
Nuplex Industries (Aust) Pty
116 Kitchener Rd
Ltd
Ascot, QLD 4007
49-61 Stephen Road
Botany NSW 2019
Thor Specialties
GPO Box 3124
Orica Australia Pty Ltd
Wetherill Park NSW 2164
1 Nicholson Street
Melbourne VIC 3001
Unilever Australasia
219 North Rocks Road
PCA Hodgson Chemicals Pty
North Rocks NSW 2151
Ltd
19-25 Anne Street
St Mary NSW 2760 Woodchem Australia Pty Ltd
Locked Bag 6
Oberon NSW 2787
Plywood Association of
Australia
13 Dunlop St
Newstead, QLD 4006
Professional Compounding
Chemists of Australia Pty Ltd
Suite 2, 1371 Botany Rd
Botany, NSW 2019
ProSciTech
PO Box 111
Thuringowa QLD 4817
Redox Chemicals Pty Ltd
Locked Bag 60
Wetherill Park NSW 2164
RH Minter Pty Ltd
17 Park Road
Oakleigh VIC 3166
Sigma Aldrich Pty Ltd
2/14 Anella Ave
Castle Hill, NSW 2154
Standards Australia
GPO Box 5420
Sydney NSW 2001
Sulzer Medica Pty Ltd
Level 5, 384 Eastern Valley
Way
Chatswood, NSW 2067
7
Formaldehyde
4. Chemical Identity and
Composition
4.1 Chemical name (IUPAC)
Methanal
4.2 Registry numbers
Formaldehyde is listed on the Australian Inventory of Chemical Substances
(AICS) as formaldehyde.
CAS number: 50-00-0
EINECS number: 200-001-8
UN numbers: 2209 for non-flammable formaldehyde solutions (25%)
1198 for flammable formaldehyde solutions
4.3 Other names
Formaldehyde solution
Formaldehyde gas
Formalin
Formalith
Formol
Formic aldehyde
Methaldehyde
Methyl aldehyde
Methylene oxide
Morbicid
Oxomethane
Oxymethylene
Paraform
4.4 Molecular formula
CH2O
8 Priority Existing Chemical Assessment Report No. 28
4.5 Structural formula
H
|
C=O
|
H
4.6 Molecular weight
30.03
4.7 Composition of commercial grade product
Pure formaldehyde is not commercially available. Formaldehyde is generally
available as a 37% to 54% (by weight) aqueous solution, known as formalin. To
reduce the intrinsic polymerisation of formaldehyde, stabilisers, such as methanol
and various amine derivatives, are added to the solution (IPCS, 2002; IARC,
1995). Methanol concentrations can be as high as 15% (by weight). The
concentrations of other stabilisers can be in the order of several hundred mg/mL
(IPCS, 1989). Formaldehyde is marketed in a solid form as trioxane (CH2O)3 and
its polymer paraformaldehyde, with 8 to 100 units of formaldehyde (IPCS, 2002;
IARC, 1995).
9
Formaldehyde
5. Physical and Chemical Properties
This section covers physical and chemical properties for both gaseous
formaldehyde gas and formalin (37% formaldehyde solution).
5.1 Physical state
At room temperature, formaldehyde is a colourless gas with a pungent, irritating
odour. The odour threshold of formaldehyde varies widely, ranging from 0.05 to
1 ppm. However, for most people the odour threshold is in the 0.5 to 1 ppm range
(OECD, 2002).
5.2 Physical and chemical properties
The physical and chemical properties of gaseous formaldehyde and formalin
(37% formaldehyde solution) are summarised in Table 5.1. The values in the
following text and in Table 5.1 are cited from the CICAD (IPCS, 2002), unless
otherwise stated.
Gaseous formaldehyde
Formaldehyde gas is highly reactive, highly flammable and can form explosive
mixtures in air. It presents a fire hazard when exposed to flame or heat. At
temperatures greater than 150oC, formaldehyde decomposes to methanol and
carbon monoxide (IPCS, 1989). It readily undergoes polymerisation.
Formaldehyde polymers or products containing formaldehyde polymers can
decompose to release significant amounts of gaseous formaldehyde when
overheated.
Formaldehyde gas is readily soluble in water, alcohol, and other polar solvents. It
can exist as methylene glycol, polyoxymethylene and hemiformal in solutions.
Formaldehyde is a reactive aldehyde that undergoes a number of self-association
reactions. For example, at concentrations above 30% the polymer precipitates.
The chemical species produced when formaldehyde associates with water may
have different properties from those of the pure monomolecular substance. These
associations tend to be more prevalent at higher concentrations of formaldehyde.
Therefore, the properties described at high concentrations may not be relevant for
more dilute concentrations.
Formalin
Formalin without methanol has a flash point of 83 to 85 °C and is combustible.
Formalin can be a flammable liquid when the formaldehyde or methanol
concentration is high. Formalin may become cloudy on standing, especially at
cool temperatures, and form paraformaldehyde at very low temperatures. It
slowly oxidizes in air to formic acid and is sensitive to light. It is easily hydrated
and polymerised if not stabilised (Keith and Walters, 1992).
10 Priority Existing Chemical Assessment Report No. 28
Table 5.1: Physical and chemical properties of formaldehyde gas and 37%
formaldehyde solution+
Property Gaseous 37% Formaldehyde solution
formaldehyde
30.03#
Relative molecular mass 30.03
-118 to -92 oC
Melting point NA
-21 to -19 oC 96 oC# (water)
Boiling point
100 mg/mL at 20.5 oC#
Water solubility 400 to 550 g/L
(at 25oC)
Henry's Law constant 0.022 to 0.034 NA
(at 25oC) Pa.m3/mol
Log Kow -0.75 to 0.35 NA
Log Koc 0.70 to 1.57 NA
Density (at 20oC) 0.82 g/mL* 1.03-1.10 g/mL*
Explosivity limits in air
7%# @
Lower (vol %) 7%*
73%# @
Upper (vol %) 73%*
Vapour pressure (at 25oC) 516 kPa* 2.26 to 2.66 kPa*
300 oC* 430 oC#
Autoignition temperature
83 - 85 oC*
Flashpoint (closed cup) NA
(for 37% formaldehyde solution
without methanol)
50 oC*
(for 37% formaldehyde solution
with 15% methanol)
+
The values are cited from the CICAD (IPCS, 2002), unless otherwise stated;
Log Kow, Log octanol/water partition coefficient;
Log Koc, Log organic carbon/water partition coefficient;
NA, not available;
*Klasco (2003);
#
Keith and Walters (1992);
@
based on release of formaldehyde from solution.
Formalin is a strong reducing agent, especially in the presence of alkalis. It is
incompatible with ammonia, alkalis, bisulfides, iron preparations, iodine, phenols,
potassium permanganate, tannin and salts of copper, iron, and silver. It combines
directly with albumin, casein, gelatin, agar and starch to form insoluble
compounds. It reacts violently with hydrogen peroxide, magnesium carbonate,
nitromethane, perchloric acid and aniline, and performic acid and also reacts with
strong oxidizers and acids. Reactions with nitrous oxides (nitrogen dioxide)
11
Formaldehyde
become explosive at 180 °C. It is corrosive to carbon steel as well as copper and
its alloys (Keith and Walters, 1992).
Paraformaldehyde emits formaldehyde gas when it is heated to decomposition. It
is also hydrolysed by hot water and alkali forming formaldehyde. It behaves like
methanol-free formaldehyde of the same concentration once it dissolves in water
(Lewis, 1996).
5.3 Conversion factors
The conversion factors for formaldehyde at 25 °C are:
1 ppm = 1.2 mg/m3
1 mg/m3 = 0.83 ppm
12 Priority Existing Chemical Assessment Report No. 28
6. Methods of Detection and
Analysis
6.1 Characterisation
Formaldehyde can be characterised by a number of methods including
spectrophotometry, high performance liquid chromatography (HPLC),
colorimetry, fluorimetry, polarography, gas chromatography (GC) using flame
ionisation detection (FID), and infrared detection. Methods based on
spectrophotometry are the most widely used, and have sensitivities of 8 to 25 ppb
(10 to 30 ”g/m3). HPLC is another method commonly used and has a detection
limit of 1.7 ppb (2 ”g/m3). The most sensitive method of detection is flow
injection, with a detection limit of 9 ppt (0.011 ”g/m3).
Information on methods of detection and analysis for formaldehyde in various
media is abundant and has been summarised in a number of reviews (IPCS, 2002;
ATSDR, 1999; IARC, 1995; IPCS, 1989). For all methods, organic and inorganic
chemicals, such as sulphur dioxide, other aldehydes and amines, can cause
interference. Therefore, the method of sampling and the treatment of the sample
before analysis are important factors in the accuracy of the determination.
This section focuses on the methods commonly used in Australia for detecting
formaldehyde in the atmosphere of workplaces, ambient air, indoor air and
emissions from products releasing formaldehyde, such as wood and textiles.
Methods of detection in other media, such as water and in biological samples, are
also briefly discussed.
6.2 Atmospheric monitoring methods
6.2.1 In the workplace
For personal monitoring during full shifts or tasks, workers are equipped with a
sampler (tube or badge) placed in the breathing zone. For area monitoring, the
tube or badge is placed at a fixed location in the workplace environment. Tubes
are connected to a portable metering pump, whereas badges sample the air by
diffusion. At the end of the sampling period, the tube or badge is sealed and
transferred to a laboratory, where the chemical is liberated from the absorbent and
quantified using different analytical methods. The result is expressed as ppm or
mg/m3 over the duration of the sampling period. The analytical detection limit
depends on the airflow across the absorbent and the duration of the sampling
period.
The US National Institute of Occupational Safety and Health (NIOSH) methods
(NIOSH, 1994) are commonly used in Australia. They are summarised in
Table 6.1.
13
Formaldehyde
Table 6.1: NIOSH methods of detection for formaldehyde (NIOSH, 1994)
Method Sampling Analytical Limit of Comment
Number method detection
Filter and Visible 0.02 ppm The most sensitive
3500
impingers absorption for an 80L air method of the NIOSH
spectrometry sample methods; Best suited for
static samples.
Solid GC, FID 0.24 ppm Suitable for the
2541
sorbent for an 10L air simultaneous
tube sample determinations of
acrolein and
formaldehyde; suited for
personal samples.
Cartridge HPLC, UV 0.021 ppm Can be used for both
2016
detection for an 15L air TWA and STEL
sample measurements.
TWA, time weighted average; STEL, short-term exposure limit.
Several other atmospheric monitoring methods for detecting formaldehyde in the
workplace are summarised in the CICAD (IPCS, 2002). These include some
methods that have been used in Australia, such as use of a formaldehyde passive
sampler/monitor followed by chromotropic acid test (detection limit of 0.083
ppm) and gas tube detectors with infrared analysers (detection limit of 0.33-0.42
ppm).
Instantaneous measurement of the concentration of airborne formaldehyde, such
as by direct read, hand-held electronic formaldehyde devices, is also used in
Australia. For example, formaldehyde meters and Interscan machines provide
instantaneous readings.
The sensor of formaldehyde meters is an electro-chemical cell which contains
electrodes that are used for temperature compensation and to improve the
selectivity. The sensor response is linear with the concentration of formaldehyde
in air. Two filters are used to eliminate interferences. Measurements are first
made with a filter that permits determination of the background or baseline.
Insertion of a second filter then permits the measurement of formaldehyde. The
limit of detection is 0.01 ppm.
The Interscan machine is an electrochemical gas detector operating under
diffusion-controlled conditions. Gas molecules from the sample are adsorbed on
an electrocatalytic-sensing electrode, after passing through a diffusion medium,
and are electrochemically reacted at an appropriate sensing electrode potential.
This reaction generates an electric current directly proportional to the gas
concentration. This current is converted to a voltage for meter or recorder
readout. The limit of detection is 0.01 ppm.
6.2.2 In the environment
The methods commonly used for measuring the concentration of formaldehyde in
ambient air fall into the following two categories (EA, 2001):
14 Priority Existing Chemical Assessment Report No. 28
· Discrete air sampling with subsequent laboratory analysis;
· Continuous or semi-continuous in-field analysis.
The most widely used method for discrete air sampling involves the collection of
air into a stainless steel canister over a predetermined period of time, such as 24
hours, followed by GC or GC-MS analysis. Discrete sampling methods determine
average pollutant levels over the sample collection time.
A commonly used continuous in-field analysis method uses an optical remote
sensing system to determine the concentration of the chemical by means of the
differential absorption of transmitted light by gaseous compounds along the light
path. The system consists of a light transmitter and sensor placed at a given
distance apart at the monitoring site. Alternatively, the concentration in air can be
analysed by semi-continuous gas chromatography. Samples are collected directly
onto solid absorbents, desorbed thermally onto the GC column and analysed
while the next sample is collected. Compared with discrete sampling method,
continuous or semi-continuous methods enable more detailed information about
concentration variations.
The analytical limit of detection of the above methods typically ranges from
0.003 to 0.1 ppb. All of the methods allow for the simultaneous determination of
several other gaseous air pollutants in the same sample.
In addition, several other methods of detection for measuring ambient air
formaldehyde levels are available including:
· United States Environmental Protection Agency (US EPA), Method TO5,
Determination of Aldehydes and Ketones in Ambient Air Using High
Performance Liquid Chromatography (HPLC) (US EPA, 1988a);
· US EPA Method TO11, Method for the Determination of Formaldehyde
in Ambient Air Using. Absorbent Cartridge Followed by High
Performance Liquid Chromatography (US EPA, 1988b).
A recent NEPM document (NEPC, 2004) recommended use of two other US
EPA testing methods:
· US EPA Compendium Method TO-11A, Determination of Formaldehyde
in Ambient Air Using Adsorbent Cartridge Followed by High
Performance Liquid Chromatography (active sampling methodology)
(US EPA, 1999a);
· US EPA Compendium Method TO15, (as an alternative method)
Determination of Volatile Organic Compounds (VOCs) in Air Using
Specially-Prepared Canisters and Analysed by Gas
Chromatography/Mass Spectrometry (GC/MS) (US EPA, 1999b).
6.2.3 Indoor air
Formaldehyde concentrations in indoor air can be measured by either active or
passive sampling using a sampler to collect the formaldehyde followed by
analysis using a number of methods. The use of passive sampling techniques
should be fully verified by active means.
15
Formaldehyde
Currently, there is an Australian Standard for testing formaldehyde in indoor air,
AS 2365.6-1995, Methods for the Sampling and Analysis of Indoor Air. Method
6: Determination of Formaldehyde Impinger Sampling- Chromotropic Acid
Method (Standards Australia, 1995). However, there are problems with use of
chromotropic acid due to interferences and quality-related issues. There are more
suitable methods including active collection onto DNPH, which are analysed via
HPLC or GC/MS or equivalent analytical methods. The US EPA methods
discussed above (TO5, TO11, TO-11A, and TO-15) are also suitable for
measuring indoor air formaldehyde.
There are a number of International Organization for Standardization (ISO)
documents on indoor air formaldehyde testing. They are:
· ISO 16000-2 Indoor air - part 2: Sampling strategy for formaldehyde
(ISO, 2004a)
· ISO 16000-3 Indoor air - part 3: Determination of formaldehyde & other
carbonyl compounds - Active sampling method. (based on US EPA
method TO-11A) (ISO, 2001)
· ISO 16000-4 Indoor air - part 4: Determination of formaldehyde -
Diffusive sampling method. (i.e. passive sampling with badges) (ISO,
2004b).
The Standards Australia Indoor Air Committee advised that the Committee would
be considering these ISO methods along with other methods such as the US EPA
methods when determining suitable testing methods for indoor air formaldehyde
in the future.
Methodology for the simultaneous sampling of a number of indoor airborne
aldehydes including formaldehyde is also available. A recent paper investigated
detecting indoor air formaldehyde using a direct reading device (Suzuki, 2003).
However, this method has certain limitations and serves mainly for screening
purposes.
6.2.4 Off-gas monitoring from wood products
Four methods have been developed to measure formaldehyde emissions from
wood products and details have been summarised in recent reviews (IPCS, 2002;
IARC, 1995).
The Standards Australia has published a number of methods for the measurement
of formaldehyde emission from particleboard, fibreboard and medium density
fibreboard (MDF). A summary of these standards is provided in Table 6.2.
Standard testing methods for formaldehyde emissions from plywood (AS/NZS
2098.11:2004) and laminated veneer limber (AS/NZS 4357.4:2004) products are
currently being considered by the Standards Australia.
16 Priority Existing Chemical Assessment Report No. 28
Table 6.2: Standards Australia methods for the measurement of
formaldehyde emissions from wood-based products
Method Sampling Principle Emission Reference
Matrix Rate
Desiccator Particleboard Emission of formaldehyde mg/L AS/NZS
and is determined by placing 4266.16:
method
fibreboard test pieces of known 2004
surface area in a (Standards
desiccator, at a controlled Australia/
temperature, and Standards
measuring the quantity of New
emitted formaldehyde Zealand,
absorbed in a specific 2004a)
volume of water during 24
h using a
spectrophotometer.
Particleboard Formaldehyde is extracted mg/100g AS/NZS
Perforator
and medium from test pieces by means 4266.15:
method
density of boiling toluene and then 1995
fibreboard transferred into distilled or (Standards
demineralised water. A Australia/
sample of the water is then Standards
analysed photometrically New
by the acetylacetone Zealand,
method. 1995)
6.3 Biological monitoring
The concentration of formaldehyde in biological samples, such as blood and
breath, has been used in attempts to monitor workers' exposure (ATSDR, 1999).
Formic acid or formate, a metabolite of formaldehyde, has been measured in
workers' urine and blood. However, it has been suggested exposure to
formaldehyde cannot be adequately assessed by these methods because
formaldehyde is rapidly metabolised and is highly reactive. Therefore, it is
unlikely to be present in samples. Urinary formate levels are also an unreliable
biomarker as formate is a metabolite of many other substances.
6.4 Water
Methods for the collection and determination of formaldehyde in atmospheric
water, drinking water and fog water have been summarised by ATSDR (1999).
These methods are similar to those for ambient air described above. The methods
for formaldehyde in drinking water and fog water rely on the formation of the
DNPH derivative followed by HPLC. The method for measuring formaldehyde in
atmospheric water relies on the reaction of formaldehyde in atmospheric water
with diketone (2,4-pentanedione) and ammonium acetate to form a fluorescent
derivative that is measured spectrophotometrically in a flow injection analysis
system.
17
Formaldehyde
6.5 Soil
One method for measuring formaldehyde in soil has been reported (Klasco,
2003). The soil is dried by addition of magnesium sulfate. Freon 113 is then used
to extract the formaldehyde and the sample is scanned with a spectrophotometer.
The concentration is determined from a calibration curve.
18 Priority Existing Chemical Assessment Report No. 28
7. Manufacture, Importation and Use
7.1 Manufacture
Formaldehyde is manufactured in Australia by catalytic oxidation of methanol.
Two methods are used; one uses a silver catalyst and the other a metal oxide
catalyst. As formaldehyde is produced in gas form, it is absorbed into water
during manufacture. The aqueous solutions are called formalin and the
concentrations of formaldehyde in formalin range from 37% to 54%. Four
companies manufacture formaldehyde at five sites around Australia. Information
on the location of the plants, manufacturing techniques and the formaldehyde
concentrations in formalin produced are summarised in Table 7.1.
Table 7.1: Manufacturers of formaldehyde in Australia
Company Location State Manufacture % Formaldehyde
technique in formalin
Woodchem Oberon NSW Metal oxide catalyst 37
Orica Deer Park VIC Metal oxide catalyst 54
Hexion Laverton VIC Silver catalyst 54
Hexion Gibson Island QLD Silver catalyst 50
Dynea Dardanup WA Silver catalyst 37
Some manufacturers also dilute the 50% and 54% formalin to as low as 26% for
use or sale.
The quantities of formaldehyde manufactured (calculated as 100% formaldehyde)
for calendar years 2000 to 2002 are shown in Figure 7.1. The information was
provided by the four manufacturers. Approximately 50 000 tonnes of
formaldehyde are manufactured annually.
The formaldehyde manufacturers advised that over 80% of formalin production is
used in resin manufacture on site. The remainder is supplied to local formulators
or end users and small amounts are exported overseas.
Paraformaldehyde is not manufactured in Australia.
Manufacturing process
Formaldehyde manufacture involves a series of continuous, enclosed processes
designed to facilitate the oxidation of methanol over a catalyst. The processes for
the two manufacturing methods used in Australia are similar and are shown in
Figure 7.2.
19
Formaldehyde
Figure 7.1: Quantities of formaldehyde manufacture in Australia
70
60
50
tonnes x 1000
40
30
20
10
0
2000 2001 2002 Mean
Year
Figure 7.2: Formaldehyde manufacturing process
Exhaust to
atmosphere
Fresh
Air
(O2)
Regas
Vapouriser Catalytic Converter
Methanol
Methanol
Water
Vapour
injected
ABSORBER and
TOWER recirculated
Formaldehyde
gas
REACTION
Heat
System CHAMBER Formaldehyde
solution to
storage
Steam for resin process
20 Priority Existing Chemical Assessment Report No. 28
Raw materials used in formaldehyde manufacture are methanol, water, air and
catalysts. Liquid methanol is fed into a vaporising chamber where it is mixed with
water and air (oxygen). The contents of the chamber are maintained at a desired
temperature range through the addition of steam. The vaporised methanol is then
directed to the top of an exothermic reaction chamber. The reaction generates
heat that is used to sustain the temperature of the catalyst and generate steam for
use in resin manufacture. Hot gaseous formaldehyde is cooled as it exits the
reaction chamber. It is then passed to absorption towers where formaldehyde is
absorbed into recirculating water. By careful control of temperature and/or flows
into the absorber tower the required concentration of formalin is achieved in the
base of the tower. Formalin is then passed through a distillation tower where any
remaining methanol is removed. Decanting of formalin is via pump and closed
pipe system to either storage tanks on site or loaded to tankers or drums for road
transport.
Most of the gas exiting the top of the absorber tower is recycled through the
process again. This lowers the oxygen level of the gas stream so that it can be
maintained below the explosive range for the methanol/air mix. Exhaust gases
pass over a catalytic converter to minimise emissions of formaldehyde, methanol
and by-products that remain. The whole manufacturing process is controlled by a
computer system operated by workers in a control room.
The metal oxide process involves the oxidation of vaporised methanol using air
whereas the silver catalyst process involves partial oxidation and
dehydrogenation of vaporised methanol in air using steam and granulated silver.
Table 7.2 shows the similarities and differences between these two manufacturing
techniques.
Table 7.2: Comparison between silver catalyst process and metal oxide
process (Kroschwitz & Howe-Grant, 1994; IARC, 1995)
Silver catalyst process
Metal oxide process
No. of reactions One Two
Exothermic Exothermic (overall)
Reaction type
Exothermic (50-60%)
Endothermic (40-50%)
CH3OH + œO2 HCHO + H2O 1) CH3OH + œO2 HCHO + H2O
Reaction
H = -156 kJ (-37.28 kcal) H = -156 kJ (-37.28 kcal)
2) CH3OH HCHO + H27
H = +85 kJ (20.31 kcal)
270-370oC 500-700oC
Temperature in
reaction
chamber
Atmospheric Atmospheric
Pressure
Carbon monoxide
Carbon monoxide
By-products
Carbon dioxide
Dimethyl ether
formed
Methyl formate
Carbon dioxide
Formic acid
Formic acid
Hydrogen
21
Formaldehyde
7.2 Importation
Information on the quantities of formaldehyde imported was provided by
importers of formalin and products/mixtures containing formaldehyde, for the
years 2000 and 2001. Predicted quantities for the year 2002 were also provided.
Furthermore, as paraformaldehyde can be a significant source of formaldehyde,
imported quantities of paraformaldehyde for the same periods were provided.
The reported quantities of imported formaldehyde are listed in Table 7.3. The
amount of formaldehyde (calculated as 100%) was estimated by multiplying the
volume of formalin or product by the % of formaldehyde in the formalin/product.
The quantity of imported formaldehyde is approximately 76 to 109 tonnes per
annum.
Table 7.3: Importation quantities of formaldehyde
2000 2001 2002* % Formaldehyde
(tonnes) (tonnes) (tonnes)
Formalin 36 45 60 16% - 40%
Formaldehyde 14 18 24
(calculated as 100%)
Formaldehyde products 4500 4200 4400 0.0002% - 40%
Formaldehyde 95 58 61
(calculated as 100%)
Total Formaldehyde 109 76 85
(calculated as 100%)
*Estimated figures
Formalin is imported in packaging of various sizes including 220 kg drums, 20 L
drums, 22 kg carboys, 2.5 L bottles, 500 mL bottles and 10 mL ampoules.
Imported formalin is transported in pallets in full container loads or on trucks
mainly by road. The majority of imported formalin is used in resin manufacture
and as laboratory reagents.
The information provided to NICNAS indicates that more than 250
formaldehyde-containing products, such as formaldehyde resins, film processing
products, surface coating products, and preservatives, are imported. The
concentrations of formaldehyde in the imported products vary widely, however,
the majority of them are less than 1%. Imported products are either further
incorporated into end products or used directly by end users. Some end use
products containing formaldehyde are imported and sold directly to the general
public. Examples include cosmetics products and other consumer products, such
as fabric softener, surface liquid cleaners and dishwashing liquids.
Paraformaldehyde is imported as prills or powder in 25 kg bags. The
concentrations of formaldehyde in these prills/powder range from 81% to 99%.
22 Priority Existing Chemical Assessment Report No. 28
The total reported importation of paraformaldehyde is shown in Figure 7.3 and is
approximately 700 tonnes per year. It was reported that most imported
paraformaldehyde is used in resin manufacture.
Figure 7.3: Importation of paraformaldehyde
900
800
700
600
tonnes
500
400
300
200
100
0
2000 2001 2002*
Ye a r
*Estimated figure
7.3 Use
Formalin is either used by manufacturers/importers, and/or supplied to
formulators to produce intermediate or end products, or sold directly to end users.
A similar distribution pattern exists for imported products containing
formaldehyde. The distribution chains vary as repackaging and reselling may
occur as intermediate steps.
Information on uses of formalin and products containing formaldehyde in
Australia was provided by industry and also obtained by site visits and a
questionnaire survey (the NICNAS survey). The NICNAS survey attempted to
reach users of formaldehyde through the distribution chains. The information
collected by the NICNAS survey included product details, description of
formulation/use processes, use of personal protective equipment, current controls
and potential release to environment. A copy of the NICNAS survey form for
formulators and manufacturers of formaldehyde products is provided in Appendix
2. The NICNAS survey form was modified for repackers, resellers and end users
of formaldehyde. The formulators and end users were randomly selected from
customer lists provided by importers and manufacturers, covering as many
industry sectors as possible. However, the profile of users contacted during the
NICNAS survey might not be fully representative of an industry sector, as
response rate to the NICNAS survey was about 60% after a follow up attempt.
Moreover, operation processes vary from site to site.
Formalin is used as a raw material for the manufacture of formaldehyde-based
resins, which are widely used in a variety of industries, predominately the wood
industry.
23
Formaldehyde
Formalin is also used directly or in blends, typically in the following industries:
· Forensic/hospital mortuaries and pathology laboratories;
· Embalming;
· Photographic film processing;
· Leather tanning;
· Sanitising treatment;
· Lubricant;
· Analytical laboratories;
· Fumigation;
· Personal care products; and
· Consumer products.
As paraformaldehyde has similar applications to formalin, the uses of
paraformaldehyde are not specifically described in this section.
Formaldehyde has some other applications in Australia, including poultry shed
disinfections, sheep foot rot treatments and uses of formaldehyde products as
biocides and preservatives for non-industrial applications, such as pharmaceutical
products. These applications are not considered in this assessment, as they are not
as defined as `industrial uses' by the Industrial Chemicals (Notification and
Assessment) Act 1989 (Cwlth).
7.3.1 Formulation of formaldehyde products
The majority of formalin is used in the production of formaldehyde resins.
Formalin and/or formaldehyde-containing products are also used as raw materials
in blends to formulate non-resin industrial and/or consumer end products.
Resin manufacture
All formaldehyde manufacturers use the majority of the formalin they produce to
manufacture formaldehyde resins. The total formaldehyde resins manufactured by
the four companies are approximately 266 600 tonnes in calendar year 2000,
342 200 tonnes in 2001 and 257 300 tonnes in 2002 (estimation). Some importers
of formalin or paraformaldehyde, and formulators who purchase formalin or
paraformaldehyde locally, also manufacture formaldehyde resins. The total
quantity of formaldehyde resins manufactured in Australia cannot be estimated as
not all formulators were identified during the assessment. The types of resins that
are manufactured in Australia include urea formaldehyde, melamine
formaldehyde, phenol formaldehyde resins and combination of these resins, such
as melamine urea formaldehyde resins.
The resin making process involves the reaction of formaldehyde with other
reactants, such as urea, melamine and phenol or combinations of these reactants.
The manufacture of resins is a batch process and conducted in enclosed systems.
The manufacturing process varies from site to site. Typically, formalin is
transferred through a fixed piping system and charged into resin reactors. Manual
24 Priority Existing Chemical Assessment Report No. 28
charging of formalin from drums occurs at some smaller resin manufacturing
sites. In the situation that paraformaldehyde is used, it is charged manually from
sealed bags into the reactor. Each batch typically takes about 8 to 12 hours, but
can vary from 5 to 30 hours depending on the technical grade of the resin.
Decanting of the resins is via a closed pipe system to storage tanks on site from
which it is pumped to drums, bulk containers or bulk tankers for road transport.
Some workplaces decant the resins manually into 8 to 200 L drums.
The typical resin manufacture process is summarised in Figure 7.4. The majority
of the formaldehyde resins contain < 0.2% free formaldehyde, but some contain
> 0.2% depending on the applications of the resins. For example, some fibreglass
resins contain up to 13% free formaldehyde.
Solid phenol formaldehyde resin powder is also manufactured in Australia. The
molten phenol formaldehyde resin is dropped from the reactor onto a cooling
floor where it becomes a brittle solid, which is then manually broken into lumps.
The lumps are subsequently blended with curing agents and ground to a powder
which is then packed in 15 kg or 700-800 kg bags for sale. The resin powder does
not contain any free formaldehyde and is used as a binder in the manufacture of
abrasive products, such as grinding wheels, brake components (for example,
brake linings), and refractory products. These products are typically compression
moulded and then heat cured.
Formulation of formaldehyde products (other than resins)
Both formalin and products containing formaldehyde are used to formulate a
large number of end products that are used in various industries. In general,
formulation is a batch process, in which measured amounts of formaldehyde or
product containing formaldehyde and other components are added to mixing
vessels and blended to form end products. The product is then transferred to
containers and dispatched to customers. However, the blending processes vary
from site to site. A number of examples have been selected from the industry
submissions and the NICNAS survey, and are presented in Table 7.4, to illustrate
the differences in formulation processes.
In general, manual processes occur in small batch productions, such as
formulation of anti-graffiti wall sealer. Typically, formalin or product containing
formaldehyde is decanted into a vessel for weighing before being poured into an
open tub and stirred. Decanting is done with a small jar and funnel. Equipment is
cleaned manually between different products with either water or cleaning
solvents.
For larger-scale production, such as detergents and disinfectants formulations,
formalin or product containing formaldehyde is either directly poured into a
mixing tank using a drum lifter or is transferred via a transfer pump. Other
ingredients are then added, followed by mechanical stirring. For some
formulations, formalin or product containing formaldehyde is premixed with
other ingredients before adding into the main mixing vessel. The mixing
operation is usually conducted under closed or partially closed conditions and the
final product is pumped into drums for transport to customers. Decanting is
usually an automated process. Table 7.4 shows that the duration and frequency of
the formulation process vary largely depending on a number of factors, such as
customer orders, batch sizes and properties of ingredients.
25
Formaldehyde
Figure 7.4: Typical resin manufacture process
Formaldehyde or Urea
Reactants
Formaldehyde Concentrate
(urea, phenol,
melamine)
Distillate water
Reactor
Agitation
Steam
pH adjustment
(formic/caustic)
and
heating/cooling
Operators + Laboratory Staff
- control
- sampling
- quality analysis
Formaldehyde resins
Drums Storage
Trucks to
tanks
customers
26 Priority Existing Chemical Assessment Report No. 28
Table 7.4: Examples of formulation processes for formaldehyde products
Product % FA in raw % FA in end Work process Duration Frequency
formulated material product (day/year)
Loading Mixing Heating Sampling Decanting Cleaning
Fixative solutions 37 4-32 E O N NR A NR >0.5 h NR
Embalming fluids 37 20-30 M O Y NA M M 6-8 h 20
Film processing 37 10.4 E E N M A E 1h 5
Preservative fluid 37 4 E NA N M M M 5 min 1
Leather tanning 37 <1% E E Y M M E 2.5-10 h 240
Anti-graffiti wall 37 0.6 M O N M M M 1-2 h 2
sealer
Biocides 37 <0.6 E E N M A M 6h 200
Textile treatment 37 <0.5 E E N M M M 2-3 d 72
Surfactants 37 <0.2 E O N M Semi-A M 12 h 260
Consumer products 37 <0.2 O O N M M M 2-4 h 208
Disinfectant 37 <0.2 E PE Y NR A E 0.4-2 h 240
Detergents 3-21 <0.2 E PE Y M A E 0.5-3 h 240
Scour pads 3 <0.2 E PE N NA A M 2h 100
Furniture lacquer <3 <0.2 M PE N NR M M 4h 6
Paints 0.7-3 <0.2 M O N M M M 1-3 d 100
FA, formaldehyde; NR, not reported; NA, not applicable; E, enclosed process; PE, partially enclosed process; O, open process; A, automated process; M, manual; N, no; Y,
yes.
27
Formaldehyde
Table 7.5: Examples of repackaging processes for formalin and/or products containing formaldehyde
Product Package size Repackaged size Work process Duration Frequency
(day/year)
Formalin (40%) 200 L drum 20 L, 5 L, 2.5 L, Drums are transferred to packing area by a forklift truck. A worker 0.1 h 2
500 mL bottle connects a hose to a tap on the drum and formalin is transferred
into smaller containers by gravity.
2h 200
Formalin (37%) Bulk tank 20 L, 200 L drums, Formalin is pumped from the bulk storage tank into various size
1000 L bulk box containers through an enclosed tubing system. Caps are manually
screwed on and the containers are taken away using forklift to
storage area. The bulk storage tank is dedicated to formalin only
and is not cleaned on a regular basis.
1h 8
Formaldehyde 205 L drum Various sizes Drums are transferred to packing area on a pallet via a forklift
product truck. A worker inserts a drum pump into the drum opening and
product is transferred by weight into various smaller containers.
Caps are manually screwed on and the containers are taken away
using forklift to storage areas.
3h 2
Formaldehyde 200 L drum 20 L plastic pail Drums are transferred to packing area on a pallet via a forklift
product truck. A drum pump is manually inserted into the drum opening
and product is transferred by weight into 20 L plastic pails. Pails
are packed onto a disposable wooden pallet, steel banded and
shrink wrapped prior to transport.
8h 40
Paraformaldehyde 25 kg paper 3 kg paper bag Bags are opened and tipped into a 200 L bin by hands. Workers
bag scoop out the powder and weigh them into 3 kg paper bags. Paper
bags are glued shut and vacuum packed into plastic bags which are
then packed in boxes and stored on pallets before transport.
28 Priority Existing Chemical Assessment Report No. 28
7.3.2 Repackaging
Repackaging of both manufactured and imported formalin and products
containing formaldehyde occurs in Australia. The package sizes before and after
repackaging vary greatly and repackaging processes differ from company to
company. Again, several examples of the repackaging processes have been
selected from the industry submissions and the NICNAS survey and are presented
in Table 7.5. Most repackaging of formalin or product containing formaldehyde is
from 200 L drums to smaller containers, such as 5 L and 20 L containers. They
are decanted into smaller containers either through a pump (enclosed process) or
fed via gravity. Repackaging is usually not a continuous operation and the
duration and frequency of the operation vary from site to site.
Formalin is also repacked from large storage tanks. The material is pumped into
the storage tanks and transferred into various size containers using a pump and an
enclosed tubing system.
Manual and open repackaging processes were reported during repackaging
paraformaldehyde powder (see Table 7.5). It is assumed that enclosed processes
may also occur in Australia.
7.3.3 End use of formaldehyde products
Formaldehyde resins
The uses of formaldehyde resins are diverse in Australia. Reported industrial uses
include:
· manufacture of pressed wood products and their applications;
· paper treating and coating;
· textile treatments;
· foundry industry;
· fibreglass industry;
· composites construction;
· foam insulation;
· firelighter manufacture; and
· anti-graffiti wall sealer.
Manufacture of pressed wood products
Pressed wood products are sheet materials in which wood is predominant in the
form of strips, veneers, chips, strand or fibres. The categories usually recognised
within this group of panel materials are:
· particleboard, including wood particleboard (chipboard), flaxboard and
cement-boned particleboard;
· fibreboard, including medium density fibreboard (MDF);
29
Formaldehyde
· oriented strand board (OSB); and
· plywood, including blockboard and laminboard.
Particleboard and fibreboard manufacture and their applications
The majority of the formaldehyde resins are used as adhesives in the production
of particleboard and MDF in the timber industry. The types of formaldehyde
resins used in this industry include urea, phenol, melamine formaldehyde resins
and some combination of these resins, such as melamine urea and melamine urea
phenol formaldehyde resins. The concentrations of free formaldehyde in the
resins used in this industry range from < 0.2% to 0.5%. Information from the
Australian Wood Panel Association (AWPA) indicates that 932 000 m3 MDF and
965 000 m3 particleboard were manufactured using formaldehyde resins in year
2001-2002. However, no information is available for the total consumption of
each type of formaldehyde resins in this industry. AWPA represents all
particleboard and MDF manufacturers in Australia. Information from Australian
Customs indicates that approximately 233 000 m3 wood panel products were
imported in Australia in financial year 2001-2002.
Figure 7.5 is a flow diagram showing the typical process of particleboard and
MDF manufacture, which is a continuous process. The formaldehyde resins are
charged into storage tanks and injected and mixed with refined wood fibre
through an enclosed system. The particleboard and MDF are rolled and pressed in
a semi-enclosed area during the hot press stage (the temperature is 160°C to 200
°C) where resins set.
These wood panel products have both industrial and do-it-yourself (DIY)
applications for decorative, structural and industrial purposes, such as shelving.
Decorative applications include furniture, shelving, panelling/partitioning,
mouldings and doors. Examples of structural applications are domestic and
commercial flooring, access flooring, concrete formwork and exterior signs.
Manufacture of plywood and its applications
Formaldehyde resins containing < 0.2% to up to 5% free formaldehyde are used
in the manufacture of plywood and associated structural veneer based products,
such as laminated veneer lumber (LVL). The types of plywood products used in
Australia include structural plywood, concrete formwork plywood, marine
plywood, exterior and interior plywood, and overlaid and composite plywood.
Phenol formaldehyde resin, which is the predominate resin (approximately 88%)
used in this industry, is used for bonding structural, exterior and marine plywood
and structural LVL. Urea and melamine urea formaldehyde resins are usually
used for interior and some formply products. According to the information from
the Plywood Association of Australia (PAA), 189 533 m3 of plywood and LVL
were produced in the year 2001-2002 with total consumption of 3340 tonnes
phenol formaldehyde and 500 to 850 tonnes of urea formaldehyde resins. PAA
represents manufacturers who produce approximately 98% of plywood and LVL
in Australia. PAA advised that Australian-made plywood occupies 55% of the
Australian market. Information from Australian Customs indicates that
approximately 74 000 m3 plywood products were imported in Australia in
financial year 2001-2002.
30 Priority Existing Chemical Assessment Report No. 28
Figure 7.5: Simplified flow chart of typical particleboard and MDF
manufacture
MDF
Particleboard
LOGS/CHIPS LOGS/CHIPS
(RADIATA)
BAR
DIGESTER STEAM
PROCESSED TO (2-3 MINUTES) PRESS
FINE FLAKES
UF/MUF/
PF/MUPF REFINER
DRIER (FIBERIZES WOOD)
BLENDER Resin Wax
BLOWLINE
Catalyst
MAT
DRIER
FORMATION
HOT PRESS
HOT PRESS
(160-200ș C)
(160-200ș C)
COOL PANELS COOL PANELS
SANDING
SANDING
CUT TO SIZE
CUT TO SIZE
UF, urea formaldehyde resin; MUF, melamine urea formaldehyde resin; PF, phenol formaldehyde
resin; MUPF, melamine urea phenol formaldehyde resins
31
Formaldehyde
Plywood/LVL manufacturing processes are similar throughout Australia.
Formaldehyde resins are delivered in tankers and transferred into a holding tank
from where they are pumped into enclosed mixing vessels and mixed with
extenders (wheat flour), fillers (shell flour) and water. The mixed resin is then
pumped into glue spreaders and applied to the veneer using rubber rollers or
pressurised curtain coaters, which is an open process. The spread packs of veneer
are then cold pressed and finally hot pressed at about 140 °C, where the
formaldehyde resins are set.
Plywood and associated structural veneer based products are used in a number of
areas:
· Residential buildings including mobile homes, such as caravans and
manufactured homes. Residential building applications include LVL
framing, flooring, bracing, plywood webbed beams, roofing, cladding,
interior wall and ceiling linings, plywood in domestic wet areas;
· Building components for commercial and industrial structures including
relocatable buildings (classrooms, offices etc.). Structural LVL and
plywood components for commercial and industrial structures include
flooring, stressed skin panels, beams, arches, gussets, portal frames, and
bracing walls;
· Material handling, such as pallets, shelving, containers, bins and transport
equipment;
· Construction on site applications, such as structural ramps, overhead
protection barriers, runways etc.; and
· DIY in a wide range of projects, such as flooring, wall and ceiling lining,
boat building.
Paper treating and coating
Urea and melamine resins containing up to 1.5% free formaldehyde are used in
paper treating and coating. Paper treating is an automatic, continuous process
involving two resin stages. In the first resin stage, urea resin is pumped from
storage tanks to an automatic closed batching station where additives, water and a
catalyst are added to help with paper saturation and promote curing in later drying
and laminating processes. This mixture is pumped into the first stage bath where
the paper for impregnation is automatically fed by rollers through the bath at a
speed of approximately 40 meters per minute and is impregnated as it passes
through the bath. The bath is open at the top. The paper then passes into a closed
oven with temperatures ranging from 120°C to 170°C for drying.
In the second resin stage, melamine resin is pumped into an automatic closed
batching station and mixed with a release agent and a catalyst. This mixture is
then pumped into a second stage resin application station where the paper (after
the first resin stage) is fed through the rollers and is coated with the resin
mixtures automatically. The coated paper then goes into the second drier. Finally,
the paper is automatically cut to length and stacked in plastic wrapped packs for
shipment.
32 Priority Existing Chemical Assessment Report No. 28
Textile treatment
The formaldehyde resin products used in the textile industry include printing inks,
dyes and textile finishing products. The concentrations of free formaldehyde in
these products are generally < 2%.
Textile printers use formaldehyde resins as a cross-linking agent in acrylic binder
systems for pigment printing of polyester/cellulose or synthetic materials. The
formaldehyde resin is diluted with water and mixed with print paste for
approximately 10 minutes in a vat by either manual stirring or mechanical
mixing. Typically 1% to 3% of the resin product is used in the print paste
depending on the depth of shade of the print required. The print paste is then
transferred onto the fabric using a print screen (flat bed printer). The print is
generally cured at 150 °C for up to 3 minutes to cross link the acrylic resin
binder.
At large textile dyeing enterprises, formaldehyde resin is pumped from drums
into a large storage/dispensing vessel and then transferred to the dyeing
equipment where the product is diluted at a rate of 1-2 g/L. The temperature
inside the dyeing machine is about 100 °C. The product is rinsed off after dyeing
and the water goes to trade waste. The operation is a daily activity and manual
processes occur at some smaller sites.
Formaldehyde resins are used as cross-linking agents for cotton fabric and other
cellulosics to produce a finish that resists hydrolysis and is inert, durable and
unaffected by heat or bleach. Formaldehyde resin is poured into an open tank and
diluted with water to ratios of 1:10 to 1:20. Textile finishing processes include
padding, drying, and curing. The padding is normally done by immersing the
fabric in the resin aqueous solution, followed by squeezing it between two rollers,
and finally drying and curing. The durations of the padding vary depending on the
type of fabrics.
Foundry industry
Formaldehyde resins are used as a sand binder to coat sand which is then used in
core making for casting operations in the foundry industry.
At sand coating sites, the resin is pumped into a mixer at a rate of 1% to 1.2%
resin by weight of sand. At some sites, the resin is decanted from drums manually
into a measuring cup and then poured into a mixing vessel. Mixing normally
takes about 5 minutes and the coated sands are then decanted into bags ready for
core making at foundries. This is a batch operation and the frequency of the
operation varies from site to site.
At foundry sites, a variety of iron castings are produced for the automotive
industry. Foundry using sand as the moulding material consists of six basic
processes: pattern making, core making, moulding, metal melting and pouring,
and casting cleaning (fettling). Core making is the process of creating solid
shapes from sand using a variety of binding system. These solid shapes, called
`cores', determine the internal cavities of the casting. Hot, warm and cold box
core making techniques are used in the foundry. About 90% of the cores are
produced by hot and warm box technologies, using urea formaldehyde resin,
phenol, and furfuryl alcohol systems. The hot box resin system contains typically
5% to 6% free formaldehyde in the resin, whilst the warm box typically contains
33
Formaldehyde
2% to 3% free formaldehyde. Typically, the sand coated with formaldehyde
resins is blown into a hot mould (with temperatures around 110 °C) where
formaldehyde resin melts and functions as a bonding agent to make cores. At
larger enterprises, sand coating and core making occurs in an enclosed system.
Drums containing formaldehyde resins are connected to an automatic dosage
system, which supplies a set dosage of the resin into core making machines.
Fibreglass industry
Formaldehyde resins containing up to 13% free formaldehyde are used as fire
resistant laminates in the fibreglass industry, such as manufacture of fireproof
hubcaps used in the mining industry. Formaldehyde resin is diluted with up to
40% water before it is mixed with other ingredients by manual stirring. The
mixture is applied to a mould using mop rollers or bristle rollers. The mould is
then put in an oven at temperatures up to 60 °C for about 12 hours, where the
resin is cured.
Formaldehyde resins are also used as bonding resins to make glass fibre materials
for use in the building industry. The concentration of free formaldehyde in the
resins is about 1%. The resin and other ingredients are diluted with water and
mixed in an open tank. The mixture is sprayed onto the glass fibres, which then
pass through an oven (temperature 220°C to 300°C) where the resin is cured.
Composite construction industry
Formaldehyde resins containing about 3% free formaldehyde are used for the
manufacture of composite parts that are used in the automotive industry,
especially racing car parts. These parts are made of a few layers of either
fibreglass or carbon fibre clothes coated with formaldehyde resins. The resin is
mixed manually with a hardener in a ratio of 20:3. A worker applies the blend
onto each fibreglass or carbon fibre cloth sheet using a brush, before piling
several sheets together to make a mat. The mat is then moulded into the shape of
a car part. Depending on the application of the part, it is either left at room
temperature or gradually heated up to 250 °C in an oven for 1 to 2 days when the
resin is cured.
Foam insulation
Formaldehyde resins containing up to 5% free formaldehyde are used to make
foam insulation for industries, such as the floral industry. Formaldehyde resins
are pumped into a mixing bowl and blended with other ingredients for about 5
minutes in an open system. The blend is then tipped into a mould and baked
under 45 °C in an oven for about 90 minutes to make solid foams. The foam is
then cut and processed into various shapes and sizes to sell to wholesale
companies.
Firelighter manufacture
Formaldehyde resins containing up to 1% free formaldehyde are used in
firelighter manufacture. The resin is pumped from a refrigerated storage tank into
an enclosed mixing tank and mixed with other ingredients. The resin accounts for
approximately 11% of the total mixture. The mixed product is then automatically
deposited into trays, which are then wrapped and boxed approximately one
minute after initial deposit into tray. Firelighter manufacture is a daily operation.
34 Priority Existing Chemical Assessment Report No. 28
Anti-graffiti wall sealer
The product is a low gloss resin containing up to 1% free formaldehyde. The
product is stirred manually prior to use and during application. It is applied at a
rate of not less than 200 mL/m2 using airless spray equipment. For porous
surfaces, such as blockwork, an application rate of up to 400 mL/m2 may be
necessary to ensure total saturation.
Formaldehyde products other than resins
Forensic/hospital mortuaries, pathology laboratories and other
medicine-related uses
Formalin is used as a fixative in many medicine-related industries. The most
commonly used solutions are neutral buffered formalin solutions containing 4%
formaldehyde. The solutions are either purchased from suppliers already in
aliquot containers/specimen jars or made on site by diluting concentrated
formalin solutions containing 20% to 32% formaldehyde. The dilution process
varies depending on the quantities used. Where large quantities are used, such as
some forensic or hospital mortuaries and anatomy laboratories, the concentrated
formalin solution is manually poured into an enclosed mixing system, diluted
with water in ratios of 1:5 to 1:8 and mixed with other ingredients. These aqueous
solutions are stored in enclosed large tanks (up to 1000 L) and are automatically
decanted into smaller containers before end use. The aqueous solutions are
manually dispensed into specimen jars and used for fixing human tissues and
organs after autopsy. At workplaces where small quantities of formalin solutions
are used, such as pathology laboratories, concentrated formalin solutions are
diluted manually with water using measurement equipment and funnels.
The neutral buffered formalin solutions already aliquoted into specimen jars are
used in hospitals and doctors' rooms for preserving human tissues from biopsy.
The specimen jars are sealed and sent to pathology laboratories. In pathology
laboratories including histopathology laboratories, human tissues are taken out of
the specimen jars and accessioned (`cut-up') to certain sizes or shapes which are
then placed on a tray that goes through a processing machine (`processor').
Accession is undertaken manually on benches equipped with `down draught'
extraction systems. The processor has a number of containers holding different
chemical liquids including neutral buffered formalin solution, which needs to be
topped up regularly (up to once a day in large laboratories). During the topping
up, the container is taken out of the processor and the solution is poured in using
a funnel. After the processing, the specimens are waxed and cut to prepare slices
for microscopic observations.
In anatomical pathology laboratories, the corpse is transported to the cadaver
preparation laboratory and kept in cold storage until embalming. The embalming
procedure is conducted by laboratory technicians and formalin solutions
containing 10% to 13% formaldehyde are used. The procedure is similar with that
described for embalming in funeral homes below. The embalmed bodies are then
used by students and prosectors for examination and dissection involving cutting
and removing tissues to reveal anatomical features for further study or
examination. In addition to intact cadavers, separated limbs and organs, such as
the brain, lungs, and kidneys are stored in the dissection laboratory in different
sized containers filled with solutions containing 1.5% to 5% formaldehyde. These
35
Formaldehyde
containers are distributed around the dissection laboratory and specimens are
often used in classes for wet specimen observation. A stainless steel trap with a
waste shredder is used for disposal of old biopsy specimens and the
accompanying formalin solutions.
The 4% buffered formalin solution is also used for transporting explanted
orthopaedic prostheses, which have been removed from a patient by a surgeon.
The solution is stored in a `Histological Retrieval Kit' containing a number of
small plastic bottles of various sizes for different sized explants. One kit usually
has a total of approximately 0.75 L of the formalin solution. The kits are supplied
to hospital staff who sterilise the explant and transfer it to the selected container.
It is then sealed for transport to overseas for investigations.
Other medicine-related uses include sterilisation of dialysis machines in hospital
dialysis units. Formalin (40%) is added to the dialysis machines for
approximately 15 minutes. The solution becomes diluted as water is also flushed
through the machines. The solution is fed into a small open stainless steel drain
when it is pumped out of the machines.
Embalming at funeral homes
Formalin is used extensively as a preservative fluid during embalming in the
funeral industry. It is used as an arterial, internal cavities, and hypodermic
injection fluid and on surface packs. The concentrations of formaldehyde in the
products range from < 10% to 40%. Information from the Australian Funeral
Director Association (AFDA) indicates that approximately 30% to 40% of
deceased bodies are embalmed in Australia for various purposes, such as allowing
long distance transportation of bodies, particularly by airplanes, allowing more
time for the planning and arrangement of the funeral, and allowing the body to be
viewed under optimal conditions. The degree of body embalming varies.
A typical embalming procedure involves cleansing and disinfections of body
surfaces and orifices, arterial embalming, cavity embalming, and supplemental
embalming. Formalin products containing < 10% of formaldehyde are usually
used for cleansing and disinfections of body surfaces and orifices, destroying
maggots and vermin, and spray to preserve, disinfect and deodorise external body
surfaces.
Arterial embalming is a process whereby a disinfecting and preserving fluid is
injected into a large artery and then blood is flushed out of the circulatory system
by opening a vein. One or more points may be used for arterial injection
depending on the circumstances. One point injection is usually sufficient in the
case of natural death where no post-mortem is performed. Cavity embalming is a
process by which the contents of hollow organs in the abdomen and thorax are
aspirated by means of a trocar (a metal tube with a sharp point) inserted through
the abdominal wall and this is followed by the injection of cavity fluid. For
arterial/internal cavities injections, products containing greater than 10%
formaldehyde are diluted with warm water, in dilution ranges of 1:10 to 1:33.
For areas that have not received arterial fluid or received insufficient amounts of
preservative solution during arterial injection, supplemental embalming is
conducted. This process includes hypodermic and surface embalming.
Hypodermic embalming is the sanitation and preservation of a local area by
subcuticular injection of a suitable solution. The solution may be injected by a
36 Priority Existing Chemical Assessment Report No. 28
hypodermic needle, syringe, or an infant trocar attached by tubing to a pressurised
embalming machine. Surface embalming applies surface packs to external skin,
such as bedsores, ulcers, burned areas, gangrenous areas and decomposed tissue,
or to internal surfaces, such as within the thoracic or abdominal cavity of an
autopsied body. This form of formaldehyde products, such as gel and semi-
viscous, contains approximately 15% to 18% formaldehyde.
In the case of embalming a post-mortem body, the procedure is more complicated
due to disruption of normal anatomy and sometimes the resultant inaccessibility
of vessels. Excised viscera are often contained in a plastic bag placed in the body
cavity at the time of autopsy. This bag is removed and the viscera are washed in
water and placed in a covered bucket, either with formalin (37%) or treated with
paraformaldehyde powder (containing up to 99% formaldehyde) for at least 30
minutes. For arterial injections, a six-point injection, comprising 2 carotid arteries
(neck), 2 fermoral arteries (thigh) and 2 auxiliary arteries (shoulder), is usually
undertaken. The cranial, thoracic and abdominal cavities are aspirated and dried
and the internal walls may be coated with gel products. Next the bag containing
the treated viscera is sealed and replaced in the body cavity. Alternatively, the
organs are replaced loose and packed with granular paraformaldehyde.
Paraformaldehyde is also used to absorb moisture in incisions, lacerations and
wounds.
Considerable leakage can occur through severed blood vessels in the head and a
pool of arterial fluid can build up in the open abdominal cavity. Blood and excess
formalin solutions go to a draining system connected to the embalming table.
Infectious waste is placed in labelled plastic bags and disposed by incineration in
a facility approved by the State Environment Protection Authority (EPA). The
transport of the waste is required to comply with the relevant EPA regulations.
After embalming, the embalming room and equipment are cleaned. The
embalming table/trolley is washed and disinfected after each use. All tubing used
are washed by flowing water and then flushed with disinfectant. Floors are
cleaned using detergent and hot water. Equipment cleaning and sterilisation are
undertaken by autoclaving (a process which uses steam under increased pressure
to destroy all organisms), chemical disinfectants, or boiling.
The handling of formalin products in the funeral industry is usually carried out by
embalmers.
Photographic film processing
Products containing formaldehyde are used in the photographic industry as a
preservative/stabiliser/replenisher in final baths to prevent deterioration of image
quality on colour negative and colour reversal films. They are also used as a
hardener in final baths to prevent damage to the gelatine emulsion coating of
black and white films during machine processing.
Formaldehyde products containing high concentrations of formaldehyde (20% to
35%) are used in final baths of some specialised film processing, such as aerial
film processing. The products are in 9L or 19 L plastic drums and carried from
the storage area to the film processing area. Workers open the cap and insert a
tube into the drum. The product is pumped into the bottom of an enclosed wash
tank (final bath) in an enclosed machine. Water is injected at the same time to
dilute the solution. The formaldehyde concentration in the working solution is
37
Formaldehyde
< 1%. The aerial film goes through the final bath before passing a dryer (at 140
°C) and being developed. The wash goes to drain after use. The empty drums are
sent to landfill or rinsed with water for re-use.
Most commercial film processing sites use enclosed machines (processors) that
have a final bath tank specifically for formaldehyde aqueous solutions. The
concentrations of formaldehyde in the solutions range from 0.1% to 15%. The
solution is poured into the tank and diluted with water in the required ratios
ranging from 1:100 to 1:1000. Typically, the processors are operated for an
average of 4 or 5 hours a day, 5 days a week. The final bath is replenished about 1
to 2 times a week. The waste generated during film processing either goes to
drain or is collected in a container for disposal.
Manual film processing also occurs at some workplaces (for example, quality
control trials at aerial film companies) or at homes where people do their own
film processing. Solution containing 10% formaldehyde is diluted at a ratio of
1:40 and poured into a deep tray where negative or film paper is merged to
develop photos in a dark room.
Leather and fur tanning
Formalin containing 37% formaldehyde is used as a cross-link agent in fur
tanning processes. Workers dilute the formalin solution at a ratio of 1:10. The
working solution is then added manually to an enclosed processing drum. This
operation takes about 5 minutes. Furs are added into the drum and mechanically
rotated for 18 to 24 hours. The solution is drained before furs are removed
manually to an open tub. The tanned furs then go through drying, staking and
other numerous processes. The NICNAS survey data indicates that formalin is
used occasionally in fur tanning, for example, one leather processing company
uses it 6 times a year.
Products containing 10% to 15% formaldehyde are used daily in general leather
tanning. The processes are similar with the fur tanning, except the addition of the
product from intermediate bulk container to the processing drum is via an
enclosed system.
Information from the Department of Textile and Fibre Technology (Leather
Research Centre) of Commonwealth Scientific and Industrial Research
Organisation (CSIRO) (CSIRO, 2004) indicates that a limited number of leather
tanning companies use formalin.
Sanitising treatment
Formalin containing 37% to 40% formaldehyde is used as an additive to sanitise
water treatment plants. The formalin is manually measured and poured into a
water holding tank to make a 1% formaldehyde solution. The diluted solution is
then pumped through the water pipe system for cleaning. This operation is
undertaken occasionally, for example, one company conducts the treatment about
twice a year.
Products containing up to 10% formaldehyde are also used to sanitise bins and
digest portable toilet contents. For the bin disinfectants, product is usually diluted
at ratios of 1:6 to 1:10 and added manually to sanitary bins. Toilet sanitizers are
poured into portable toilets at a rate of 20 to 50 mL product per 5 L of holding
38 Priority Existing Chemical Assessment Report No. 28
tank capacity per week. For recirculating toilets, 200 mL product is needed for
initial charge. The waste goes to sewage systems.
Lubricant products
Some industrial lubricants contain > 0.2% formaldehyde as a preservative. For
example, conveyor lubricant (0.3% formaldehyde) is used to provide lubrication
and equipment protection for conveyor belts made of steel and plastic. Before
use, the product is manually poured into a big container diluted with water to
0.1%. The diluted product is continuously dispersed onto the conveyor belt
through an enclosed automatic system.
Laboratory reagents
Analytical grade formalin and paraformaldehyde powder/prill are commonly used
in research laboratories as reagents. The concentrations of formaldehyde in
formalin products range from 0.2% to 40%. The paraformaldehyde powder/prill
contains 95% to 97% formaldehyde. Most of the analytical grade products are
supplied to laboratories as imported/formulated. Some importers repackage the
products before selling to either distributors or end users including commercial
enterprises, such as contract and company in-house analytical laboratories,
universities and government laboratories. Quantities imported are relatively
small. The average importation quantity for the calendar years 2000 to 2002 was
1100 L formalin products and 150 kg paraformaldehyde prills per year.
Information on the quantities of analytical grade formalin formulated in Australia
is not available.
Fumigation
Paraformaldehyde, in granular form, is used for fumigation of sterile areas, such
as pharmaceutical plants. Workers transfer the paraformaldehyde granules into
gas generators, which contain silicone oil. The paraformaldehyde granules are
placed on the top of silicone oil. The oil is heated and the formaldehyde gas
generated is released into the air at a dispensing rate of 10 g/m3. The activation of
the fumigation generators is remote controlled and the gas generation continues
for 3 hours. No access is allowed to the area for 30 hours after the fumigation and
the air conditioning is initiated 8 hours after the fumigation and remains on for at
least 28 hours. Air monitoring is conducted and must be less than 0.2 ppm before
access is allowed. The residue in the generators is tipped into a waste drum and
sent to an approved waste destruction company. The operation is run 1 to 2 times
a year.
Products containing < 0.2% free formaldehyde
Industry uses numerous end products containing < 0.2% free formaldehyde (see
Table 7.6).
Cosmetics and consumer products containing formaldehyde
Formaldehyde functions as a drying agent, surfactant or preservative in cosmetics
and consumer products, such as homecare products and household cleaning
products. Table 7.7 lists reported products containing formaldehyde.
39
Formaldehyde
Table 7.6: Products other than cosmetics or consumer products containing
< 0.2% formaldehyde
Product Use
·
Adhesive products Formaldehyde functions as a biocide in water based
adhesives and sealants which are used in insulation and
construction industry, hardware and DIY soft floor
adhesives
· Use of starch adhesives to manufacture corrugated boards
that are used in packaging industry to increase water
resistance properties
· Laminating paper
· Bonding of paper when manufacturing industrial paper bags
· Trim adhesives for automobile industry
·
Surface coating Coating cookware, bake ware, scissors, photocopy rollers
products and other surfaces where non-stick, low friction qualities are
required
· Thermosetting coating in coil and automotive steel coating
industry
· Coating cans
· As preservatives (biocide) in paints/printing inks
·
Concrete Enhance properties, such as flow, setting times and strengths
admixtures of the plastic and/or hardened concrete
·
Cementitious Cement containing compounds are used as concrete repair
compounds and levelling or as grouts
·
Cross linker Rubber, emulsion polymers, paper filter, paint, adhesive,
products textiles
·
Metal treatment Metal plating, such as Nickel plating
products · As a biocide in metal working fluids
·
Fire barrier & caulk Caulk for fire-rated walls
·
Carpet protector Mill applied carpet protection
·
Rubbing compound Removal of colour sanding scratches leaving minimal swirl
marks while polishing
·
Floor finish Used to seal and polish floors in large areas, such as
products supermarket and nursing homes
·
Industrial cleaning Industrial laundry and housekeeping products, floor cleaner,
products/ carpet cleaner, truck wash liquid, dishwasher detergents
disinfectants/
sterilisers
40 Priority Existing Chemical Assessment Report No. 28
Table 7.7: Reported cosmetics and consumer products containing
formaldehyde
Cosmetics and personal care Shampoos and conditioners
products Shower gels
Liquid hand soaps
Cream cleansers
Skin moisturiser
Toothpastes
Nail hardeners
Household cleaning products Sink detergent
Toilet cleaner
Stainless steel cleaner
Glass cleaner
Leather cleaner
Laundry liquid cleaners/sprays
Surface liquid cleaners
Floor cleaner
Rinse aid
Carpet cleaners
Dishwashing liquids
Homecare products Fabric conditioners/softeners
Fabric wash
Wool wash
Concentrations of formaldehyde in cosmetics and consumer products are
generally less than 0.2%. Reported products containing > 0.2% formaldehyde
include concentrated fabric softener (0.3%), concentrated detergent (0.3%),
concentrated dishwashing liquids (0.6%), and nail hardeners (up to 1%).
Formaldehyde donor products
Products designed to slowly release formaldehyde during use are used in
Australia. 1,3-dihydroxymethyl-5, 5-dimethyl hydantoin (usually called DMDM
Hydantoin) is the most commonly used chemical to release formaldehyde in this
type of product. According to the industry submissions, approximately 16 000 kg
DMDM Hydantoin was imported in the year 2000. Small amounts of other
formaldehyde releasing chemicals/products, such as imidazolidinyl urea and tris-
(hydroxy methyl) nitromethane, are also imported.
Formaldehyde releasing chemicals and/or products containing formaldehyde-
releasing chemicals are used as preservatives for the control of bacteria and fungi
in water-based solutions and for the long-term preservation of starch solutions
including both industrial products and a wide range of consumer products, mainly
cosmetics and toiletry products. Use of formaldehyde-releasing-chemicals as
hardeners in the manufacture of phenolic based refractory binders and as a
biocide in industrial emulsions, such as for aluminium rolling, are also reported.
The free formaldehyde content in DMDM Hydantoin is usually up to 2%.
DMDM Hydantoin is typically used at a concentration of 0.2% in personal care
products. Therefore, the concentrations of free formaldehyde in the end products
are much less than 0.2%. However, information from suppliers indicates that the
content of DMDM Hydantoin in final products can be up to 40% in some
industrial products.
41
Formaldehyde
Once in contact with water in a mixer, DMDM hydantoin releases a molecule of
formaldehyde. Rate of release can be controlled by pH adjustment or temperature.
This results in an equilibrium state in the product where 0.2% Hydantoin
molecules co-exist with free formaldehyde molecules at a very low concentration.
If the product encounters any bacterial activity, these free molecules of
formaldehyde are consumed against the bacterial cells. This will again result in
the replenishment of formaldehyde molecules in the product from the donor
molecule till equilibrium is reached. Over a period of time all formaldehyde from
the donor molecule is used up in preserving the product against microbes.
7.4 Export
Formaldehyde manufactured in Australia is generally not exported. One of the
formaldehyde and resin manufacturers reported an export of approximately 75
tonnes formaldehyde resins per year to New Zealand.
42 Priority Existing Chemical Assessment Report No. 28
8. Environmental Release, Fate and
Effects
Formaldehyde occurs naturally in the atmosphere and biosphere, where it is
released through a variety of biological and chemical processes. The most
important process responsible for natural background concentrations of
formaldehyde in the environment is the photochemical oxidation of atmospheric
methane. Other processes responsible for release of formaldehyde to nature are
reactions of hydroxide radicals (OH) with terpenes and isoprene emitted from the
foliage of plants, direct emission of formaldehyde during decomposition of
organic matter (Martin et al. 1999), photochemical production of formaldehyde in
snowpack, and direct emissions from algae living in the snow (Sumner and
Shepson, 1999). Formaldehyde occurs naturally in plants and animals (IARC
1995).
A wide range of human domestic and industrial activities is responsible for both
direct and indirect releases of formaldehyde into the atmosphere from diffuse and
point sources. Emission from fuel combustion is perhaps the single most
important anthropogenic source of atmospheric formaldehyde, with formaldehyde
being released directly or subsequently formed by oxidation of higher alkanes,
hydrocarbons, or other precursors, released from combustion processes (Lowe et
al. 1980). Release of formaldehyde into the atmosphere or aquatic environment
may also occur during its manufacture, or when used as an intermediate in
manufacturing, and during use of products containing formaldehyde.
8.1 Release
8.1.1 Emissions to the atmosphere
Recent data from the Australian National Pollution Inventory (NPI) database for
emissions of formaldehyde indicate that almost all formaldehyde is released to
the atmosphere, with total emissions estimated to be 7150 tonnes for the year
2002-2003 compared with 6600 tonnes for the year 2001-2002.
Figure 8.1 is a summary of the atmospheric emissions estimates by source
category. For the estimation methods, refer to the relevant NPI Emissions
Estimation Technique Manuals, which are available on the NPI website (NPI,
2005a). The estimates include aggregated emissions estimates reported by state
government departments and data reported by industry from individual industrial
facilities (labelled `industry emissions'). Aggregated emissions are derived from
domestic, mobile and non-industrial facilities, and from smaller industrial
facilities not meeting the thresholds criteria for industry reporting, while industry
emissions are derived from a large number of industrial activities emitting above-
threshold levels of formaldehyde. The threshold criteria is use of 10 tonnes of
formaldehyde per year, where "use" is defined as the handling, manufacture,
import, processing, coincidental production, or other uses.
43
Formaldehyde
Figure 8-1: Annual formaldehyde atmospheric emissions for (a) 2001-2002
and (b) 2002-2003 (NPI).
(a) Formaldehyde Emissions 2001-2002
35 0 0
30 0 0
25 0 0
20 0 0
Emission (tonnes)
15 0 0
10 0 0
500
0
Domestic Fuel Transport Industry Misc Misc activities
Emmisions combustion
(b))FormaldehydeEmmissions2002-2003 (1000 Kg)
(b Formaldehyde Emissions 2002-2003
3500
3000
Emission (tonnes)
2500
2000
1500
1000
500
0
Do m est ic Fuel T r an sp o r t I n dust r y Misc Misc activities
Em m isio n s co m bust io n
The NPI data indicate that most of the atmospheric emissions of formaldehyde
occur through combustion processes from diffuse sources. The primary
combustion activities are burning of domestic fuel and transportation. The
domestic fuel category includes burning solid and liquid fuels and gas for
domestic heating and cooking, and lawn mowing. The transportation category
includes emissions from motor vehicles, rail transport, recreational boating,
commercial shipping, and air transport.
44 Priority Existing Chemical Assessment Report No. 28
Formaldehyde emissions from industrial facilities are predominantly point source
emissions including both direct emissions of vapour and emissions from fuel
combustion. According to the NPI estimates, point source emissions from
industrial activities contributed about 16% of the total formaldehyde emissions
for 2001-2002 (1085 of 6600 tonnes) and around 14% for 2002-2003 (1022 of
7150 tonnes).
Miscellaneous combustion and miscellaneous activities also contribute diffuse
and point source emissions of formaldehyde. The miscellaneous combustion
category includes burning of vegetation for fuel reduction, regeneration,
agricultural management, and wildfires, in addition to fuel combustion from sub-
reporting threshold industrial and commercial facilities, and cigarette smoking.
Miscellaneous activities include direct vapour emissions and fuel combustion
from use of domestic and commercial aerosols, operation of agricultural
machinery, and contributions from the operation of schools, laundries, bakeries,
pubs and other small business enterprises.
8.1.2 Emissions to water and soil
Emissions of formaldehyde to water and soil may be expected to occur via
sewage treatment facilities during manufacture of formaldehyde and
formaldehyde products and during use of products containing formaldehyde,
including consumer products.
However, formaldehyde emissions to water and soil are significantly less than
emissions to the air. Emissions data from the NPI indicate only about 1000 kg of
formaldehyde was released into water and/or onto land from point sources in the
reporting year 2001-2002 and only 5 kg in 2002-2003. No distinction was made
between amounts released to soil and that to water.
Formaldehyde is present in low concentrations (the majority < 0.2%) in a wide
variety of consumer products. These products include household cleaning
products, such as dishwashing liquids, disinfectants, fabric conditioners, and
cosmetics products, such as shampoos, conditioners, and shower gels etc.
(Section 7.3.3). Many of these products are released directly into wastewater
streams during their use, and hence are a diffuse source of formaldehyde, which
may contribute to formaldehyde levels in water.
Formaldehyde emissions to soils are most likely to occur through disposal of
solid wastes containing formaldehyde. A number of companies indicated that
they disposed of small amounts of solid waste containing formaldehyde (mainly
solidified resin waste and sludge from on-site treatment facilities) into landfill.
8.2 Fate
This section summarizes the environmental fate of formaldehyde, emphasizing
the atmospheric fate, as more than 99% of formaldehyde is released to air, with
only small amounts being released to water and soil. The information is derived
from the published literature and a number of peer-reviewed reports on
formaldehyde. The latter include US EPA (1993), IPCS (1989), IPCS (2002), and
the Canadian Priority Substance List report (Environment Canada, 2001). Data
cited from existing reports are referenced as such and not necessarily by the
original authors of the particular studies.
45
Formaldehyde
8.2.1 Atmosphere
In the atmosphere, formaldehyde has a high degree of chemical reactivity and is
capable of undergoing a wide variety of chemical reactions (Section 5). However,
the major mechanism of destruction of formaldehyde is by photolysis. Less
important removal mechanisms are reactions with photochemically produced OH
radicals and other trace substances, including nitrate (NO3) and hydroperoxyl
(HO2) radicals, hydrogen peroxide (H2O2), ozone (O3), and chlorine (Cl2), and all
classes of hydrocarbon pollutants (Atkinson, 1990).
The oxidation of formaldehyde with OH radicals proceeds primarily by H-atom
abstraction, forming formyl (HCO) radicals, which then rapidly react with O2 to
form carbon dioxide (CO2) and hydroperoxyl (HO2) radicals. Other products
formed during these reactions include water, formic acid, carbon monoxide (CO),
and hydroperoxyl/formaldehyde (HCO3) adduct (US EPA, 1993).
During direct photolysis, formaldehyde absorbs UV radiation from below 290 nm
to about 340 nm. The dominant photolytic pathway produces stable molecular
hydrogen (H2) and carbon monoxide (Atkinson et al., 1990; Lowe et al., 1980). A
second photolytic pathway produces an HCO radical and a hydrogen atom, both
of which react quickly with oxygen to form hydroperoxyl radicals and carbon
monoxide (US EPA, 1993).
Formaldehyde is an important precursor in smog formation in the urban
atmosphere, where it reacts with nitrogen oxides and other compounds to
eventually form ozone, peroxyacetyl nitrate and other compounds.
The daytime half-life of formaldehyde in ambient air is generally short. The
calculated half-life of formaldehyde with respect to photolysis is about 4 hours,
and to reactions with OH radicals is 1.2 days. Reactions with NO3 radicals and O3
are slower, with the half-life times for NO3 reactions of 80 days, and for ozone
reactions of > 4.5 years (Atkinson, 2000; US EPA, 1993).
The atmospheric residence time of formaldehyde varies with the availability of
hydroxyl and nitrate radicals to react with formaldehyde, which is principally
controlled by the season, time of day, intensity of sunlight, temperature and cloud
cover. Table 8.1 provides the calculated atmospheric residence times (in hours) of
formaldehyde, taking into account gas-phase reactions with OH, NO3, and H2O,
photolysis, in-cloud reactions with OH, and wet and dry deposition (US EPA,
1993).
During the day, reaction with hydroxyl radicals is an important removal process
of formaldehyde when their concentration is high. At night, reaction with nitrate
radicals is an important (although slower) removal process, particularly in
polluted urban areas where the concentration of nitrate radicals is high (Atkinson,
2000; IPCS, 2002). In the absence of nitrogen dioxide, the half-life of
formaldehyde is approximately 50 min during the daytime. In the presence of
nitrogen dioxide, this drops to about 35 min (IPCS, 1989). In winter on clear
days, residence times of formaldehyde will be longer than in summer because the
intensity of sunlight is lower.
Because of its high water solubility, formaldehyde is efficiently transferred into
clouds and rain, where it can react with aqueous hydroxyl radicals in the presence
of oxygen to produce formic acid and hydroperoxide. The formic acid may then
46 Priority Existing Chemical Assessment Report No. 28
be removed in rainfall. Small amounts of formaldehyde may also be removed by
dry deposition. The atmospheric residence time of formaldehyde under rainy
conditions ranges from minutes in cold climates to a few hours in warm climates
(Atkinson, 2000; US EPA, 1993). Table 8.1 shows that wet deposition results in
significantly more rapid removal rates of formaldehyde during winter on rainy
days.
Table 8.1: Seasonal and diurnal variations in the atmospheric residence
times of formaldehyde (US EPA, 1993)
Atmospheric residence times (hours)
Weather Time of Day
conditions
New York Atlanta
Summer Winter Summer Winter
Day 3 17 2 10
Clear sky
Night 20-110 90 20-70 80
Average 5 40 4 20
Day 6 30 3 19
Cloudy sky
Night 18-50 80 6-8 70
Average 9 50 4 30
Day 3 0.8 2 1.6
Rainy
Night 3 0.5 3 0.7
Average 3 0.6 2 0.9
8.2.2 Water
Formaldehyde is highly water soluble, with a solubility of up to 550 g/L at 25°C.
Concentrations as high as 95% formaldehyde in water are obtainable if suitable
temperatures are maintained and methanol and other substances are added as
stabilizers (IPCS, 1989). The concentrations of formaldehyde in formalin
solutions manufactured in Australia range from 37% to 54%. In dilute aqueous
solutions, formaldehyde exists almost exclusively in the hydrated gem-diol form
[CH2O + H2O CH2(OH)2], while at higher concentrations formaldehyde forms
other species, such as methylene glycol, polyoxymethylene and hemiformals
(Environment Canada, 1985; Dong & Dasgupta, 1986).
Most aqueous formaldehyde released into water is expected to remain dissolved
in the aquatic compartment where it would enter sewage treatment facilities.
While the vapour pressure of formaldehyde indicates a high volatility (516 kPa at
25°C), the Henry's Law Constant (0.022-0.034 Pa.m3/mol) indicates only a
moderate volatility from water (Mensink et al., 1995).
Limited degradation data are available. It is expected that formaldehyde will be
degraded relatively rapidly in sewage treatment plants and in surface water.
Formaldehyde does not contain any hydrolysable groups, and hence hydrolysis
will not be a degradation pathway. However, at low concentrations, formaldehyde
is readily biodegradable, with 90% degradation reported in a closed bottle test (at
2-5 mg/L) after 28 days (Gerike & Gode, 1990). Howard et al. (1991) estimate
57% to 99% removal from sewage treatment plants with secondary treatment.
The aqueous anaerobic half-life times are predicted to be from 1 to 7 days in
unacclimated sludge. The estimated half-life times in surface water are 24-168
hours, and in groundwater are 48 to 336 hours (Howard et al., 1991).
47
Formaldehyde
8.2.3 Soil and sediment
Limited data are available about the fate of formaldehyde in soil and sediment.
Formaldehyde is formed in the early stages of decomposition of plant residues in
soils and is degraded by soil bacteria such that accumulation in soil does not
occur (IPCS, 1989). The high water solubility and low partition coefficient
(maximum Log Kow of 0.35) indicates a low potential for adsorption onto
suspended sediments in the soil solution or in aqueous environments. Aqueous
solutions of formaldehyde released into soil through spills or disposal would be
expected to infiltrate into the soil, from where it may leach into surface and
ground water. However, since formaldehyde is susceptible to biodegradation by a
range of micro-organisms, it is expected to be readily degraded, and not
accumulate. Howard et al. (1991) estimates a soil half-life of 24 to 168 hours,
based on the estimated aqueous aerobic biodegradation half-lives.
8.2.4 Biota
Formaldehyde occurs naturally in plants and animals, and is readily metabolised
by organisms. The measured Log Kow indicates a low potential for
bioaccumulation. This is confirmed by negative results of bioaccumulation
studies with shrimp and fish showing no bioaccumulation of formaldehyde
(OECD, 2002). A bioconcentration factor of 0.19 has been calculated based on a
log octanol/water partition coefficient of 0.65 (IPCS, 2002).
8.3 Effects on organisms in the environment
The ecotoxicity data presented here are summarized from existing reports on
formaldehyde, on-line computer databases, and the published literature. Due to
the large volume of data, for example, 655 records in the US EPA ECOTOX (US
EPA, 2002) database, predominantly for aquatic organisms, not all studies have
been evaluated.
A recent paper by Hohreiter and Rigg (2001) highlights the poor reliability and
quality of much of existing data on the aquatic toxicity of formaldehyde (the
same can be said for the terrestrial toxicity data). The main criticisms were a lack
of analytical confirmation of the concentrations of formaldehyde (most endpoints
being reported as nominal concentrations), and the lack of GLP compliance
(many of the studies were conducted prior to the introduction of GLP). A further
criticism was the lack of available chronic toxicity data. Where possible, any
anomalous or unreliable data are indicated.
8.3.1 Aquatic organisms
Fish
The US EPA ECOTOX database (US EPA, 2002) lists acute toxicity endpoints of
formaldehyde for a large number of fish species. Many of these endpoints appear
to be derived from non-standard tests. The 96-hour test data show that
formaldehyde is practically non-toxic to fish, with most species listed having
lethal concentration (LC50) values above 100 mg/L. The lowest recorded 96-hour
LC50 in the database is 1.51 mg/L for Bluegill sunfish (Lepomis macrochirus).
However, the original source of the latter endpoint is uncertain. The reference
48 Priority Existing Chemical Assessment Report No. 28
indicates the data is from the Environmental Effects Database, Office of Pesticide
Programs of US EPA.
The Hohreiter and Rigg review (2001) suggests that acute toxicity endpoints do
not vary greatly between fish species. In their review of the most reliable existing
data, striped bass (Morone saxatilis) is indicated to be the most sensitive fish
species, with adjusted mean (to formaldehyde concentration) 96-h LC50 values of
16.9 mg/L (range 7.26 mg/L to 24.44 mg/L, of 13 endpoints). The most resistant
fish species to formaldehyde are rainbow trout, with LC50 values of 58.7 mg/L,
and Atlantic salmon with LC50 values of 69.8 mg/L.
Fajer-Ávilla et al. (2004) have recently reported a study of the effects of formalin
on bullseye puffer fish (Sphoeroides annulatus Jenyns, 1843). The replicated
static study determined a 72-hour LC50 of 79 mg/L based on measured
concentrations. The study also reported sublethal effects, including immobility
and slow reaction to external stimulation, in the concentration range 24 mg/L to
103 mg/L. At concentrations above 75 mg/L, the test fish showed glassy
exophthalmic eyes with an opaque film after 13 hours and haemorrhages in fins
and eyes by 20 hours. Effects on the epithelial structure and mucous cell densities
in rainbow trout (Onchorhyncus mykiss) have also been reported at concentrations
between 50 ppm and 300 ppm (Buchmann et al., 2004).
Recent replicated static renewal studies with 7-day-old fathead minnow
(Pimephales promelas) and conducted according to GLP indicated 96-hour LC50
and median effective concentration (EC50) (lethality and behavioural effects)
values of 27.2 mg/L (Hohreiter & Rigg, 2001).
Amphibians
The responses of various species of amphibians are similar to those of fish, with
median acute LC50 ranging from 10 mg/L to 20 mg/L for a 72-hour exposure.
For example, leopard frog tadpoles (Rania pipiens) had a 72-hour LC50 value of
8.7 mg/L, and toad larvae had a 72-hour LC50 value of 18.6 mg/L. The available
data indicate that tadpoles are more sensitive to formaldehyde than most species
of fish and aquatic invertebrates. No data are available on long-term aquatic
studies (IPCS, 1991; Hohreiter and Rigg, 2001).
Aquatic invertebrates
Unlike fish, aquatic invertebrates show a wide range of responses to
formaldehyde. Available acute toxicity endpoints [adjusted by Hohreiter and Rigg
(2001) to reflect formaldehyde content] indicate a range of 96-hour LC50 values
between 0.42 mg/L for the seed shrimp (Cypridopsis sp.) and 337 mg/L for
backswimmers (Notonecta sp.). Data in the US EPA ECOTOX database (US
EPA, 2002) show EC50 values for mussels (Mytilus edulis) ranging between 5
mg/L and 60 mg/L. Hohreiter and Rigg (2001) list adjusted endpoints for
molluscs (Corbicula and Helisoma sp) of between 35 mg/L and 50 mg/L.
The above data indicate that the seed shrimp is the most sensitive organism.
However, Hohreiter and Rigg (2001) believe this endpoint (attributed to Bills et
al. 1977) is anomalous. More recent replicated tests, performed under standard
conditions with analytical confirmation of nominal formaldehyde concentrations,
indicate much higher 96-hour EC50 values of 54.4 mg/L to 68.6 mg/L for
Cypridopsis. The NOEC is 18.8 mg/L (measured) for both survival and
49
Formaldehyde
reproduction, and the LOEC is 50 mg/L. The most sensitive species attained from
the most reliable endpoint for invertebrates reviewed in Hohreiter and Rigg
(2001) is 5.8 mg/L for Daphnia pulex (96-hour EC50).
Available data indicate formaldehyde is slightly to moderately toxic to Daphnia.
In the US EPA ECOTOX database (US EPA, 2002), the 48-hour EC50 values
reported for the water flea (Daphnia magna) ranged between 14 mg/L and 58
mg/L. Recent replicated tests reported by Hohreiter and Rigg (2001) showed
comparable values, with 48-hour static acute LC50 values of 9.45 mg/L for
Ceriodaphnia dubia and 14.75 mg/L for Daphnia pulex.
Chronic toxicity of formaldehyde to Ceriodaphnia dubia in two 7-day tests for
immobility and mortality gave NOEC and LOEC values of 3.0 mg/L and 6.0
mg/L, and 1.0 mg/L and 3.0 mg/L, respectively. The geometric mean of each test
provide two chronic values of 4.24 mg/L and 1.73 mg/L, respectively (Hohreiter
and Rigg, 2001).
Algae and aquatic plants
Only a limited number of studies have been carried out to evaluate the toxicity of
formaldehyde to aquatic plants. In general, these data suggest that formaldehyde
is slightly to moderately toxic to aquatic plants. However, much of the data is
difficult to evaluate owing to the non-standard test methods used. The SIAR
(OECD, 2002) indicates the toxic threshold (192 hours) of formaldehyde to
Scenedesmus quadricauda in a static cell multiplication inhibition test using an
aqueous solution of formaldehyde (35% solution) is 0.88 mg/L. The toxic
threshold is defined in the cited investigation as the concentration of the test
substance causing 3% inhibition of cell multiplication compared to untreated
controls. The IPCS Report (1991) lists a 24-hour LC50 value of 0.4 mg/L for
Scenedesmus sp. The US EPA ECOTOX database (US EPA, 2002) lists the
following LOEC and NOEC values for algae: Blue-green algae (Microcystis
aeruginosa) = 0.39 mg/L, Brown algae (Phyllospora comosa) = 0.1 mg/L to 10
mg/L; and Green algae (Scenedesmus quadricauda) = 0.3 mg/L to 2.5 mg/L.
Most of these data are for 4 to 8 day tests, and are therefore not standard
endpoints.
Hohreiter and Rigg (2001) did not estimate a final value for aquatic plants
because most of the data they reviewed did not meet US EPA requirements.
However, they believe that criteria protecting aquatic animals should also
adequately protect aquatic plants.
8.3.2 Terrestrial organisms
Relatively few data are available on the toxicity of formaldehyde to terrestrial
organisms. The US EPA ECOTOX database (US EPA, 2002) lists only 11
records for terrestrial organisms including plants, and with only two studies on
birds. For the majority of these records, no endpoints are reported.
The studies on birds indicate that formaldehyde is practically non-toxic to
Mallard duck (Anas platyrhynchos) and Northern bobwhite quail (Colinus
virginianus), with the Mallard having an 8-day LC50 > 5000 ppm, and the
Northern bobwhite having an 8 day LC50 > 5000 ppm and a 14 day LD50 of 790
mg/kg.
50 Priority Existing Chemical Assessment Report No. 28
Several studies cited in the CICAD (IPCS, 2002) indicate potentially adverse
effects on terrestrial plants after exposure to formaldehyde in air and fog. Bean
plants (Phaseolus vulgaris) exposed to formaldehyde in air at concentrations
between 65 ppb to 365 ppb for up to 4 weeks exhibited no short-term effects, but
showed an imbalance in shoot and root growth, which could increase the
vulnerability of plants to environmental stresses, such as drought.
Plants exposed to formaldehyde in fog water for 40 days (4.5 hour/night, 3
nights/week) at concentrations equivalent to 18 ”g/m3 and 54 ”g/m3 (14.9 ppb
and 44.8 ppb) showed a range of potentially adverse effects. Rapeseed (Brassica
rapa) exhibited a reduction in leaf area, leaf and stem dry weight, and flower and
seedpod numbers, while slash pine (Pinus elliotti) exhibited an increase in needle
and stem growth. Wheat (Triticum aestivum) and aspen (Populus tremuloides)
exposed to formaldehyde in fog during the study exhibited no effects.
Pollen germination has been shown to be sensitive to some air pollutants. Pollen
grains of Lilium longiflorum, sown in a straight line on a culture medium, were
exposed separately for one, two, and five hours to formaldehyde gas at
concentrations of 0.44 mg/mł (0.35 ppm) and 2.88 mg/mł (2.3 ppm). Grains
exposed to the lower concentration for five hours showed a significant reduction
in pollen-tube length, whereas a one- or two-hour exposure time had no effect.
Pollen grains exposed to formaldehyde concentrations of 2.88 mg/mł showed a
decrease in tube length after one hour of exposure (IPCS, 1989).
8.3.3 Micro-organisms
Formaldehyde is toxic to a range of micro-organisms and is known to kill viruses,
bacteria, fungi, and parasites when used at relatively high concentrations.
Consequently, it has long been employed as a disinfectant and parasiticide in
many industries. For example, in Australia, formaldehyde is commonly used for
the control of fungal infections, protozoan and metazoan ectoparasites in
aquaculture systems, and as a general disinfectant in animal husbandry situations.
Unicellular micro-organisms, such as algae and protozoa appear to be most
sensitive to formaldehyde, with acute lethal concentrations ranging from 0.3
mg/L to 22 mg/L. Various species of microscopic fungi including Aspergillus,
Scopulariopsis and Penicillium crustosum are also sensitive to formaldehyde gas,
with 100% of spores exposed to 2 ppm of gaseous formaldehyde reported to be
killed within 24 hours (IPCS, 1989).
A few studies summarized in the IPCS (1989) report indicate formaldehyde can
negatively impact soil microbial biomass and activity. One study reports that
formaldehyde was able to inhibit the enzyme which catalyses deamination of the
amino acid L-histidine, an important nitrogen source for plants and microbes.
Another study reported a significant reduction in bacterial populations in soils
near industrial sites polluted with formaldehyde and in soils on sites using urea-
formaldehyde fertilizers. Several studies also cited in the IPCS report (IPCS,
1989) indicated some strains of bacteria (e.g. Psuedomonas) are able to utilize
formaldehyde as a carbon source.
Sewage micro-organisms were inhibited at 30 mg/L in a Closed Bottle test
suggesting that sewage treatment plant performance would only be impaired at
relatively high concentrations of formaldehyde (Gerike and Gode, 1990).
51
Formaldehyde
There is some evidence that certain soil mesofauna may be adversely affected by
formaldehyde. The IPCS (1989) report indicated that nematodes in peat were
killed by application of formalin (37% formaldehyde solution) at 179 mL/mł.
However, in another study, cereal cyst nematode populations significantly
increased following soil treatment with formalin, presumably due to suppression
of fungal parasites, which attack the nematodes.
8.3.4 Summary
For aquatic organisms (Table 8.2), the available data indicate daphnia to be the
most sensitive species, with EC50 of 5.8 mg/L. The most sensitive fish species is
striped bass, with mean LC50 values of 16.9 mg/L. The responses of various
species of amphibians are similar to those of fish, with LC50 ranging from 10
mg/L to 20 mg/L. While no EC50 endpoints are available, the data suggest that
formaldehyde is only slightly to moderately acutely toxic to aquatic plants and
algae.
Table 8.2: Summary of the most sensitive aquatic species to formaldehyde
based on acute toxicity endpoints
Aquatic organisms Species Endpoint
Fish Striped bass (Morone 96-h LC50 = 16.9
mg/L
saxatilis)
Amphibians 72-h LC50 = 8.7 mg/L
Rania pipiens
96-h EC50 = 5.8 mg/L
Aquatic invertebrates Daphnia pulex
Molluscs Corbicula sp 96-h EC50 = 35 mg/L
Algae Freshwater green algae No reliable data
For terrestrial organisms (Table 8.3), the available data indicate that
formaldehyde is practically non-toxic to birds exposed to formaldehyde in food.
Formaldehyde in air and fog water has potentially adverse effects on some plant
species when exposed. The lowest effect concentration of formaldehyde in air
was 65 ppb and 14.9 ppb in fog. Gaseous formaldehyde also kills the spores of
microscopic fungi within 24 hours at concentrations of 2 ppm. Pollen grains of
Lilium longiflorum, exposed to 0.35 ppm of formaldehyde gas showed a
significant reduction in pollen-tube length after 5 hours. Pollen grains exposed to
formaldehyde concentrations of 2.3 ppm showed a decrease in tube length after 1
hour of exposure.
52 Priority Existing Chemical Assessment Report No. 28
Table 8.3: Summary of the effects of formaldehyde on terrestrial organisms
Terrestrial organisms Effects Endpoint
Northern bobwhite quail 14-d LD50 790 mg/kg
(Colinus virginianus)
Bean plants (Phaseolus Imbalance in shoot and root growth 65 ppb (fog)
vulgaris) after up to 4 weeks exposure
Rapeseed (Brassica rapa) Reduction in leaf area, leaf and 14.9 ppb (fog)
stem dry weight, and flower and
seedpod numbers
Lilium longiflorum Reduction in pollen tube length 0.35 ppm (gas)
after 5 hours
Microscopic fungi 100% mortality in 24 hours 2 ppm (gas)
(Scopulariopsis and
Penicillium)
53
Formaldehyde
9. Kinetics and Metabolism
9.1 Absorption
Inhaled formaldehyde is mostly deposited and readily absorbed in the regions of
the upper respiratory tract with which it comes into initial contact, owing to its
high water solubility and reactivity with biological macromolecules (Heck et al.,
1983; Swenberg et al., 1983). A complex relationship between nasal anatomy,
ventilation and breathing patterns (nasal or oronasal) determines where in the
upper respiratory tract formaldehyde absorption occurs in species. In rodents,
which are obligate nasal breathers, deposition and absorption occurs primarily in
the nasal passage. In contrast, primates are oronasal breathers, and although
absorption and deposition is likely to occur primarily in the oral mucosa and nasal
passages it can also occur in the trachea and bronchus (Monticello et al., 1991).
At the site of contact, formaldehyde has been shown to produce intra and
intermolecular crosslinks with proteins and nucleic acids (Casanova et al., 1989;
1991).
There are no direct toxicokinetic studies on formaldehyde following oral or
dermal administration. However, the use of physiochemical and toxicological
data allows a qualitative assessment of the toxicokinetic behaviour of
formaldehyde to be made for these routes of exposure. On the basis of its low
molecular weight, high water solubility and moderate octanol/water partition
coefficient (Log P) value, it is likely that significant absorption via the oral route
would occur. These physiochemical characteristics of formaldehyde would also
favour dermal absorption. The observation of skin sensitisation in animal studies
(Section 10.3) indicates that such absorption can occur.
9.2 Distribution
No increase in formaldehyde concentration was seen in blood in humans, rats,
and monkeys following exposure to concentrations of 1.9 ppm (2.3 mg/m3), 14.4
ppm (17.3 mg/m3) and 6 ppm (7.2 mg/m3) gaseous formaldehyde, respectively
(IPCS, 2002). This has been attributed to the deposition of formaldehyde
principally in the respiratory tract and its rapid metabolism (Heck et al., 1985;
Casanova et al., 1988). The half-life in circulation has been shown to range from
1 to 1.5 minutes between animal species following intravenous administration
(Rietbrock, 1969; McMartin et al., 1979). Such rapid metabolism would inhibit
systemic distribution of formaldehyde.
9.3 Metabolism
Formaldehyde can be metabolised by a variety of pathways: (1) incorporation
into the one-carbon pool pathway, (2) conjugation to glutathione then oxidation
by formaldehyde dehydrogenase, and (3) oxidation by the peroxisomal enzyme
catalase (Kallen & Jencks, 1966; Uotila & Koivusalo, 1974a; Waydhas et al.,
1978).
Formaldehyde is rapidly metabolised to formate by a number of widely
distributed cellular enzymes, the most important of which is formaldehyde
54 Priority Existing Chemical Assessment Report No. 28
dehydrogenase that metabolises the formaldehyde-glutathione conjugate to
formate. Formaldehyde dehydrogenase has been detected in human liver and red
blood cells and a number of tissues in the rat including respiratory and olfactory
epithelium, kidney and brain (Uotila & Koivusalo, 1974b; Casanova-Schmitz et
al., 1984). Both formaldehyde and formate are incorporated into the one-carbon
pathways involved in the biosynthesis of protein and nucleic acid via direct
reaction with tetrahydrofolate. Formaldehyde can also be oxidised to formic acid
by catalase, though this reaction probably represents a minor pathway for
formaldehyde metabolism. Additionally, it should be noted that formaldehyde is
itself formed endogenously during the metabolism of amino acids and xenobiotics
(Johansson & Tjalve, 1978; Upreti et al., 1987).
9.4 Elimination and excretion
Due to the rapid metabolism of formaldehyde, much of the material is eliminated
as carbon dioxide in expired air shortly after exposure, and as formate in urine
(Keefer et al., 1987; Heck et al., 1983). Elimination of total radioactivity
following exposure of rats to [14C]-formaldehyde indicated that 40% of the
inhaled [14C] was excreted in expired air, 17% in urine and 5% in faeces. The rest
of the radioactive label (35% to 39%) remained in the tissues and carcass,
presumably as products of metabolic incorporation (Heck et al., 1983).
55
Formaldehyde
10. Effects on Laboratory Mammals
and Other Test Systems
This chapter is a summary of the health effects of formaldehyde. It is mainly
based on the Concise International Chemical Assessment Document (IPCS,
2002), the Toxicological Profile (ATSDR, 1999) and the SIDS Initial Assessment
Report (OECD, 2002). Articles published post 1998 are summarised in this
chapter.
10.1 Acute toxicity
Formaldehyde has been found to be moderately toxic in laboratory animals
exposed via inhalation, dermal and oral routes. The acute toxicity of
formaldehyde has been studied in several animal species and is summarised in
Table 10.1.
Table 10.1:Summary of LD50 and LC50 values for formaldehyde
Route Species Measure Result Reference
Inhalation Rat LC50 480 ppm Nagorny et al., 1979
3
(4 hours) (578 mg/m )
Inhalation Mouse LC50 414 ppm Nagorny et al., 1979
3
(4 hours) (497 mg/m )
800 mg/kg bw Smyth et al., 1941
Oral Rat LD50
Oral Guinea-pig LD50 260 mg/kg bw Smyth et al., 1941
Dermal Rabbit LD50 270 mg/kg bw Lewis & Tatken,
1980
Clinical signs of toxicity, observed following single exposure of formaldehyde
vapour at concentrations > 100 ppm (> 120 mg/m3) were hypersalivation, acute
dyspnoea, vomiting, muscular spasms, and death (Skog, 1950; Horton et al.,
1963; Bitron & Aharonson, 1978).
10.2 Corrosivity/Irritation
10.2.1 Skin and eye irritation
With the exception of a recently conducted eye irritation study by Maurer et al.
(2001) summarised below, the limited data available for skin and eye irritation
are from old briefly reported studies. These studies state that aqueous solutions of
0.1% to 20% formaldehyde were irritating to rabbit skin (NRC, 1981), and
aqueous solutions of 5% and 15% formaldehyde were irritating to rabbit eyes
(Carpenter and Smyth, 1946). In a mouse repeated dermal study (see Section
10.4.3), skin irritation was observed with 0.5% formaldehyde solution and above.
No skin irritation was seen at 0.1% (Krivanek et al., 1983). The SIAR (OECD,
56 Priority Existing Chemical Assessment Report No. 28
2002) and IPCS report (1989) concluded that although formaldehyde solution is
known to be a primary skin and eye irritant in animals this is based on anecdotal
evidence rather than robust animal studies. Skin irritation studies in animals using
gaseous formaldehyde were not found.
In a recent well-reported study, Maurer et al. (2001) investigated the ocular
irritation of formaldehyde solution in a series of experiments. In a low-volume
eye test (LVET), 10 ”l of 37% formaldehyde solution was applied directly to the
cornea of 12 rabbits. Eyes were macroscopically examined to determine the
degree and extent of irritation to the cornea, iris and conjunctiva at 3 hours post
instillation and 1-4, 7, 14, 21, 28 and 35 days after treatment. The maximum
score obtainable was 110 (cornea = 80, iris = 10, conjunctiva = 20). Additionally,
from this group of 12 rabbits, 3 animals were sacrificed at 3 hours, 1, 3 and 35
days post-instillation, and the eyes were removed, sectioned, stained and
examined by light microscopy to determine the extent of corneal and conjunctiva
changes (< 5% slight, 6% to 30% mild, 61% to 90% marked and 91% to 100%
severe). Macroscopic observations showed that formaldehyde solution produced
irritation of the cornea, conjunctiva and iris 3 hours after application. An irritation
score of 53.5/110 was determined. This value increased to a maximum of
80.0/110 (time of scoring not reported). Microscopic examination indicated that
severe irritation had occurred to the cornea and conjunctiva. Observations
included erosion, denudation and oedema to the corneal and conjunctival
epithelium. "Necrosis/loss" of corneal keratocytes was also observed 1 day after
instillation in all 3 rabbits. At study termination on day 35, both macro- and
microscopic examination revealed corneal irritation in all animals.
In a further experiment, Maurer et al. (2001) determined the initial corneal injury
3 hours and 1-day post-instillation of 10 ”l of 37% formaldehyde solution by
post-mortem quantitation of dead corneal epithelium and keratocytes, using a
scanning laser confocal microscopy. Post mortem quantitation indicated that
corneal injury extended deeply into the stroma, at times to 93.2% of the corneal
thickness on day 1. Dead corneal epithelial cells and keratocytes were also
observed on day 1.
10.2.2 Respiratory irritation
No internationally validated animal tests are currently available for this endpoint.
Data are available from a study investigating effects on the mucociliary clearance
and histopathological changes in Fischer 344 (F344) rats using light microscopy
after a single 6-hour exposure to 0, 2, 6 or 15 ppm (0, 2.4, 7.2 or 18 mg/m3)
gaseous formaldehyde (Morgan et al., 1986). At 15 ppm, slowing or cessation of
mucous flow was detected in the nasal tract along with separation of epithelial
cells and intravascular margination and local tissue infiltration by neutrophils and
monocytes. No effects were seen at 2 or 6 ppm formaldehyde. However, in a
study using electron microscopy to investigate histopathological changes in the
nasal tract of F344 rats following a single exposure to formaldehyde (Monteiro-
Riviere & Popp, 1986), loss of microvilli in ciliated cells, autophagic vacuoles in
basal cells and cytoplasmic vacuoles in most cell types were seen at > 6 ppm.
Although altered cilia were seen at 0.5 ppm and 2.2 ppm (0.6 mg/m3 and 2.6
mg/m3), such changes were also occasionally reported in control animals.
Consequently, it cannot be determined whether these findings at 0.5 ppm and 2.2
ppm are attributable to formaldehyde exposure or inter-animal variations.
57
Formaldehyde
In an Alarie assay in Swiss mice (Kane & Alarie, 1997), a 10-minute exposure to
3.1 ppm (3.7 mg/m3) formaldehyde was calculated to depress the respiratory rate
by 50% (RD50 value). Additionally, tracheal cannulation of mice was seen to
produce a minimal decrease in respiratory rate; 4.2% compared to 54% in un-
cannulated controls. In a recent modified Alarie assay (Nielsen et al., 1999),
respiratory patterns and parameters were continuously measured in BALB/c mice
exposed (head only) to formaldehyde at concentrations ranging from 0.2 to 13
ppm (0.24 to 15.6 mg/m3) for 30 minutes. A 10-minute RD50 of 4 ppm (4.8
mg/m3) was calculated, which was reported to be due to irritation of the upper
respiratory tract. At concentrations above the RD50 value both upper respiratory
tract irritation and bronchoconstriction were involved in the decrease in
respiratory rate.
10.3 Sensitisation
10.3.1 Skin
The skin sensitisation potential of formaldehyde solutions has been investigated
in numerous studies in the guinea-pig and mouse. A positive response to
formaldehyde solution was seen in a large number of these studies. For example,
strong positive responses to formaldehyde solution were observed in well-
conducted guinea-pig maximisation tests, a Buehler occluded patch test and
murine local lymph node assays (Kimber et al., 1991; Hoechst, 1994; Hilton et
al., 1996). The details of the studies were summarised in ATDSR (1999).
Furthermore, the cytokine secretion profile of formaldehyde was recently
determined in mice and compared with that produced by a reference skin and
respiratory sensitiser. Previous studies by the authors had shown that skin
sensitisers stimulated a cytokine profile associated with the activation of T helper
type 1 cells, compared to T helper type 2 cells for respiratory sensitisers. Topical
exposure of mice to a 50% formaldehyde solution resulted in a cytokine secretion
profile identical to that induced by the reference contact allergen (Dearman et al.,
1999).
There is no evidence in inhalation studies with rats, mice, hamsters or monkeys
that formaldehyde gas induces skin sensitisation.
10.3.2 Respiratory
No internationally validated animal test is currently available that allows
prediction of the ability of a chemical to induce respiratory sensitisation.
However, data are available from non-validated studies investigating this
endpoint in mice and guinea pigs.
Formaldehyde was negative in immunoglobulin-E (IgE) tests in the mouse (Potter
& Wederbrand, 1995; Hilton et al., 1996;) and guinea-pig (Lee et al., 1984). This
predictive test method for assessment of respiratory sensitisation potential
measures induced changes in serum concentration of IgE following topical
exposure of mice to the test chemical. Furthermore, in a study investigating the
cytokine secretion profile in mice (Dearman et al., 1999), topical exposure to
formaldehyde did not induce a profile comparable to that of the reference
respiratory sensitiser (i.e. secretion of cytokines associated with selective
activation of T helper type 2 cells).
58 Priority Existing Chemical Assessment Report No. 28
Data is also available from studies that investigated whether pre-exposure to
formaldehyde may enhance allergenic responses to ovalbumin. Compared to
controls, a statistically significant increase in specific anti-ovalbumin antibody
levels were seen in mice exposed to 1.67 ppm (2.00 mg/m3) formaldehyde daily
for 10 days (Tarkowski & Gorski, 1995), and guinea-pigs to 0.25 ppm (0.3
mg/m3) daily for 5 days (Riedel et al., 1996), prior to induction then bronchial
challenge with ovalbumin.
10.4 Repeat dose toxicity
Repeated dose studies are available via the inhalation, oral, and dermal routes of
exposure.
10.4.1 Inhalation
For repeated inhalation exposure the database is extensive. Studies have generally
been conducted in rats, though data are also available in mice, hamsters and
monkeys. These studies clearly show that the target organ following
formaldehyde exposure is the nasal tract, where effects observed have included
alterations in mucociliary clearance, cell proliferation and histopathological
changes to the nasal epithelium.
In the only study that investigated effects on the nasal mucociliary apparatus
(Morgan et al., 1986), male F344 rats were exposed to 0, 0.5, 2, 6, or 15 ppm (0,
0.6, 2.4, 7.2 or 18 mg/m3) formaldehyde 6 hours/day, 5 days/week for up to 2
weeks. Inhibition of mucociliary clearance (i.e. reduced mucous flow rate) was
observed at 6 ppm and above in the 9-day exposure group. The inhibitory effect
of formaldehyde was mostly observed in the lateral aspect of the nasoturbinate
and dorsal or medial aspects of the maxilloturbinate. No evidence of reduced
mucous flow rate was seen at 2 ppm.
Short-term and sub-chronic exposure studies
In the rat, studies with exposure durations from 2 days to a lifetime are available.
An overview of the results seen in short-term to sub-chronic exposure studies is
presented below [see CICAD (IPCS, 2002) for a more detailed summary of the
data].
In short-term to sub-chronic exposure studies with exposure periods of 6-8
hours/day, 5 days/week, conclusive evidence of squamous metaplasia and/or cell
proliferation of the nasal epithelium were seen with light microscopy at > 3.2
ppm (3.8 mg/m3) formaldehyde for 2-3 days exposure (Swenberg et al., 1983;
Monteiro-Riviere and Popp, 1986; Morgan et al., 1986; Cassee et al., 1996); > 5
ppm (6 mg/m3) formaldehyde in a 4-week study (Wilmer et al., 1987); > 6.2 ppm
(7.4 mg/m3) formaldehyde in a 6-week study (Monticello et al., 1991); and > 3
ppm (3.6 mg/m3) formaldehyde in studies with exposure durations of
approximately 13-weeks (Feron et al., 1988; Woutersen et al., 1987; Zwart et al.,
1988; Wilmer et al., 1989; Casanova et al., 1994).
In these short-term to sub-chronic studies, the severity of histopathological
changes was seen to increase with concentrations (e.g. in the study by Monticello
et al. (1991). Epithelial cell vacuolar degeneration, individual cell necrosis,
epithelial exfoliation and multifocal erosions were observed at > 10 ppm
59
Formaldehyde
(> 12 mg/m3) formaldehyde). Some studies (Wilmer et al., 1986; 1987) indicated
that it is the concentration rather than the total dose (i.e. concentration x time of
exposure) that determines the severity of this cytotoxicity.
In a rat study with a near continuous exposure period (i.e. 22 hours/day),
hyperplasia and metaplasia were observed in the nasal epithelium following 3
consecutive days exposure to 3.1 ppm (3.7 mg/m3) formaldehyde (Reuzel et al.,
1990).
In a recent study, a decrease in testicular zinc (52% - 65%) and copper
concentrations (40-68%), increase in testicular iron concentrations (17% 76%)
and reductions in body weight gain (38% 87%) were seen in male Wistar rats
exposed to 10.2 or 20.3 ppm (12.2 or 24.4 mg/m3) formaldehyde gas 8 hours/day,
5 days/week for 4 and 13 weeks compared to controls (Ozen et al., 2002;
exposure concentrations confirmed by personnel communication). The effects
seen on these testicular trace elements are considered a secondary non-specific
consequence of marked general toxicity, seen as growth retardation.
Data are also available from short-term to sub-chronic studies in other species.
Hyperplasia of the nasal epithelium was seen in mice exposed to 15 ppm (18
mg/m3) gaseous formaldehyde 6 hours/day for 3 consecutive days (Swenberg et
al., 1986). In a 13-week mouse study (Maronpot et al., 1986), minimal squamous
metaplasia was observed in the nasal tract of 1/10 males, but absent in females,
exposed to 4 ppm (4.8 mg/m3) formaldehyde 6 hours/day 5 days/week. Data are
also available in the monkey. Histopathological changes in the nasal cavity and
upper portion of the respiratory tract (trachea and bronchial biforcation) were
seen in male rhesus monkeys exposed to 6 ppm (7.2 mg/m3) formaldehyde 6
hours/day 5 days/week for 1 or 6 weeks (Monticello et al., 1989). A comparative
study of the effects of near continuous exposure to formaldehyde (i.e. 22
hours/day 7 days/week) for 26 weeks is available in cynomologus monkeys, F344
rats and Syrian hamsters (Rusch et al., 1983). Comparable effects were seen
between F344 rats and cynomologus monkeys at 3 ppm (3.6 mg/m3)
formaldehyde. In contrast, no conclusive evidence of histopathological changes in
the respiratory tract was observed in hamsters at 3 ppm. Together, the data from
these two studies suggests that rats and monkeys may be equally susceptible to
epithelial damage from formaldehyde exposure, but a wider regional distribution
of formaldehyde occurs in the upper respiratory tract of (rhesus) monkeys than in
rats.
Although no obvious clinical signs of neurotoxicity or histopathological changes
in the brain have been observed in rodent inhalation studies, a recent sub-chronic
inhalation study is available investigating the effect of formaldehyde on
behaviour in male and female Wistar rats (Pitten et al., 2000). Compared to
controls, exposure to 2.6 or 4.6 ppm (3.1 or 5.5 mg/m3) formaldehyde 10
min/day, 7 days/week for 13 weeks was seen to produce a statistically significant
increase in the time to find the food, and number of mistakes made in a maze.
However, the small group sizes (13-14/dose), assessment of a single
neurobehavioral trait and absence of dose-response relationship for observed
effects prevent any reliable conclusions being drawn from the data on the
neurotoxic potential of formaldehyde.
60 Priority Existing Chemical Assessment Report No. 28
Long-term exposure studies
Data are available from seven chronic inhalation studies in rodents. All these
studies, which employed an exposure period of 6 hours/day 5 days/week, are
presented below.
In a study by Kerns et al. (1983), F344 rats and B6C3F1 mice (approximately 120
per species per sex per concentration) were exposed to 0, 2, 5.6 or 14.3 ppm (0,
2.4, 6.7 or 17.2 mg/m3) formaldehyde for up to 24 months. In rats, rhinitis,
epithelial dysplasia and squamous metaplasia of the nasal tract was observed at 2
ppm and above. In mice, histological changes were seen at 5.6 ppm and above,
along with rhinitis in a "few" animals at 2 ppm (no further details available).
In a study by Appelman et al. (1988), male Wistar rats (40 per concentration)
were exposed to 0, 0.1, 1 or 9.4 ppm (0, 0.12, 1.2 or 11.8 mg/m3) formaldehyde
for 12 months. Rhinitis, hyperplasia and squamous metaplasia were observed in
animals at 9.4 ppm only.
In a study by Woutersen et al. (1989), male Wistar rats (30 per concentration)
were exposed to 0, 0.1, 1 or 9.8 ppm (0, 0.12, 1.2 or 11.8 mg/m3) formaldehyde
for up to 28 months. At 9.8 ppm rhinitis, disarrangement of the olfactory
epithelium, hyperplasia and squamous cell metaplasia were observed in the nasal
tract. No histopathological changes were observed at 0.1 or 1.0 ppm.
In a study by Monticello et al. (1996), male F344 rats (90-150 per concentration)
were exposed to 0, 0.7, 2, 6, 10 or 15 ppm (0, 0.84, 2.4, 7.2, 12 or 18 mg/m3)
formaldehyde for up to 24 months, and effects determined at seven sites within
the nasal tract: anterior lateral meatus, posterior lateral meatus, anterior mid-
septum, posterior mid-septum, anterior dorsal septum, medial maxilloturbinate
and maxillary sinus. At > 6 ppm hyperplasia and squamous metaplasia were
observed in the nasal tract, mainly at the anterior lateral meatus. No
histopathological changes were observed in the nasal tract at 0.7 or 2 ppm.
In a study by Kamata et al. (1997), male F344 rats (36 per concentration) were
exposed to 0, 0.3, 2.17 or 14.85 ppm (0, 0.36, 2.6 or 17.8 mg/m3) formaldehyde
for up to 28 months. At > 2.17 ppm a statistically significant increase in
squamous metaplasia in the nasal tract was observed both in the presence and
absence of epithelial hyperplasia. At 0.3 ppm, although not statistically
significant, squamous metaplasia was seen in the absence (1/5 animals at 18
months) and presence of hyperplasia (1/5 animals at 24 months and 3/11 animals
at 28 months). However, the small group sizes and number of animals at interim
sacrifice limits the significance that can be attached to the results of this study.
Hyperplasia and squamous metaplasia were observed in the nasal tract of rats in
studies by Sellakumar et al. (1985) and Holmstrom et al. (1989) that are of
limited value as they only employed a single (high) exposure level; 14 and 12
ppm (16.8 and 14.4 mg/m3) formaldehyde, respectively.
In these studies no conclusive evidence of systemic toxicity following inhalation
exposure to formaldehyde was seen. The principal non-neoplastic effect observed
in animals after repeated inhalation exposure was histological changes at the site
of contact (i.e. in the nasal tract) due to irritation. The available data provide a
dose-response range for histopathological changes in the nasal tract of rats, with
effects being seen at 2 ppm (2.4 mg/m3) and above. Overall, the data also indicate
61
Formaldehyde
similar effects are observed irrespective of exposure period. Although
histopathological changes to the nasal tract were observed in rats at 0.3 ppm
following 28 months exposure (Kamata et al., 1997), study limitations reduce the
significance that can be attached to the data. Furthermore, no histopathological
changes were seen at 0.7 and 1 ppm in studies of 24 and 28 months duration,
respectively (Monticello et al., 1996; Woutersen et al., 1989). Consequently, a
LOAEC of 2 ppm (2.4 mg/m3) is identified for histopathological changes to the
nasal tract from an 18- and 24-month rat studies (Swenberg et al., 1980 and Kerns
et al., 1983, respectively) with a NOAEC of 1 ppm (1.2 mg/m3) identified from a
rat 28-month study (Woutersen et al., 1989).
10.4.2 Oral
Data are available from studies in rats and a dietary study in dogs.
In short-term drinking water studies in rats, histopathological changes to the fore-
stomach were seen at 125 mg/kg bw/day in a 28-day study following
administration of formaldehyde solution (95% paraformaldehyde prill and 5%
water) at dose levels of 5, 25, 125 mg/kg bw/d (Til et al., 1988). In contrast, a
reduction in body weight gain was seen in a 13-week study [administering
formaldehyde solution (95% paraformaldehyde prill and 5% water) in drinking
water at 0, 50, 100, 150 mg/kg bw/d] at 100 mg/kg bw/day but no treatment-
related histopathological changes were reported up to 150 mg/kg bw/day
(Johannsen et al., 1986). A 28-day study is also available investigating the
immunotoxicity of formaldehyde solution (28.44%) in male rats (Vargova et al.,
1993). Animals were administered 0, 20, 40 or 80 mg/kg bw/day formaldehyde
by gavage. Compared to controls, the only effects seen were a statistically
significant increase in haematocrit concentration and decrease in body weight
gain at > 40 and 80 mg/kg bw/day, respectively. However, the magnitude of
changes were < 10% and are not considered biologically significant.
Additionally, although lymph node weight was significantly increased at 80
mg/kg bw/day no histopathological changes were seen in the lymph node organs.
Consequently, this study is not considered to provide conclusive evidence that
formaldehyde possesses an immunosuppressive potential.
Data are also available from long-term drinking water studies in the rat. In a study
by Tobe et al. (1989), male and female Wistar rats (20 per sex per concentration)
were administered formaldehyde solution in drinking water at concentrations of
0, 0.02, 0.1, 0.5% (approximately 0, 10, 50 or 300 mg/kg bw/day formaldehyde
solution) for up to two years. However, the small group sizes employed and
significant increase in mortality rate at the top dose (45% females and 55% males
had died at 12 months) limits the value of this study for identification of a robust
no-effect level. In contrast, a 2-year study by Til et al. (1989) was both well
conducted and reported. In this study, groups of male and female Wistar rats (70
per sex per concentration) were administered formaldehyde solution (95%
paraformaldehyde prill and 5% water) at dose levels of approximately 0, 1.2, 15
or 82 mg/kg bw/day in males and 0, 1.8, 21 or 109 mg/kg bw/day females for up
to 2 years. At the top dose, histopathological changes including hyperplasia,
hyperkeratosis, and focal ulceration of the forestomach epithelium, as well as
focal atrophic gastritis, glandular hyperplasia and ulceration in the glandular
stomach, were observed in both sexes. A reduction in body weight gain, liquid
intake and an increased incidence in renal papillary necrosis were also seen in
62 Priority Existing Chemical Assessment Report No. 28
both sexes at the top dose. As these findings were not seen in other studies they
are considered likely to be a secondary consequence of the severe effects seen in
the stomach. No treatment-related effects were seen in either sex in the mid and
low dose groups.
In a 90-day oral study in dogs administering formaldehyde solution (95%
paraformaldehyde prill and 5% water) in drinking water at 0, 50, 100 mg/kg bw/d
(Johannsen et al., 1986), no treatment-related effects were reported up to 100
mg/kg bw/day. The absence of toxicity in both the dogs and rats in this study
suggests that the target intakes may not have been achieved. Furthermore, it is not
reported whether histopathological examination of the stomach was conducted in
this study.
Therefore, from the available data there is no conclusive evidence of systemic
toxicity following oral administration of formaldehyde. The principal non-
neoplastic effect observed in animals after repeated oral dosing was irritation at
the site of contact (i.e. fore- and glandular-stomach). From the available data, a
NOAEL of 15 mg/kg bw/day and a LOAEL of 82 mg/kg bw/day were identified
for histopathological changes to the stomach from a well-conducted 2-year oral
study in the rat (Til et al., 1989).
10.4.3 Dermal
The limited data available on the repeat dermal toxicity of formaldehyde solution
are from briefly reported mouse initiation/promotion studies (Krivanek et al.,
1983; Iversen, 1986). None of these studies showed evidence of systemic toxicity.
The study by Krivanek et al. (1983) contained a briefly reported dose ranging
test. Groups of female CD-1 mice (number/dose not reported) received 100 ”l of
a 10%, 2% or 1% formaldehyde solution in acetone (equivalent to 10, 2 and 1
mg) 5 days/week for 2 weeks or, 0.5% or 0.1% (equivalent to 0.5 or 0.1 mg) 5
days/week for 3 weeks. Skin irritation was observed at 0.5% and above, whose
severity increased with concentration. Systemic toxicity was not seen at any dose
level. However, the limited details provided prevent identification of a reliable
NOAEL or LOAEL from this study.
10.5 Genotoxicity
10.5.1 In vitro studies
A large number of studies have been conducted in vitro with either gaseous or
aqueous formaldehyde and a wide variety of endpoints assessed. An overview of
these results is presented below [see IARC (1995) for a comprehensive summary
of the available data].
The majority of Ames tests with Salmonella typhimurium produced a positive
result in the absence of metabolic activation, as seen in more recent studies by
Marnett et al. (1985) and Takahashi et al. (1985). Positive results, generally
weaker, have also occasionally been reported in the presence of metabolic
activation (Connor et al., 1983; Donovan et al., 1983; Pool et al., 1984; Schmid et
al., 1986; Temcharoen & Thilly, 1983). Positive results have also been reported in
the reverse mutation assay with Escherichia coli in the absence of metabolic
activation (Takahashi et al., 1985; O'Donovan & Mee, 1993).
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Formaldehyde
In mammalian cells, positive results have been reported in gene mutation assays
in the absence of metabolic activation (Goldmacher & Thilly, 1983; Crosby et al.,
1988; Liber et al., 1989). Furthermore, loss of heterozygosity analysis following a
positive gene mutation assay in the absence of metabolic activation suggested that
small-scale chromosomal deletion or recombination is the mechanism of mutation
formation in mammalian cells in vitro (Speit and Merk, 2002). Additionally,
increased incidences of chromosomal aberrations and SCE have been observed in
the presence and absence of metabolic activation (Basler et al., 1985; Galloway et
al., 1985; Natarajan et al., 1983; Schmid et al., 1986). Formaldehyde has also
been reported to produce DNA damage (single strand breaks), and DNA-protein
cross-links (DPX) in the absence of metabolic activation (Ross et al., 1981;
Grafström et al., 1984; Grafström, 1990).
10.5.2 In vivo studies
In somatic cells
Data are available from a number of in vivo studies that are presented below.
Some of these studies did not follow validated test methods with regard to the
tissues examined or the exposure duration employed (i.e. prolonged).
In a bone marrow cytogenetic assay (Natarajan et al., 1983), no increased
incidence in chromosome aberrations or micronuclei were seen in male and
female CBA mice that received two intraperitoneal injections of formaldehyde
solution (concentrations not stated) over 24 hours for total doses up to 25 mg/kg
bw. Additionally, no increased incidence in chromosome aberrations was seen in
spleen cells. In a further ip bone marrow study (Gocke et al., 1981), no significant
increase was seen in micronuclei in male and female Sprague-Dawley following a
single injection of formaldehyde solution (concentration not reported) up to 30
mg/kg bw. No information on cytotoxicity was reported for either of these
studies.
In an inhalation bone marrow cytogenetic study by Kitaeva et al., 1990 (reported
in Russian, summary from IPCS, 2002), a statistically significant increase in the
proportion of cells with chromosomal aberrations (chromatid or chromosome
breaks) were seen in female Wistar rats exposed to 0, 0.42, or 1.3 ppm (0, 0.50 or
1.56 mg/m3) gaseous formaldehyde for 4 hours/day for 4 months (0.7%, 2.4% and
4%, respectively). No further details are reported in the CICAD (IPCS, 2002).
Whereas, no significant increase in chromosome aberrations was seen in the bone
marrow of male Sprague-Dawley rats exposed up to 15 ppm (18 mg/m3)
formaldehyde 6 hour/day, 5 days/week for 1 or 8 weeks (Dallas et al., 1992). A
marginal but statistically significant increase in chromosome aberrations
(predominantly chromatid breaks) was seen in pulmonary lavage macrophages in
the same study at 15 ppm only following 1 and 8 weeks exposure (7.6% and
9.2%, respectively, compared to 3.5% and 4.8% in controls). No information on
cytotoxicity was reported. In a further inhalation study (Kligerman et al., 1984),
no significant increase in SCE or chromosome aberrations were seen in peripheral
lymphocytes from male and female F344 rats exposed up to 15 ppm (18 mg/m3)
formaldehyde 6 hour/day for 5 days. No information on cytotoxicity was
reported.
Compared to controls, a statistically significant increase in the proportion of cells
with micronuclei and nuclear anomalies (e.g. karyorrhexis, pyknosis, vacuolated
64 Priority Existing Chemical Assessment Report No. 28
bodies) were observed in the stomach, duodenum, ileum and colon of male
SpragueDawley rats after a single dose of 200 mg/kg bw formaldehyde solution
by gavage (Migliore, et al., 1989). Although no statistically significant effect was
seen on the mitotic index in formaldehyde treated rats, the observed increased
incidences in micronuclei and nuclear anomalies were reported to clearly
correlate with severe local irritation (hyperaemia to haemorrhage), indicating that
the observed micronuclei and nuclear anomalies in this study are a likely
consequence of cytotoxicity.
Additionally, formaldehyde-induced DPX have been detected in the nasal mucosa
of male F344 rats exposed to 0.3, 0.7, 2, 6, or 10 ppm (0.36, 0.84, 2.4, 7.2 or 12
mg/m3) gaseous formaldehyde for 10 hours (Casanova et al., 1989), and in male
rhesus monkeys exposed to 0.7, 2 and 6 ppm for 6 hours (Casanova et al., 1991).
Although the precise nature of these cross-links is unknown the possibility that
these DPX may produce DNA replication errors cannot presently be dismissed.
In germ cells
Data are also available from studies determining the genotoxicity of
formaldehyde in germ cells. None of the following studies reported information
on cytotoxicity. In an ip study (Fontignie-Houbrechts, 1981), no chromosome
aberrations were seen in spermatocytes from male Q mice 8-15 days after a single
injection of 50 mg/kg bw formaldehyde solution. A dominant lethal assay was
also conducted in this study, in which male Q mice were mated for 7 weeks
following a single ip injection of 50 mg/kg bw formaldehyde solution. Compared
to controls, a statistically significant increase in post-and pre-implantation loss
was seen at week 1 and pre-implantation loss at week 3. However no significant
effects was seen on the number of pregnant females or live embryos per dam.
Therefore, this study is not considered to have demonstrated a genotoxic effect.
Additionally, no significant increase in potential dominant lethal findings were
seen after single ip injection of up to 40 mg/kg bw formaldehyde solution
(reported to be the ip LD50) to male ICR/Ha mice which were mated for 3 or 8
weeks (Epstein et al., 1972), and following ip injection of 20 mg/kg bw
formaldehyde solution (reported to be the ip LD50) to male CD-1 mice which
were mated for 8 weeks (Epstein et al., 1968).
In contrast, daily ip injection of rats with 0.125, 0.25 or 0.5 mg/kg bw/day
formaldehyde solution (1/4 to 1/16 of the determined ip LD50) for 5 days resulted
in a dose related statistically significant increase in epididymal sperm head
abnormalities (> 106%) and decrease in epididymal sperm count (> 41%) at 0.125
mg/kg and above compared to controls (Odeigah, 1997). This study also included
a dominant lethal assay in which male rats received daily ip injections of 0, 0.125,
0.25 or 0.6 mg/kg bw/day for 5 days prior to mating for 3 weeks. A significant
and dose related decrease was seen in the number of pregnant females mated 1-7
and 8-14 days after treatment of males with > 0.125 mg/kg bw/day (6-19/24
pregnancies compared to 29/30 in the control group), together with a significant
dose related increase in the number of dead implants per dam in females mated 1-
7 days after treatment of males with > 0.125 mg/kg bw/day (> 1.23 compared to
0.43 in controls) and was associated with a corresponding decrease in the number
of live foetuses per dam (< 5.95 compared to 7.43 in controls).
65
Formaldehyde
10.6 Carcinogenicity
The carcinogenic potential of formaldehyde has been investigated in a number of
animal studies, predominantly by the inhalation route of exposure.
10.6.1 Inhalation
In the only study conducted in both sexes, groups of F344 rats (approximately
120 per sex per concentration) were exposed to 0, 2.0, 5.6 or 14.3 ppm (0, 2.4, 6.7
or 17.2 mg/m3) formaldehyde 6 hours/day, 5 days week for up to 24 months
(Kerns et al., 1983). All animals were subject to a complete and thorough gross
and microscopic examination. A significant increased incidence in nasal
squamous cell carcinomas was observed in both sexes at 14.3 ppm in the presence
of irritation to the nasal tract. The overall incidence in this tumour type at 0, 2.0,
5.6 and 14.3 ppm was 0/118, 0/118, 1/119 and 51/117 in males, and 0/118, 0/118,
1/116 and 52/119 in females, respectively. There were no significant tumour
findings in any other tissue. In a further study, groups of male F344 rats (90-150
per concentration) were exposed to 0, 0.7, 2, 6, 10 or 15 ppm (0, 0.84, 2.4, 7.2, 12
or 18 mg/m3) formaldehyde 6 hours/day, 5 days/week for up to 24 months
(Monticello et al., 1996). This study is considered the most extensive bioassay
conducted to date as proliferative responses were determined at the anterior
lateral meatus, posterior lateral meatus, anterior mid-septum, posterior mid-
septum, anterior dorsal septum, medial maxilloturbinate and maxillary sinus sites
within the nasal tract after 3, 6, 12 and 18 months exposure, as well as at the end
of the study. The overall incidence of nasal squamous cell carcinoma in animals
was 0/90, 0/90, 0/90, 1/90, 20/90 and 69/147 exposed to 0, 0.7, 2, 6, 10 and 15
ppm, respectively. These tumours were mainly located in the anterior lateral
meatus, the posterior lateral meatus and the mid-septum. Nasal polypoid
adenomas, located in or adjacent to the lateral meatus, were also observed at 10
ppm (5/90 rats) and 15 ppm (14/147 rats) only. Both tumour types were observed
in the presence of irritation to the nasal tract.
Additional bioassays are available in male F344 rats [Tobe et al., 1985 (cited in
IPCS, 2002); Kamata et al., 1997]. Exposure-responses in these studies were
similar to those seen in the studies by Monticello et al. (1996) and Kerns et al.
(1983), that is, an increased incidence in nasal tumours at concentrations > 5.6
ppm (> 6.7 mg/m3) formaldehyde in the presence of irritation (i.e. tumours
observed at approximately 14 ppm [16.8 mg/m3] in the studies by Tobe et al.,
1985 and Kamata et al., 1997).
Data are available in other strains of rat. In a study in male Sprague-Dawley rats
employing a single exposure concentration to formaldehyde (Sellakumar et al.,
1985), a significant increase in the incidence of nasal squamous cell carcinoma
was observed in animals exposed to 14 ppm (16.6 mg/m3) formaldehyde 6
hours/day, 5 days/week for approximately 24 months compared to controls (0/99
and 38/100, respectively). These tumours were mainly located at the naso-
maxillary turbinates and nasal septum and observed in the presence of irritation to
the nasal tract. There were no significant tumour findings in any other tissue. In a
study in male Wistar rats (26-28/concentration) no significant increase in nasal
tumours was observed in animals exposed to 0, 0.1, 1, or 9.8 ppm (0, 0.12, 1.2 or
11.8 mg/m3) formaldehyde 6hours/day, 5days/week for 28 months (Woutersen et
al., 1989).
66 Priority Existing Chemical Assessment Report No. 28
Additional studies are available in male Wistar and female Sprague-Dawley rats
(Appelman et al., 1988; Feron et al., 1988; Holmstrom et al., 1989). No
significant increase in tumour formation was seen in these studies. However, the
small group sizes and/or short duration of exposure to formaldehyde used in these
studies limits the significance that can be attached to the data.
Data are also available in other species. In B6C3F1 mice (120 per sex per
concentration) exposed to 0, 2.0, 5.6 or 14.3 ppm (0, 2.4, 6.7 or 17.2 mg/m3)
formaldehyde 6 hours/day, 5 days/week for up to 24 months, squamous cell
carcinomas of the nasal tract were seen in two males at the top exposure
concentration in the presence of irritation to the nasal tract. No squamous cell
carcinomas of the nasal tract were observed in females (Kerns et al., 1983). A
study is available in C3H mice that did not observe an increased incidence in
pulmonary tumours (Horton et al., 1963). However, the short duration of
exposure to formaldehyde (35 weeks), lack of histological examination of the
nasal tract and concerns over the health status of the animals, limits the
significance that can be attached to the data. In male golden Syrian hamsters (50
per concentration), no tumours were seen in the nasal or respiratory tract, the only
tissues examined, of animals exposed to 10 ppm (12 mg/m3) formaldehyde,
6hours/day, 5days/week for life, or 30 ppm (36 mg/m3) 6 hours/day, once a week
for life (Dalbey, 1982).
10.6.2 Oral
Data are available from drinking water studies in the rat. In the study summarised
below by Soffritti et al. (1989) the dose administered were reported in mg/L only.
Therefore, the default values in Table 10.2 have been applied to convert mg/L to
mg/kg bw. These values are taken from Gold et al. (1984).
Table 10.2: Default values for dose calculations
Species Sex Body weight (kg) Food intake Water intake
(g/day) (ml/day)
Rat M 0.5 20 25
(lifetime studies) F 0.35 17.5 20
Rat M 0.2 20 25
(other studies) F 0.175 17.5 20
In the most comprehensive study available (Til et al., 1989), male and female
Wistar rats (70 per sex per dose) were administered formaldehyde solution in
drinking water for up to 24 months at dose levels that equated to approximately 0,
1.2, 15 or 82 mg/kg bw/day in males and 0, 1.8, 21 or 109 mg/kg bw/day in
females. Selected organs of animals in the low and mid dose groups were
examined at necropsy (including the stomach), while a complete and thorough
gross and microscopic examination was conducted on control and top dose group
animals. There were no significant tumour findings in any tissue. Similarly, no
significant tumour findings were seen in selected organs (including the stomach)
from male and female Wistar rats (20 per sex per dose) administered
formaldehyde solution in drinking water for up to 24 months at dose levels that
equated to approximately 0, 10, 50 or 300 mg/kg bw/day (Tobe et al., 1989).
In contrast, Soffritti et al. (1989) reported a marked increased incidence in
tumours in Sprague-Dawley rats (50 per sex per group) administered 1500 mg/L
67
Formaldehyde
(the top dose level) for life. These tumours were leukaemias (all
`haemolymphoreticular neoplasias') in males and females (22% and 14%,
respectively, compared to 4% and 3% in controls), along with adenomas of the
stomach (4%), intestinal adenocarcinomas (2%) and leiomyosarcomas (4%) in
males, and intestinal leiomyomas in females (6%). No gastrointestinal tumours
were seen in control animals. Using the default values given in Table 10.2, the
daily intake of aqueous formaldehyde at the top dose was estimated to have been
75 and 100 mg/kg bw/day in males and females, respectively. However, the
pooling of tumour types reported as leukaemias and lymphomas, together with
the final report of this study by Soffritti et al. (2002) that reports an increased
incidence of these tumours compared to the original summary (with no
explanation provided by the authors), means no reliable conclusions can be drawn
from the data for these tumours. The later report by Soffritti et al. (2002) provides
information on tumour incidences in additional tissues to those reported earlier.
Although an increase in testicular interstitial cell adenomas was seen in males, it
was not dose related or statistically significant at the top dose. Similarly, although
a statistically significant increase was seen for all mammary tumours in females
at the top dose (24% compared to 11% in controls), the increase was not dose
related, while no dose related or statistically significant increase was seen for
specific histologic tumours of the mammary gland.
In an initiation/promotion study in male Wistar rats (Takahashi et al., 1986),
papillomas of the forestomach were reported in the presence of irritation in 8/10
animals administered approximately 0.5% formaldehyde solution in drinking
water for 32 weeks. No forestomach tumours were seen in control animals.
10.6.3 Dermal
No standard studies are available. Data are available from mouse
initiation/promotion studies. No skin tumours were seen in mice (16-20 per sex
per dose) topically administered 1% or 10% formaldehyde solution only 3
times/week for 26 weeks (Krivanek et al., 1983,) or 10% formaldehyde solution
only 2 times/week for 60 weeks (Iversen, 1986). However, the small group sizes
and short duration of exposure to formaldehyde used in these studies prevent any
reliable conclusions on the carcinogenic potential of formaldehyde by the dermal
route.
10.7 Reproductive toxicity
In the only reproductive study available, a 1-generation study in minks (Li et al.,
1999), groups of 12 females were fed 0, 550 or 1100 ppm formaldehyde solution
in the diet from 1 month prior to mating (with untreated males) until weaning of
kits. However, dose levels of formaldehyde in the feed were determined to be 17,
291 and 662 ppm. No toxicity was observed in parental females. No effect was
observed on fertility index or litter size. A statistically significant decrease in kit
survival was reported at birth at the top dose (87% compared to 96% in controls).
Kit survival was unaffected 3 and 6 weeks post partum. The decrease in kit
survival at birth was observed in the absence of a significant increase in mean
number dead kits/dam or decrease in live kits/dam. These mean values are
considered more reliable markers of adverse effects on fertility. Consequently, it
is concluded that no adverse effects on fertility were observed in this study.
68 Priority Existing Chemical Assessment Report No. 28
However, the absence of parental toxicity means there are concerns that
formaldehyde was not robustly tested in this study.
Data are also available from a study by Ward et al. (1984) that investigated the
reproductive effect of formaldehyde in both mice and humans. In this study,
administration of 100 mg/kg bw/day formaldehyde solution (the only dose level
tested) to mice via gavage for 5 consecutive days had no effect on epididymal
sperm morphology. Furthermore in a rat 2-year repeated oral study, no
histological changes were observed in the testes or ovaries up to and including the
top dose, 82 mg/kg bw/day (Til et al., 1989). Similarly, in repeated inhalation
studies of 18 months duration and longer, no histological changes were observed
in reproductive organs at the maximum exposure concentration: 14.3 ppm (17.2
mg/m3) in rats and mice (Kerns et al., 1983). Although changes were seen in
testicular trace element concentrations (zinc and copper) at 10.2 ppm (12.2
mg/m3) and 20.3 ppm (24.4 mg/m3) gaseous formaldehyde (see details in section
10.4.1), they were considered to be a secondary non-specific consequence of
severe general toxicity; reductions in body weight gain of 38% to 87% (Ozen et
al., 2002).
In contrast, effects on male reproductive organs were observed in rodent
intraperitoneal (ip) studies. In rats, ip administration of formaldehyde solution for
30 consecutive days resulted in a statistically significant decrease in testicular
weight at > 5 mg/kg bw/day (magnitude not reported), a statistically significant
decrease in epididymal sperm count (44%), mobility (4%) and viability (17%) at
10 mg/kg bw/day, and histological changes in Leydig cells at > 10 mg/kg bw/day
(Chowdhury et al., 1992; Majumder & Kumar, 1995). In further studies, ip
administration of formaldehyde for 5 consecutive days resulted in a statistically
significant increase in epididymal sperm head abnormalities (> 106%) in rats at
> 0.125 mg/kg bw/day (Odeigah, 1997), and in mice a statistically significant
decrease in sperm mobility (5%) and viability (53%) at > 4 mg/kg bw/day, and
sperm count (54%) at > 10 mg/kg bw/day (Yi et al., 2000). However the
relevance of these studies are questionable, as ip administration is not a relevant
route of human exposure.
10.8 Developmental toxicity
Data are available from studies via inhalation, oral and dermal routes of exposure.
In an inhalation study (Saillenfait et al., 1989), groups of 25 mated female
Sprague-Dawley rats were exposed (whole-body) up to 0, 5.2, 9.9, 20 or 39 ppm
(0, 6.2, 11.9, 24.0 or 46.8 mg/m3) gaseous formaldehyde for 6 hours/day from day
6 to 20 of gestation. At 39 ppm only, a statistically significant decrease in dam
body weight gain (51%) and male (21%) and female (19%) foetal body weight
was observed compared to controls. A slight (5%) but statistically significant
decrease in male foetal body weight was also seen at 20 ppm. No other treatment-
related effects were observed on development. The slight decrease in foetal body
weight in males only at 20 ppm is not considered sufficient magnitude to be
biologically significant. While the statistically significant decrease in foetal body
weight gain at 39 ppm was seen in the presence of a substantial decrease in dam
body weight gain, and is therefore considered to be a secondary non-specific
consequence of severe maternal toxicity.
69
Formaldehyde
In a further inhalation study in Sprague-Dawley rats (Martin, 1990), groups of 25
mated females were exposed (whole-body) up to 10 ppm formaldehyde for 6
hours/day from day 6 to 15 of gestation. At 10 ppm only, a statistically significant
reduction in maternal body weight gain was observed (magnitude not reported).
No treatment-related effects were seen on development. Thus, formaldehyde did
not exhibit developmental toxicity in this study up to a concentration producing
maternal toxicity.
In a dietary study (Hurni & Ohder, 1973), groups of 9-10 pregnant Beagle dogs
were administered formaldehyde solutions in the diet at dose levels corresponding
to approximately 0, 3.1 and 9.4 mg/kg bw/day from day 4 to 56 of gestation. No
developmental or maternal toxicity was observed with formaldehyde at either
dose level, and therefore, there are concerns that dose levels were not maximised
in this study.
A briefly reported dermal study is available in pregnant hamsters (Overman,
1985). Groups of 5-6 pregnant females received a single topical application of
0.5ml of a 37% formaldehyde solution for 2 hours on day 8, 9, 10 or 11 of
gestation. A control group of 4 pregnant females received water. An observed
increase in resorptions in all formaldehyde treated groups (from 3.2% to 8.1%
compared to 0% in controls) was attributed to the severe stress reported in these
animals during treatment with formaldehyde. No other maternal or developmental
effects were seen. However, the lack of information on the amount of
formaldehyde absorbed together with the small group sizes limits the significance
that can be attached to the data.
70 Priority Existing Chemical Assessment Report No. 28
11. Human Health Effects
This chapter is a summary of the health effects of formaldehyde. It is mainly
based on the Concise International Chemical Assessment Document (IPCS,
2002), the Toxicological Profile (ATSDR, 1999) and the SIDS Initial Assessment
Report (OECD, 2002). Articles published post 1998 are summarised in this
chapter.
11.1 Acute toxicity
There are no reports in the literature of human deaths following acute dermal or
inhalation exposure to formaldehyde. Human deaths following ingestion of
formaldehyde have been reported (Kline, 1925; Levison, 1904). However, the
data are from very old case reports (1899-1919) whose reliability cannot be
determined. Information is available from more recent cases, which report
ulceration and damage along the aero-digestive tract following ingestion of
formaldehyde (Allen et al., 1970; Kochhar et al., 1986). Though these cases did
not result in death, significant toxicity was observed, requiring drastic medical
procedures to be undertaken.
In the case reported by Kochhar et al. (1986), a 26 year old woman who
accidentally ingested 45 ml (42.5 grams) 37% formaldehyde solution (equivalent
to approximately 700 mg/kg assuming the woman weighed 60 kg) vomited
streaks of blood immediately following ingestion. Examination 4 days later
showed severe to moderate ulceration of the oesophagus and stomach that
resulted in a feeding jejunostomy being performed. In the case reported by Allen
et al. (1970) a tracheostomy was conducted on a 14 year old boy following
ingestion of approximately 120 ml formaldehyde solution (concentration not
reported, nor whether ingestion was accidental or deliberate). Six days later a
laparotomy revealed multiple areas of gastric necrosis and, hence, a total
gastrectomy and a feeding jejunostomy were performed.
11.2 Irritation/Corrosivity
11.2.1 Skin irritation
The skin irritation potential of formaldehyde solution has been evaluated in a
number of international reviews (IPCS, 1989; IARC, 1995; IPCS, 2002; OECD,
2002) and all report formaldehyde solution to be a skin irritant in humans.
However, this conclusion is based on anecdotal evidence, with a review of the
effects of formaldehyde in solutions on human skin by Maibach (1983)
sometimes cited. This review reported that though formaldehyde solution is said
to have irritant potential based on human experience, little quantitative data
exists. This review also makes the point that since formaldehyde solution is
known to cause skin sensitisation, reported irritant effects may be sensitisation
effects. Skin rashes were reported by embalmers in the NICNAS survey.
71
Formaldehyde
Acute controlled exposure studies of volunteers exposed to airborne
formaldehyde at concentrations up to 3 ppm have not found increased reporting
of skin irritation symptoms (ATSDR 1999).
11.2.2 Sensory irritation
Sensory irritation is the result of the chemical stimulating the trigeminal nerve
endings in the cornea and nasal mucosa, which evokes a stinging or burning
sensation in the eyes and upper respiratory tract (nose and throat). This is a
receptor mediated mode of action and occurs at relatively low concentrations.
Sensory irritation is different to eye and skin irritation/corrosivity used for hazard
classification (Section 12.2) and also different from the irritation leading to
cytoxicity, hyperplasia and nasal tumours (Section 10.4.1). These latter examples
are a result of physical damage to the cells, whereas sensory irritation is a nerve
response.
Formaldehyde exposure has long been associated with irritation to the eyes and
upper respiratory tract. Repeated complaints, such as sore eyes and throat by
embalmers were reported in the NICNAS survey.
In more recent years, chamber studies have investigated sensory irritation
following short-term exposures to known low levels of gaseous formaldehyde.
In chamber studies in healthy and asthmatic volunteers, mild to moderate eye
irritation was self-reported following exposure to formaldehyde levels ranging
from 0.25 to 3 ppm (0.3 to 3.6 mg/m3) for up to 5 hours, though exposures were
generally < 3 hours. Overall, the data from these studies indicate that eye
irritation is a more sensitive parameter than nose and throat irritation which was
generally self-reported at concentrations > 1 ppm (Weber-Tscopp et al., 1977;
Andersen & Molhave, 1983; Bender et al., 1983; Day et al., 1984; Schachter et
al., 1986; 1987; Sauder et al., 1986; 1987; Green et al., 1987; 1989; Kulle et al.,
1987; Kulle, 1993; Witek et al., 1987). A summary of these studies can be found
in Table 11.1.
It should be noted that a study by Pazdrak et al. (1993) is not included in Table
11.1 because of major methodological shortcomings (e.g. exposures could not be
verified as information was not provided regarding the techniques used to
generate the aerosol or the methods used to measure formaldehyde). A study by
Krakowiak et al. (1998) also has methodological shortcomings and is also not
included.
Sensory irritation due to exposure to formaldehyde has rapid onset (Sauder et al.
1987, Yang et al. 2001) and the intensity of effect does not appear to significantly
increase with longer exposures (Sauder et al. 1987). This is in accord with the
theoretical considerations of sensory irritation where the intensity of response is
dependent on the concentration of the substance and not the duration of exposure.
A study is available where exposure to formaldehyde was through modified eye
goggles (Yang et al., 2001). Eight volunteers were exposed to 0, 1.65, 2.99 or
4.31 ppm formaldehyde for 5 minutes and eye irritation was self-reported.
Individual scores were not reported. Although the higher formaldehyde
concentrations resulted in greater eye irritation scores, compared to control
exposures irritancy scores were only statistically significant at 1.65 and 4.31 ppm,
and only 1.5, 2.5 and 3.0 minutes after the onset of exposure. A study is available
72 Priority Existing Chemical Assessment Report No. 28
where exposure was via a facemask (Reed & Frigas, 1984). Thirteen subjects who
had reported respiratory symptoms to previous exposures of formaldehyde were
exposed for 20 minutes to concentrations up to 3 ppm (3.6 mg/m3) formaldehyde.
No significant effect was seen on pulmonary function, while self-reports of eye,
nose and throat irritation occurred as frequently with clean air as with
formaldehyde. A summary of these studies is included in Table 11.1.
With the exception of Weber-Tschopp et al. (1977), Bender et al. (1983), Pazdrak
et al. (1993) and Yang et al. (2001), the studies in Table 11.1 also determined the
effect of formaldehyde exposure on pulmonary functions. No statistically
significant exposure-related effect was seen on forced vital capacity (FVC),
forced expiratory volume in 1.0 second (FEV1.0), peak expiratory flow rate
(PEFR), or the maximal flow at 50% of the vital capacity (MEF50%) in healthy
and asthmatic subjects exposed up to 2.0 ppm (2.4 mg/m3) for up to 3 hours.
In contrast, small but statistically significant decreases were seen in FEV1.0 (2 %)
and FEFR (7%) in 9 healthy volunteers after 30 minutes exposure to 3 ppm (3.6
mg/m3) formaldehyde but not after 1 or 3 hour exposure periods (Sauder et al.,
1986). In a further study by this project team, using the same exposure level and
duration, no effects were observed in asthmatics (Sauder et al., 1987). In a study
by Green et al. (1987), exposure to 3 ppm formaldehyde for approximately 1-2
hours resulted in small but statistically significant decreases (2% to 3%) in FEV1.0
and FVC in 22 healthy volunteers. Conversely, no significant deficits in
pulmonary function were seen in 16 asthmatic subjects similarly exposed. In a
further study by Green et al. (1989), although there was no effect on FVC, a small
(6%) decrease in forced expiratory flow rate between 25% and 75% FVC
(FEFR25-75) was seen in 24 healthy volunteers exposed to 3 ppm formaldehyde for
approximately 2 hours.
Overall, the weight of evidence indicates there is no effect on pulmonary function
at concentrations up to 3 ppm, the highest exposure level tested.
A study is available investigating mucous flow rate in the nasal cavity of 16
volunteers exposed to 0.25, 0.4, 0.8 or 1.7 ppm (0.3, 0.48, 0.96 or 2.0 mg/m3)
formaldehyde for 4-5 hours (Andersen & Molhave, 1983). Compared to control
values, the mucous flow rate was reduced at 0.25 ppm and above. However, the
response did not increase at concentrations above 0.4 ppm. The relevance of this
finding to human health is unclear.
Data are available from community (Ritchie & Lehnen, 1987; Broder et al., 1988)
and workplace studies (Alexandersson & Hedenstierna, 1988; 1989; Holmstrom
& Wilhelmsson, 1988; Horvath et al., 1988; Holness & Nethercott, 1989; Uba et
al., 1989). However, for determining the irritant potency of formaldehyde, the
data from these uncontrolled environments are not considered as reliable as data
from controlled chamber studies, due primarily to the unknown contribution of
other substances. The workplace and community studies are summarised in
Section 11.4.
An extensive review of chamber, community and workplace studies to
formaldehyde was recently conducted (Bender, 2002). Overall, this review
concluded that it is not possible to identify a specific threshold for irritation, due
primarily to the self-reporting of irritation that has no diagnostic accuracy. This is
demonstrated by reports of irritation with placebo (zero) exposures in chamber
(see Table 11.1) and workplace studies (Holness & Nethercott, 1989). However,
73
Formaldehyde
Bender (2002) went on to state that using chamber studies, which provide the
highest quality data, some individuals (5% to 20%) begin to sense irritation from
0.5 to 1 ppm (0.6 to 1.2 mg/m3), though the reported response rate is often similar
in controls (i.e. a response rate of 20% to 30% is not unusual). At levels of 1 ppm
(1.2 mg/m3) and greater, one can attribute responses to formaldehyde with greater
certainty. Furthermore, although asthmatics are thought to be more sensitive to
irritants, studies by Green et al. (1987), Sauder et al. (1986; 1987) and Witek et
al. (1987) have demonstrated that at concentrations of 2 - 3 ppm (2.4 - 3.6 mg/m3)
for up to 3 hours, asthmatics were no more sensitive to formaldehyde than non-
asthmatics.
Therefore, although formaldehyde is a known eye and upper respiratory tract
irritant in humans, the limitations of the available data and subjective nature of
sensory irritation do not allow identification of a definitive no-observed-effect
level (NOEL). The data from chamber studies demonstrate that the sensory
irritation responses at levels of 1 ppm (1.2 mg/m3) can definitely be attributed
to formaldehyde. Some individuals begin to sense irritation from 0.5 ppm (0.6
mg/m3), although the response rate is often similar to that reported in controls.
Although there is limited evidence that some individuals report sensory irritation
at concentrations as low as 0.25 ppm (0.3 mg/m3) the data are very unreliable.
Therefore, the LOEL is considered to be 0.5 ppm.
The odour threshold of gaseous formaldehyde varies widely ranging from 0.05 to
1.0 ppm. However, for most people the odour threshold is in the 0.5 to 1.0 ppm
range (OECD, 2002).
11.3 Sensitisation
11.3.1 Skin
There are many published case reports and clinical studies that clearly indicate
aqueous formaldehyde to be a human skin sensitiser (Lindskov, 1982; Andersen
& Molhave, 1983; Cronin, 1991; Ebner & Kraft, 1991; Liden et al., 1993;
Trattner et al., 1998). Indeed, formaldehyde solution has long been known as a
cause of contact allergy and is included in all standard series for patch testing.
Data from several recent patch tests studies are presented below, and support the
conclusion that formaldehyde is a skin sensitiser.
Over the last 10 years, 1691 workers with suspected contact dermatitis were
referred to the Occupational Dermatology Research and Education Centre
(ODREC) in Melbourne and were routinely patch tested using a standard series of
30 common allergens including formalin and formaldehyde releasing
preservatives. In addition, formaldehyde resins were included in the test when
clinically relevant. The results are summarised in Table 11.2.
74 Priority Existing Chemical Assessment Report No. 28
Table 11.1: Irritative effect of gaseous formaldehyde in humans
Duration Physical Number of Results Reference
activity volunteers
90 min None 15 asthmatics (7 Pulmonary irritation: No significant change to FEV1.0 following exposure to 0.007, 0.1 or 0.7 ppm Harving et
male and 8 formaldehyde. al.,1990
females, all non- Comment: no significant correlation between exposure levels and change in FEV1.0 in the group as a
smokers) whole or volunteers with the highest histamine reactivity. Effects of sensory irritation were not reported.
Andersen &
5 hr None 16 (11 males and Eye irritation
Molhave,
5 females) of and/or dry
1983
which 5 were nose/throat
19 %
smokers 0.25 ppm
31 %
0.4 ppm
94 %
0.8 ppm
94%
1.7 ppm
Pulmonary irritation: No significant change in FVC, FEV1.0 and FEFR25 75 following exposure to 0.25,
0.4, 0.8 or 1.7 ppm formaldehyde.
Comment: Individuals were asked to rate their level of discomfort. At all exposure levels, the highest
individual rating was `discomfort', which was the middle rating. The average rating for all exposures was
`slight discomfort'. Following the first 2 hours exposure, 0.25 ppm caused more `discomfort' that 0.4 ppm.
The results are not published in a peer reviewed journal.
Bender et
6 min None 28 at 0 ppm, 12 Eye irritation
al., 1983
at 0.35 ppm, 26 and/or dry
at 0.56 ppm, 7 at nose/throat
Not applicable
0 ppm
0.70 ppm, 5 at
42 %
0.35 ppm
0.90 ppm and 27
54 %
at 1.00 ppm 0.56 ppm
57 %
0.70 ppm
60 %
0.90 ppm
74 %*
1.00 ppm
Comment: Eye irritation measured as percentage of subjects whose response time to formaldehyde was
less than response time to clean air. Individuals were known to respond to formaldehyde (previously
reporting eye irritation) and served as own controls.
75
Formaldehyde
Table 11.1: Irritative effect of gaseous formaldehyde in humans (continued)
Duratio Physical Number of Results Reference
n activity volunteers
Kulle, 1993;
3 hr During 19 (10 males and Eye irritation Odour perception Nose/throat irritation
Kulle et al.,
exposure to 2 9 females) non- 0 ppm 5% 5% 16 %
1987
ppm smokers exposed 0.5 ppm 0% 40 %** 10 %
26 % 26 % 5%
intermittent to each 1.0 ppm
moderate concentration 2.0 ppm 53 %*** 58 %** 37 %
exercise for 8 except 0.5 ppm 3.0 ppm 100%*** 78 %** 22 %
min every half (10 volunteers) Pulmonary irritation: No significant dose response in pulmonary function was observed (no further
hour and 3 ppm (9 details available).
volunteers). Comment: authors estimated threshold values were
Odour perception: < 0.5 ppm
Eye irritation: 0.5 1.0 ppm
Nose/throat irritation: 1.0 ppm
90 min None 18 (9 had Day et al.,
Eye and throat irritation: Following exposure to 1 ppm formaldehyde 83 % and 28 % of volunteers
previous 1984
reported eye and throat irritation, respectively.
complaints of Pulmonary irritation: No statistically significant change on FVC, FEV1.0 and FEFR25 75 following
effects to UFFI#) exposure to 1 ppm formaldehyde.
Comment: complaints of eye and throat irritation were common in both groups (i.e. those previously
complaining of effects to UFFI and those who had not) exposed to formaldehyde.
1.5 min None 48 Volunteers exposed to concentrations ranging from 0.3 4.0 ppm formaldehyde. The authors report that Weber-
the irritation threshold was situated between 1 and 2 ppm. No further data available. Tschopp et
al., 1977
5 min None 8 (4 males and 4 Eye irritation: Mild to moderate irritation ratings seen following exposure to 1.65, 2.99 and 4.31 ppm. Yang et al.,
females) of Severity was greatest 1.0 1.5 minutes after the onset of exposure and then declined. At 5 minutes, eye 2001
which 1 male irritation ratings to 1.65 ppm and clean air (0 ppm) were comparable.
and 1 female Comment: Eye irritation reported to clean air with a slight increase in intensity seen with exposure
were smokers duration.
76 Priority Existing Chemical Assessment Report No. 28
Table 11.1: Irritative effect of gaseous formaldehyde in humans (continued)
Duration Physical Number of Results Reference
activity volunteers
40 min R = rest 15 non-smokers Schachter et
Slight to severe:
E = 10 min al., 1986
Eye irritation Odour perception Nose irritation Throat irritation
moderate 0 ppm (R) 0% 47 % 27 % 13 %
exercise 0 ppm (E) 7% 13 % 13 % 0%
(conducted on 2.0 ppm (R) 53 % 80 % 40 % 27 %
a different 2.0 ppm (E) 53 % 87 % 33 % 33 %
day) Pulmonary irritation: Pulmonary function measured 5, 15, 20 and 40 minutes after the onset of
exposure. Compared to baseline values, no statistically significant decreases in FVC, FEV1.0, MEF50%
and MEF40% were seen with exposure to 2 ppm formaldehyde during both resting and exercise.
Comment: interpretation of the results by Paustenbach et al., (1997): eye irritation more sensitive
parameter than nose and throat irritation.
40 min R = rest 15 laboratory Schachter et
Slight to severe:
E = 10 min workers, exposed al., 1987
Eye irritation Odour perception Nose irritation Throat irritation
moderate long-term to 0 ppm (R) 0% 47 % 7% 7%
exercise formaldehyde 0 ppm (E) 0% 33 % 0% 0%
(conducted on 2.0 ppm (R) 47 % 80 % 0% 0%
a different 2.0 ppm (E) 40 % 87 % 7% 0%
day) Pulmonary irritation: pulmonary function measured 5, 15, 20 and 40 minutes after the onset of
exposure. Compared to baseline values, no statistically significant decreases in FVC, FEV1.0, PEFR,
MEF50% and MEF40% were seen with exposure to 2 ppm formaldehyde during both resting and
exercise.
Comment: authors concluded that persons exposed long-term to formaldehyde had similar upper
respiratory symptom frequency and severity as persons not previously exposed (see Schachter et al.,
1986).
77
Formaldehyde
Table 11.1: Irritative effect of gaseous formaldehyde in humans (continued)
Number of Results Reference
Duration Physical
activity volunteers
40 min R = rest, 15 asthmatics Witek et al.,
Eye irritation Odour perception Nose irritation Throat irritation
E = 10 min 0 ppm (R) 7% 33 % 20 % 27% 1987
moderate 0 ppm (E) 14 % 57 % 14 % 21 %
exercise 2.0 ppm (R) 73 % 100 % 47 % 33 %
2.0 ppm (E) 36 % 100 % 36 % 43%
Pulmonary irritation: Although some reductions were seen to FEV1.0 and MEF50% over the exposure
duration they occurred randomly with exposure to clean air and 2 ppm formaldehyde. No significant
reduction was seen in FVC.
Comment: authors considered that the observed reductions in pulmonary function probably represented
airway lability in asthmatics.
Green et al.,
22 healthy
1 hr Healthy Symptoms scored moderate to severe:
1987
persons (H)
persons: Eye irritation Odour Perception Nose/throat irritation
16 asthmatics
intermittent 0 ppm 0% 0% 0%
(A)
strenuous 3.0 ppm (H) 27 %** 23 %** 32 %**
activity 3.0 ppm (A) 19 %** 31 %** 31 %**
Pulmonary irritation: Pulmonary function measured prior to exposure and 17, 25, 47 and 55 minutes
Asthmatics:
after the onset of exposure. In healthy volunteers, and compared to control exposures, a statistically
intermittent
significant decrease of 2 %* on FCV was seen after 47 minutes to 3ppm and of 3 %* on FVC, FEV1.0 and
moderate
FEV3.0 after 55 minutes exposure. No statistically significant reduction was seen at other assessment times
exercise
or on FEFR25 75 in healthy volunteers, or on FVC, FEV1.0, FEV3.0 and FEFR25 75 in asthmatics.
Comment: asthmatics were not more sensitive to the irritant effects of formaldehyde than non-asthmatics.
78 Priority Existing Chemical Assessment Report No. 28
Table 11.1: Irritative effect of gaseous formaldehyde in humans (continued)
Duration Physical Number of Results Reference
activity volunteers
2 hrs Intermittent 24 healthy Eye, nose and throat irritation: Compared with exposures to clean air, a statistically significant effect Green et al.,
physical persons (non- was seen at all time points on eye, nose and throat irritation with exposure to 3 ppm formaldehyde. 1989
exercise smokers) Pulmonary function: Pulmonary function measured prior to exposure and 20, 50, 80 and 110 minutes
after the onset of exposure. Compared to control exposures, a statistically significant decrease (< 10 %) in
FEFR25 75 was only reported with 50 and 80 minutes exposure to 3 ppm formaldehyde. No statistically
significant reductions were seen on FVC, FEV1.0 or FEV3.0.
Comment: a significant formaldehyde effect on odour was also reported (no further details available).
Sauder et
3 hr Intermittent 9 healthy Individual scores for severity ranged from none to moderate:
al., 1986
physical persons (non- Eye irritation Odour Perception Nose/throat irritation
exercise smokers) 0 ppm 0.00 0.22 0.22
3.0 ppm 0.78** 1.22**** 1.33**
Pulmonary irritation: Pulmonary function measured prior to exposure and 15, 30, 60, 120 and 180
minutes after the onset of exposure. Compared to control exposures, a statistically significant decrease of
2 %* on FEV1.0 and 7 %** on FEFR25 75 was seen only with 30 minutes exposure to 3.0 ppm
formaldehyde. No statistically significant reduction was seen on FVC.
Comment: individual responses to formaldehyde exposure ranged from 5% to +1% for FEV1.0 and
14% to +2% for FEFR25 75.
3 hr Intermittent 9 asthmatics Individual scores for severity ranged from none to severe: Sauder et
physical (non-smokers) 0 ppm al., 1987
Eye irritation Nose/throat irritation
exercise 3.0 ppm 0.00 0.55
1.33** 1.00
Pulmonary function: Pulmonary function measured prior to exposure and 15, 30, 60, 120 and 180
minutes after the onset of exposure. Compared to control exposures, no statistically significant decrease in
FVC, FEV1.0 or FEFR25 75 at any assessment time with exposure to 3.0 ppm formaldehyde.
Comment: asthmatics were not more sensitive to the irritant effects of formaldehyde than non-asthmatics
(see Sauder et al., 1986).
79
Formaldehyde
Table 11.1: Irritative effect of gaseous formaldehyde in humans (continued)
Duration Physical Number of Results Reference
activity volunteers
20 min None 13 persons (2 Eye, nose and throat irritation: Self-reports of eye, nose and throat irritation occurred as frequently with Reed &
males and 11 clean air [symptoms were not reported for the different exposure levels (0.1, 1.0 and 3.0 ppm)]. Frigas, 1984
females) with Pulmonary function: Pulmonary function measured prior to exposure, immediately after and up to 24
symptoms of hours after the onset of exposure. Compared with exposures to clean air, no significant decrease reported
asthma. in FEV1.0 or FEFR25 75 with exposure concentrations up to 3.0 ppm formaldehyde.
Comment: Of the 13 subjects, 3 and 5 subjects were not challenged as they had unequivocal or
convincing histories of asthma, respectively, 2 subjects were not challenged with methacholine because of
time restraints, and 1 of remaining 3 gave a positive challenge to methacholine.
* Significantly different from control (p < 0.05)
** Significantly different from controls (p < 0.01)
*** Significantly different from control (p < 0.005)
**** Significantly different from controls (p < 0.02)
#
Complained of various non-respiratory adverse effects from the urea formaldehyde foam insulation (UFFI) in their homes.
FEFR25-75, Forced expiratory flowrate between 25% and 75% FVC
FEV1.0, Forced expiratory volume in one second
FVC, Forced vital capacity
MEF50%, Maximum expiratory flow at 50% of vital capacity
PEFR, Peak expiratory flow rate
Ppm, Parts per million
80 Priority Existing Chemical Assessment Report No. 28
Over a 2-year period in a Danish dermatology clinic, of 40 patients who gave a
positive patch test to their own cosmetic products, 5 (12.5%) gave a positive
result to formaldehyde (Held et al., 1999). In a Finish dermatology clinic, 82 of
1414 patients (5.8%) patch tested over a 6-year period with a modified European
standard series gave a positive result to 1% formaldehyde solution (Kanerva et
al., 1999). As part of a study on occupational skin diseases, 223 nurses were patch
tested with a supplemented European standard series and prick tests conducted
for common allergens (Kiec-Swierczynska, 2000). Prick tests indicated 80 (36%)
nurses were atopic. A positive patch test to 1.0% formaldehyde solution was
observed in 46 nurses (20.6%).
A case report is available of a 30-year old man who developed occupational
allergic dermatitis working in a clothing warehouse (Cockayne et al., 2001).
Formaldehyde resins, which were used in the textile industry, were suspected.
Positive patch tests were reported with aqueous formaldehyde and formaldehyde
resin.
Table 11.2: Case report of skin sensitisation by ODREC*
Type of Formaldehyde Product Tested No. of Positive Tests
51
Formalin
Formaldehyde releasing preservatives
11
DMDM Hydantoin
Imidazolidinyl urea (Germall 115) 23
Diazolidinyl urea (Germall II) 27
Dowicil 200 (Quarternium 15) 35
Formaldehyde resins
5
Melamine formaldehyde
Phenol formaldehyde resin (Novolac) 2
Phenol formaldehyde resin 6
Urea formaldehyde 3
4-tert butyl phenol formaldehyde resin 18
*All workers were tested for formalin, but not all were tested for formaldehyde resins.
The names in bracket are trade names.
A number of human studies were conducted to induce (Marzulli & Maibach,
1974) and elicit skin sensitisation in sensitised individuals [Marzulli & Maibach,
1973 cited in the IPCS review (1989); Jordan et al., 1979; Hilton et al., 1998].
The CICAD (IPCS, 2002) concluded that the concentration of formaldehyde
likely to elicit contact dermatitis reactions in hypersensitive individuals may be as
81
Formaldehyde
low as 30 mg/L (0.003%). ATSDR (1999) concluded that allergic skin responses
in sensitised individuals exposure to concentrations below 0.25% to 0.05%
formaldehyde in solution are rare.
There are no human data to suggest that exposure to formaldehyde gas causes
skin sensitisation.
11.3.2 Respiratory
Bronchial Challenge tests
Data are available from studies that conducted bronchial challenge tests with
gaseous formaldehyde on workers with asthmatic symptoms, to determine
whether the observed asthma was attributable to this chemical. Single and/or
double blind bronchial challenge tests conducted in 13 workers exposed to
formaldehyde for up to 9 years (Frigas et al., 1984), and a single worker who had
not been exposed to formaldehyde for 3 years (Grammer et al., 1993), were
negative. In the Frigas et al. (1984) study, no reaction to bronchial challenge with
formaldehyde was seen in a worker who had hyperresponsive airways (i.e.
positive bronchial challenge to methacholine).
Positive bronchial challenges to formaldehyde have been observed in workers
with asthmatic symptoms. Over a 6-year period, 12 of 230 patients referred to a
clinic and had reportedly been exposed to formaldehyde gave positive bronchial
challenge tests to formaldehyde (Nordman et al., 1985). Only one of these 12
tests was conducted in a blind manner. Furthermore, 9 of the 12 responders had
hyperresponsive airways as shown by positive bronchial challenge tests to
histamine or methacholine.
A positive bronchial challenge to formaldehyde was observed in a recent study in
a single worker who had hyperresponsive airways (positive bronchial challenge to
methacholine) and was exposed to several chemical agents whose exact
components were unknown but did include formaldehyde (Kim et al., 2001).
Similarly, though 7 of 15 workers (47%) gave positive responses to formaldehyde
in open bronchial challenge tests (Burge et al., 1985), bronchial
hyperresponsiveness was observed in 2 responders and 1 non-responsive subject.
Additionally, co-exposure to other chemicals including isocyanates and hardwood
dust had occurred in 12 workers, of which 3 had given a positive challenge to
formaldehyde.
A study was conducted with three nurses, a technician and a visitor to a dialysis
unit who were all regularly exposed to formaldehyde and had developed
asthmatic symptoms (Hendrick & Lane, 1975, 1977). Positive bronchial
challenges to formaldehyde were seen in 2 of the nurses, one of whom had pre-
existing asthma. In a follow up study on these two nurses 2 years later, a positive
bronchial challenge to formaldehyde was only observed in the nurse with pre-
existing asthma (Henderick et al., 1982).
Open bronchial challenge tests to formaldehyde were conducted in 7 staff from an
endoscopy unit and x-ray department who had asthmatic symptoms associated
with glutaraldehyde exposure (Gannon et al., 1995). Positive responses were seen
in 3 workers, which included the only 2 individuals with co-exposure to
formaldehyde. This result suggests possible cross-reactivity between
formaldehyde and glutaraldehyde.
82 Priority Existing Chemical Assessment Report No. 28
Data are also available for healthy workers and volunteers. Negative bronchial
challenge tests were observed in 15 healthy workers exposed to formaldehyde for
between 1 to 21 years (Schachter et al., 1985). Bronchial challenges with
formaldehyde in healthy volunteers were also negative (Sauder et al., 1986).
Additionally, negative bronchial challenges were seen in 9 people who
complained of adverse health effects from the urea formaldehyde foam insulation
used in their homes (Day et al., 1984), and in asthmatic subjects with
hyperresponsive airways (Sheppard, 1984; Harving et al., 1990) and those
without hyperresponsive airways (Witek et al., 1987).
Clinical diagnosis data
Studies focusing on the clinical diagnosis of asthma in patients, where no
bronchial challenge test was performed to identify the agent responsible, are also
available.
In studies determining the effect on lung function following workplace exposure
to gaseous formaldehyde, no change in lung function was seen in a pathologist
who suffered chest tightness (Kwong et al., 1983). Comparison of formaldehyde-
exposed workers (with or without symptoms) with those not exposed revealed no
changes in lung function in one study (Nunn et al., 1990), and a slight decrease
over shift in another (Alexandersson et al., 1982). Decreased lung function was
seen in a further study in (mostly) symptomatic workers compared to unexposed
controls, though no changes in parameters were seen over a working day, week or
weekend (Schoenberg & Mitchell, 1975).
Epidemiology studies
In a Swedish population-based case-control study of 20 000 subjects, 15 813
(aged 21 - 51 years) responded to a mailed questionnaire on occupational
exposure, asthma, respiratory symptoms, smoking and atopy (Toren et al., 1999).
A total of 362 subjects with physician diagnosed asthma or self-reported asthma-
like symptoms were compared against a total of 2044 controls. Occupational
exposure to gaseous formaldehyde (information on exposure levels not obtained)
was not associated with an increased risk of asthma.
An Australian case-control study investigated the increased risk of asthma in
children from exposure to gaseous formaldehyde in 80 households (Garrett et al.,
1999). A total of 148 children aged 7 - 14 were investigated, of which 53 (36%)
were diagnosed as asthmatic by a doctor. Information was obtained from parental
interviews on parental allergy, parental asthma and presence of pets. Household
formaldehyde levels were determined by passive sampling; mean of 12.6 ppb
(15.1 ”g/m3), with a maximum of 111 ppb (133 ”g/m3). After adjustment for
confounding factors, such as parental asthma, no association was seen between
asthma and formaldehyde exposure. However, there was a weak, but not
statistically significant, trend to more children with respiratory symptoms in
higher formaldehyde exposure groups. In a further Australian case-control study
(Rumchev et al., 2002), household formaldehyde levels were determined by
passive sampling in the homes of 88 children aged 6 months to 3 years who were
diagnosed at hospital with asthma, and compared with 104 community controls.
Cases had a statistically significant higher mean formaldehyde exposure
compared to controls, 32 ppb (38 ”g/m3) and 20 ppb (24 ”g/m3), respectively.
83
Formaldehyde
After adjustment for confounding factors, such as indoor air pollutants, relative
humidity, indoor temperature, atopy, family history of asthma, age, sex socio-
economic status, pets and environmental tobacco smoke, it was reported that
children exposed to formaldehyde levels of 60 ”g/m3 have a 39% increase in odds
of having asthma compared to children exposed to < 10 ”g/m3 (OR estimated to
be approximately 1.4 95% CI 1.1-1.7 from data presented in a graph). However,
considering the marginally increased risk observed, together with the number of
potential sources of bias, such as selection bias and validity of diagnosis in the
young, this study is not considered to provide sufficiently robust evidence of an
association between formaldehyde exposure and increased risk of asthma in
children.
Immunology data
Specific immunoglobulin E (IgE) antibodies to formaldehyde-human serum
albumin conjugates have occasionally been detected in workers (Patterson et al.,
1986; Kramps et al., 1989; Grammer et al., 1993; Wantke et al., 2000) and
children exposed to formaldehyde from a school building (Wantke et al., 1996),
though without any correlation with respiratory symptoms. Other studies have
failed to detect the antibody (Nordman et al., 1985; Patterson et al., 1986;
Thrasher et al., 1987; Kramps et al., 1989; Grammer et al., 1990; Kim et al.,
1999; 2001; Baba et al., 2000). Similarly, specific IgG antibodies to the same
conjugate have only occasionally been observed in exposed people (Grammer et
al., 1990, 1993; Kim et al., 1999).
11.4 Non-neoplastic effects
11.4.1 Respiratory-related effects
The effect of gaseous formaldehyde on respiratory symptoms, pulmonary
function and morphology of the nasal tract has been investigated in populations
exposed in occupational and community environments.
Occupational exposure
Conflicting results have been observed in studies investigating the effect of
occupational exposure to formaldehyde on pulmonary functions. In a number of
studies of chemical, furniture and plywood workers, pre-shift reduction of up to
12% in lung function parameters (e.g., forced vital capacity, forced expiratory
volume, forced expiratory flow rate) were reported for mean formaldehyde
concentrations that were < 0.42 ppm (< 0.5 mg/m3) (Alexandersson &
Hedenstierna, 1988; 1989; Herbert et al., 1994; Holmstrom & Wilhelmsson,
1988) and, in one study at 1.13 ppm (1.3 mg/m3) (Malaka & Kodama, 1990).
Changes were generally small and transient over a work shift, with a cumulative
effect over several years that was reversible after relatively short periods without
exposure (e.g.. 4 weeks); effects were more obvious in smokers than non-smokers
(Alexandersson & Hedenstierna, 1989). In the only study where it was examined,
a dose-response relationship between formaldehyde exposure and decreased lung
function was observed in a group of 21 workers in wood product manufacturing
exposed to mean formaldehyde concentrations of 0.35 0.42 ppm (0.42 0.50
mg/m3) (Alexandersson & Hedenstierna, 1989). In contrast, no conclusive
evidence of diminished lung function was observed in studies of larger numbers
84 Priority Existing Chemical Assessment Report No. 28
of workers (89 -125) in resin manufacturing (Nunn et al., 1990), funeral service
industries (Holness & Nethercott, 1989) and wood product manufacturing
(Horvath et al., 1988), who were exposed to higher mean formaldehyde
concentrations (up to > 2 ppm [> 2.4 mg/m3]).
These studies also examined symptoms of respiratory irritancy in workers. A
higher prevalence of symptoms, such as nose, throat and eye irritation, cough
and/or `wheeze' was seen in workers exposed to formaldehyde compared to
controls in the studies by Alexandersson & Hedenstierna (1988, 1989); Herbert et
al. (1994); Holmstrom & Wilhelmsson (1988); Holness & Nethercott (1989);
Malaka & Kodama (1990); Uba et al. (1989); and Wilhelmsson & Holmstrom
(1992). However, these studies generally assessed a small numbers of workers
(38 103) and it was not possible to meaningfully examine exposure response. A
study by Horvath et al. (1988) did conduct such an analysis. In this study, a dose-
response relationship was seen between formaldehyde concentration and
prevalence of symptoms. Workers in this study (totalling 109) were exposed to
0.17 - 2.93 ppm (0.20 3.5 mg/m3) formaldehyde. In contrast, in a study by Nunn
et al. (1990) there was no evidence to suggest that respiratory symptoms (such as
wheeze) were more common in 125 workers exposed to concentrations up to and
greater than 2.0 ppm (> 2.4 mg/m3) formaldehyde compared to controls.
Data are also available from studies that have investigated the histological
changes within the nasal epithelium of workers occupationally exposed to
gaseous formaldehyde.
In a case-control study of 15 workers in a plywood factory exposed to 0.08 0.6
ppm (0.1 - 0.7 mg/m3) formaldehyde through use of urea-formaldehyde glue, a
statistically significant increase in the incidence of squamous metaplasia was seen
in workers exposed to formaldehyde (Ballarin et al., 1992). However, there was
also co-exposure to respirable wood dust whose contribution to these findings
cannot be excluded. The most comprehensive study, and the only one with
individual estimates of exposure based on area and personal sampling,
investigated histological effects in 70 workers at a formaldehyde manufacturing
plant and 36 controls (Holmstrom et al., 1989). A statistically significant increase
in the mean histological score for morphological changes was seen in
formaldehyde-exposed workers compared to controls; mean exposure 0.25 ppm
(0.3 mg/m3) formaldehyde, with frequent short peaks of exposures above 0.8 ppm
(0.96 mg/m3). This study also examined histopathological changes in the nasal
epithelium in workers exposed to both 0.17 0.25 ppm (0.20 - 0.3 mg/m3)
formaldehyde and wood dust, and found no significant changes when compared
to controls. A further study of 75 workers exposed to 0.08 0.9 ppm (0.1 - 1.1
mg/m3) formaldehyde (with peaks of 4.2 ppm [5.0 mg/m3] or 0.5 0.9 ppm [0.6 -
1.1 mg/m3]) and wood dust observed statistically significant increases in mean
histopathological scores for both exposure groups compared to controls (Edling et
al., 1988). There was no significant variation between the two exposure groups
themselves. The mean histopathological score was also approximately the same
regardless of duration of exposure, although this may be attributable to the small
numbers of the sub-groups (i.e. 23 - 28).
In contrast, a cross-sectional study of 80 workers in paper processing plants
exposed to 0.02 - 2 ppm (0.024 - 2.4 mg/m3) gaseous formaldehyde through use
of phenol-formaldehyde resins reported no association between "abnormal"
cytology and formaldehyde exposure after controlling for age (Berke, 1987). In a
85
Formaldehyde
case-control study, no significant difference was seen in the incidence of
histopathological findings in 37 workers at a formaldehyde manufacturing plant
exposed to 0.5 - 2 ppm (0.6 -2.4 mg/m3) formaldehyde, though the degree of
metaplastic alteration was more pronounced among formaldehyde exposed
workers (Boysen et al., 1990).
Community exposure
In a survey of 1726 occupants of homes containing urea-formaldehyde foam
insulation (UFFI) and 720 residents in control homes with median formaldehyde
levels of 38 ppb (maximum 227 ppb) and 31 ppb (maximum 172 ppb),
respectively, no effects on lung parameters were observed (Broder et al., 1988).
In contrast, levels of peak expiratory flow rates (PEFR) decreased linearly in 298
children (6 - 15 years old) exposed to 60 - 140 ppb formaldehyde in the home
(Krzyzanowski et al., 1990). The decrease at 60 ppb was equivalent to 22% of the
PEFR of non-exposed children while at 30 ppb it was 10%. In the same survey, a
small transient decrement in PEFR was seen in adults (> 16 years old) only in the
morning, and mainly in smokers.
The prevalence of self-reported symptoms, such as eye, nose and throat irritation
was determined in these community studies. There were increases in prevalence
of symptoms primarily at exposure > 120 ppb (> 0.14 mg/m3) in the study by
Broder et al. (1988). However, in this study, health complaints of residents in
UFFI homes significantly decreased after remediation (i.e. UFFI removal)
although levels of formaldehyde were unchanged. No increase in self-reported
symptoms was observed in the study by Krzyzanowski et al. (1990), though, in
contrast, the prevalence in physician-reported chronic bronchitis or asthma
increased in children (6 - 15 years old) exposed to 60 140 ppb formaldehyde,
especially in those exposed to environmental tobacco smoke. A further study
investigated the reported health complaints (eye irritation, nose/throat irritation,
and headaches) in nearly 2000 residents in mobile and conventional homes
(Ritchie & Lehnan, 1987). A higher prevalence for all symptoms was reported at
concentrations > 300 ppb (> 0.36 mg/m3) formaldehyde, with eye irritation the
most frequently reported health effect; 89% of residents exposed to this
concentration reported eye irritation. The proportion of the study group reporting
eye irritation below 100 ppb (0.12 mg/m3) was low, at 1% of residents.
Additionally, in the study investigating community exposure by Broder et al.
(1988), a small transient increase in the incidence of nasal epithelial squamous
metaplasia was seen in UFFI-subjects intending to have their UFFI removed;
18% compared to 15% in controls.
11.4.2 Neurological effects
Evidence of neurological symptoms and impaired performance in
neurobehavioral tests were seen in cross-sectional surveys of histology
technicians exposed to gaseous formaldehyde in a series of studies by the same
investigators (Kilburn et al., 1985b, 1987, 1989; Kilburn & Warshaw, 1992;
Kilburn, 1994). However, co-exposure to solvents, such as xylene, toluene and
chloroform, which are known to produce neurotoxic effects in humans, prevent
any reliable conclusions being drawn from the data on the neurotoxic potential of
formaldehyde.
86 Priority Existing Chemical Assessment Report No. 28
11.5 Genotoxicity
Surveys are available that investigated genetic effects in peripheral lymphocytes,
nasal and buccal mucosal cells of workers occupationally exposed to
formaldehyde.
In studies assessing peripheral lymphocytes, no increased incidence in either
chromosome aberrations, sister chromatid exchanges (SCE) or micronucleated
cells (MN) were seen in 15 workers manufacturing or processing formaldehyde
(Fleig et al., 1982), 30 medical students (Vasudeva & Anand, 1996), 23 anatomy
students (Ying et al., 1997; 1999) and 6 pathology students (Thomson et al.,
1984). Additionally, no increased incidence of DNA-protein cross-links was seen
in 10 furniture workers (Zhitkovich et al., 1996).
An increased incidence in SCE in peripheral lymphocytes was seen in 90
pathology students (Shaham et al., 2002), 13 workers reported to be regularly
exposed to formaldehyde (Shaham et al., 1997), 8 anatomy students (Yager et al.,
1986) and 31 workers exposed to phenol-formaldehyde resins (Suskov &
Sazonova, 1982). An increased incidence in chromosome aberrations, SCE and
MN was seen in 13 anatomy students (He et al., 1998), while an increased
incidence in MN, but not SCE, was observed in 29 mortuary students (Suruda et
al., 1993). A study of 20 paper workers reported an increased incidence in
chromosome aberrations but not SCE (Bauchinger & Schmid, 1985), however,
this study has been criticised for the statistical analysis used, and the findings
were considered incidental (Engelhardt et al., 1987). An increased incidence in
chromosome aberrations was reported in a study in children (Dobias et al., 1988)
and a study of workers (Kitaeva et al., 1996). However, only limited details were
provided for these studies, which were reported in abstract form only. An
increased incidence in DNA-protein-cross link was also seen in 12 workers,
reported to be regularly exposed to formaldehyde (Shaham et al., 1997).
In studies investigating the incidence of MN in nasal and buccal cells, an
increased incidence was seen in buccal but not nasal cells in studies of 29 and 28
mortuary students (Suruda et al., 1993; Titenko-Holland et al., 1996), while an
increase was seen in both cell types in 25 anatomy students (Ying et al., 1997).
An increased incidence in MN in nasal cells was also seen in 15 wood workers
(Ballarin et al., 1992). An increased incidence in MN in buccal cells was reported
in anatomy technicians and anatomy students, however only limited details are
available for this Russian study, as only the abstract was reported in English
(Kitaeva et al., 1996).
11.6 Carcinogenicity
The finding in the early 1980s of tumours in the nasal tract of rats exposed to
formaldehyde in inhalation studies led to concerns for workers occupationally
exposed to formaldehyde. Extensive epidemiological studies investigating
respiratory tract cancers have since been conducted in workers. These studies,
that include cohort mortality studies and case-control studies in industrial workers
and professionals, have examined the incidence of cancers in the nasal tract,
pharynx or lungs. An overview of three meta-analyses of these numerous
epidemiology studies is presented below (Blair et al., 1990a, Partanen, 1993, and
Collins et al., 1997). A more comprehensive summary of these studies can be
found in Table 9 and 10 in the CICAD (IPCS, 2002) review, which is attached in
87
Formaldehyde
Appendix 3. Additionally, recent case-control and cohort studies (post-1998),
investigating the incidence of upper respiratory tract cancers in workers
occupationally exposed to formaldehyde (Armstrong et al., 2000; Laforest et al.,
2000; Vaughan et al., 2000; Hildesheim et al. 2001; Marsh et al., 2002; Berrino et
al., 2003; Coggon et al., 2003; Elci et al., 2003; Hauptman et al., 2003; 2004;
Pinkerton et al., 2004), and a meta-analysis of 12 case-control studies
investigating the incidence of sinonasal cancers (Luce et al., 2002), are also
presented in Section 11.6.1.
Possible associations between occupational exposure to formaldehyde and non-
respiratory tract cancers have also been investigated to a lesser extent. In studies
investigating increased risks of various non-respiratory cancers, such as
melanoma, brain, connective tissue, pancreatic, and colon, increased risks have
been occasionally observed but without any consistent pattern (e.g. Stroup et al.,
1986; Stayner et al., 1988; Hayes et al., 1990; Holly et al., 1996; Dumas et al.,
2000). However, recently data has been published (including updates of major
cohort studies of industrial workers) that report a relationship between
formaldehyde exposure and lymphohematopoietic cancers (specifically
leukaemia). Since this cancer type was not specifically evaluated in the CICAD
(IPCS, 2002), a review of all the available data is presented in Section 11.6.2.
Additionally, a recently published case-control study and meta-analyses
investigating the association between formaldehyde exposure and pancreatic
cancer are also presented in Section 11.6.2.
11.6.1 Nasal tract, pharynx and pulmonary tumours
Meta-analyses
Blair et al. (1990a) conducted a meta-analysis of 321 studies covering
occupational exposure to formaldehyde in industrial workers and professionals
(embalmers, anatomy technicians and pathologists). The data were re-analysed by
Partanen (1993) and included an additional three case-control studies1.
Furthermore, in the meta-analysis by Partanen (1993) a number of changes in the
selection of input values were made that were considered more appropriate, and
relative risks determined using a different model from that of Blair et al. (1990a).
Despite these changes the results of this re-analysis were generally in close
agreement with the original meta-estimates by Blair et al. (1990a).
A significantly increased risk was found for nasopharyngeal cancers in workers
with the highest category of exposure to formaldehyde in the meta-analyses
conducted by both Blair et al. (1990a) and Partanen (1993) (meta-relative risk
value (mRR) = 2.1, 95% CI 1.1 - 3.5 and mRR = 2.7, 95% CI 1.4 - 5.6,
respectively). The two meta-analyses showed no increased risk between
formaldehyde exposure and lung cancer among professionals. The mRR for lung
1
Harrington and Oakes, 1984; Harrington and Shannon, 1975; Peterson and Milham, 1980; Jensen
and Andersen, 1982; Fayerweather et al., 1983; Friedman and Ury, 1983; Marsh, 1983; Milham,
1983; Walrath and Fraumeni, 1983; Wong, 1983; Achesson et al., 1984a; 1984b; Coggon et al.,
1984; Levine et al., 1984; Liebling et al., 1984; Malker and Weiner, 1984; Olsen et al., 1984;
Walrath and Fraumeni, 1984; Partanen et al., 1985; Stayner et al., 1985; Walrath et al 1985;
Bertazzi et al., 1986; 1989; Blair et al., 1986; 1987; 1989; 1990b; Bond et al., 1986; Gallagher et
al., 1986; Hayes et al., 1986a; Logue et al., 1986; Stroup et al., 1986; Vaughan et al., 1986a;
1986b; Roush et al., 1987; Stayner et al.,1988; Gerin et al., 1989; Hayes et al, 1990.
1
Brinton et al., 1984; Gallagher et al., 1986; Merletti et al., 1991.
88 Priority Existing Chemical Assessment Report No. 28
cancer for industrial workers was marginally, but significantly, increased for
those with low/low-medium exposure to formaldehyde (both mRR = 1.2, 95% CI
1.1 - 1.3), but a significantly increased risk was not observed in both meta-
analyses for those exposed to higher/substantial levels of formaldehyde. The
observed marginally increased risk in the low dose group in the absence of a dose
response does not demonstrate strong evidence of an association between
formaldehyde exposure and lung cancer. For nasal cancers, Blair et al. (1990a)
found no increased risk for formaldehyde exposure overall, while Partanen (1993)
found a borderline significantly increased risk of sinonasal cancers in workers
with substantial exposure to formaldehyde (mRR = 1.7, 95% CI 1.0 - 2.8).
In a more recent and comprehensive meta-analysis, Collins et al. (1997) initially
considered 47 epidemiology studies. Several of these studies were not included in
the analysis, because workers who had formaldehyde exposure were not
evaluated separately or the study only reported relative risks, the study population
was included in a more recent study, or the methodology and results were
insufficiently described. In total1 the meta-analysis was based on the results from
11 cohort, 3 proportionate mortality and 18 case-control studies, and included
new data published since Partanen (1993). Furthermore, the authors of studies
were contacted to obtain data not included in their publications. The exposure
potential of jobs that were classified as having formaldehyde exposure in the
community-based case-control studies was also reviewed, as exposure assessment
was much more uncertain in these studies than in cohort studies.
When all studies were included, no increased risk of lung cancer was seen with
exposure to formaldehyde (mRR = 1.0, 95% CI 0.9 - 1.0). In cohort studies, a
very small borderline, though significant, increased risk was seen for industrial
workers (mRR = 1.1, 95% CI 1.0-1.2), while no increased risk was seen for
pathologists (mRR = 0.5, 95% CI 0.4 - 0.6) or embalmers (mRR = 1.0, 95% CI
0.9 - 1.1). Similarly, no increased risk was seen in the case-control studies (mRR
= 0.8, 95% CI 0.7 - 0.9).
No increased risk of sinonasal cancers was seen with exposure to formaldehyde
(mRR = 1.0, 95% CI 1.0 - 1.1). Evaluating by study design revealed no increased
risk for cohort studies (mRR = 0.3, 95% CI 0.1 - 0.9) but a significantly increased
risk for case-control studies (mRR = 1.8, 95% CI 1.4 - 2.3). This increased risk
was attributable to a significantly increased risk for the combined 6 European
case-control studies (mRR = 2.9, 95% CI 2.2 4.0), whereas no increased risk
was seen for the combined 5 US case-control studies (mRR = 1.0 95% CI 0.7 -
1.5). Collins et al. (1997) report that it is difficult to reconcile European findings
with other findings unless it is assumed that confounding factors, or bias, were
affecting the results.
1
Harrington and Shannon, 1975*; Jensen and Andersen, 1982*; Fayerweather et al., 1983*:
Hernberg et al., 1983a; 1983b; Walrath and Fraumeni, 1983*; Coggon et al., 1984*; Levine et al.,
1984*; Walrath and Fraumeni, 1984*; Brinton et al., 1985; Bond et al., 1986*; Bertazzi et al.,
1989*; Blair et al., 1986*; Hayes et al., 1986a*; Olsen et al., 1986; Stroup et al., 1986*; Vaughan
et al., 1986a*; 1986b*; Roush et al., 1987*; Stayner et al., 1988*; Gerin et al., 1989*; Hayes et al.,
1990*; Partanen et al., 1990; Hall et al., 1991; Matanoski, 1991; Chiazze et al., 1993; Gardner et
al.,1993; Luce et al., 1993; West et al., 1993; Marsh et al., 1994; Andjelkovich et al., 1995 (*
included in the analysis by Blair et al., 1990a and Partanen, 1993).
89
Formaldehyde
A significantly increased risk of nasopharyngeal cancers was seen with exposure
to formaldehyde (mRR = 1.3, 95% CI 1.2 - 1.5). However, evaluation of
nasopharyngeal cancers was hampered in some industrial cohort studies, as
expected numbers were not reported when there were no observed deaths. To
overcome this, the expected number of deaths was estimated based on the ratio of
expected lung cancers to nasopharyngeal cancers in the study by Blair et al.
(1986) that reported nasopharyngeal deaths. Expected numbers were also not
reported in the cohort studies of embalmers and medical specialists. Using a
similar approach, based on the ratio of expected lung cancers to nasopharyngeal
cancers in the study by Hayes et al. (1990), a non-significant increased risk was
found for nasopharyngeal cancers and exposure to formaldehyde when all
industrial cohort studies were combined (mRR = 1.2, 95% CI 0.4 - 2.5). While no
increased risk of nasopharyngeal cancers was seen for all cohort studies
combined (mRR = 1.0, 95% CI 0.4 2.5), a non-significant increased risk of such
cancers was seen for all case-control studies combined (mRR = 1.3, 95% CI 0.9 -
2.1).
Collins et al. (1997) concluded that the data did not provide convincing evidence
of a casual relationship between formaldehyde exposure and nasopharyngeal
cancers. The authors attributed the differences in their results to the two earlier
meta-analysis to be mainly due to the inclusion of a number of recently published
negative cohort studies and the correction for non-reporting of expected deaths in
some cohort studies.
A pooled analysis of 8 case-control studies by t' Mannetje et al. (1999) are
included in a more recent review by Luce et al. (2002) who conducted a pooled
analysis of 12 case-control studies1 conducted in 7 countries. The review
examined the associations between sinonasal cancers and occupational
formaldehyde exposure. Studies were selected on availability of information on
histological type of cancer, age, sex, smoking and occupational history. A total of
930 cases (680 men, 250 women), including 432 squamous cell carcinomas (330
men, 102 women) and 195 adenocarcinomas (169 men, 26 women), diagnosed
between 1968 and 1990 were evaluated along with 3136 controls (2349 men, 787
women). The probability of exposure to a number of occupational substances
(including formaldehyde) was determined using a job exposure matrix. The study
focused on cumulative exposure although results of other exposure variables were
presented when they gave additional information. After adjustment for age, a
small non-significant increased risk was seen for squamous cell carcinomas in
males and females with a high probability of exposure (odds ratio (OR) = 1.2,
95% CI 0.8 1.8 and OR = 1.5, 95% CI 0.6 3.8, respectively for a > 90%
probability of exposure). After adjustment for age and cumulative exposure to
wood and leather dust a significantly increased risk was seen between
adenocarcinomas and medium (0.25 - 1 ppm) and high (> 1 ppm) intensity of
exposure to formaldehyde in men (OR = 2.4, 95% CI 1.3 - 4.5 and OR = 3.0, 95%
CI 1.5 - 5.7, respectively). Only age was adjusted for in women, with a
significantly increased risk seen between adenocarcinomas and high probability
of formaldehyde exposure (OR = 6.2, 95% CI 2.0 - 19.7).
1
Cecchi et al., 1980, Luce et al., 1993 and Leclerc et al., 1994; Hardell et al., 1982; Brinton et al.,
1984 and Brinton et al., 1985; Merler et al., 1986; Hayes et al., 1986a and Hayes et al., 1986b;
Vaughan et al., 1986a, Vaughan, 1989 and Vaughan and Davis, 1991; Bolm-Audorff et al., 1990;
Comba et al., 1992a; Comba et al., 1992b; Zheng et al., 1992; Magnani et al., 1993; Mack and
Preston-Martin unpublished data, presented in Luce et al., 2002.
90 Priority Existing Chemical Assessment Report No. 28
Luce et al. (2002) also evaluated cases of sinonasal adenocarcinoma where there
was no exposure to wood or leather dust. A significantly increased risk was only
seen for adenocarcinoma in females with a high probability of exposure (OR =
11.1, 95% CI 3.2 38.0, based on 5 cases). No significant increased risk was seen
in males for low, medium or high probability of exposure. An analysis was also
undertaken in men only of formaldehyde exposure by maximum exposure to
wood dust. For no or low exposure to wood dust a non-significant increased risk
was seen for adenocarcinomas with high and medium level exposure to
formaldehyde (mRR = 2.2, 95% CI 0.8 6.3 based on 4 cases).
Recent case-control studies
In a study by Berrino et al. (2003), 315 males aged less than 55 years, diagnosed
with laryngeal or hypopharyngeal cancer over a 3 5 year period in the late
seventies to the early eighties in 6 centres in France, Italy, Spain and Switzerland
were investigated. Most cases were interviewed, and information on occupational
exposures, smoking and alcohol consumption, socio-economic status and diet
obtained. Occupational exposures to substances, including formaldehyde, were
determined using a job exposure matrix. Cases in each centre were matched by
age and sex to a random sample of the general population (819 controls in total).
After adjustment for potential confounding factors, such as smoking, alcohol
consumption and other occupational exposures (including, wood dust and
asbestos), a small increased risk, not statistically significant (OR = 1.3, 95% CI
0.8 2.0), was seen for exposure to formaldehyde. Analysis of duration of
exposure (any probability) to formaldehyde showed no positive trend (although
for 10 19 years exposure OR = 2.2, 95% CI 1.2 4.2 and OR = 1.3, 95% CI 0.6
2.8 for > 20 years exposure). Additionally, for analysis of the anatomical site of
tumour origin, it was seen for endolarynx (n = 213) and hypolarynx (n = 100)
cancers that though an increased risk was seen for those workers possibly
exposed to formaldehyde (OR = 1.4, 95% CI 0.8 2.7 and OR = 1.3, 95% CI 0.6
2.6), no increased risk was seen for workers who were probably or certainly
exposed to formaldehyde.
In a study by Elci et al. (2003), 940 males diagnosed with laryngeal cancer
between 1979 and 1984 at a hospital in Istanbul, Turkey, were investigated. Cases
were interviewed and information on occupational history, smoking and alcohol
consumption obtained. Occupational exposures to substances, including
formaldehyde, were determined using a job exposure matrix. Cases were matched
with 1519 males who had other cancers thought not to share similar etiologic
factors with laryngeal cancer. After adjustment for potential confounding factors,
such as age, smoking and alcohol consumption, no increased risk was seen for
formaldehyde exposure. For analysis of the anatomical site of tumour origin, a
small non-significant increased risk was only seen for cancers originating in the
glottic area (OR = 1.2, 95% CI 0.8 2.0). No exposure-response relationship was
seen for either intensity or probability of exposure to formaldehyde and cancers
originating in the glottic area (or for laryngeal cancers originating in the
suparglottic or subglottic area).
Hildesheim et al. (2001) investigated occupational exposure to formaldehyde
among 375 newly diagnosed cases of nasopharyngeal cancers in two tertiary care
hospitals in Taiwan between July 1991 and December 1994. These cases were
matched on sex, age and geographical residence to 325 population controls. Data
were collected from cases and controls by interviews and questionnaires.
91
Formaldehyde
Occupational exposures were reviewed (blindly) by an industrial hygienist. A
total of 74 cases with formaldehyde exposure were identified. After adjustment
for a number of confounding factors, such as socio-demographic characteristics
and cigarette smoking, a small non-statistically significant increased risk was
seen for nasopharyngeal cancers and exposure to formaldehyde (OR = 1.4, 95%
CI 0.93 2.2). Additionally, no statistically significant trend was seen for either
duration or cumulative exposure to formaldehyde and nasopharyngeal cancers.
Similarly, no dose response was observed for analysis of years since first
exposure. Exposure to wood dust, with the exception of age at first exposure > 25
years, resulted in greater increased risks than for exposure to formaldehyde, and
the authors concluded that exposure to formaldehyde is less clearly linked to
nasopharyngeal cancer than wood dust.
The study by Hildesheim et al. (2001) also tested blood samples from cases and
controls for various anti-Epstein-Barr virus (EBV) antibodies which, the authors
report, are associated with nasopharyngeal cancers. Among those seropositive to
antibodies for EBV (360 cases, 94 controls), a significantly increased risk was
seen for exposure to formaldehyde (OR = 2.7, 95% CI 1.2 - 6.2). However, as
with the above analysis, no dose response was seen with increasing duration or
cumulative exposure to formaldehyde.
In a study by Armstrong et al. (2000), 282 Chinese residents in Malaysia
diagnosed with nasopharyngeal carcinomas between January 1987 and June 1992
were investigated. These residents were interviewed about their occupational
history, diet, alcohol consumption and tobacco use, and each case matched by age
and sex to a Malaysian Chinese control. Following adjustment for potential
confounders, no increased risk was found for nasopharyngeal cancers and
occupational exposure to formaldehyde. Additionally, no dose response was
observed for duration of exposure to formaldehyde and nasopharyngeal
carcinomas. However, only 51 of 564 cases reported occupational exposure to
formaldehyde, and of these 51 cases only 8 had accumulated exposure > 10 years.
Laforest et al. (2000) investigated occupational exposure to formaldehyde among
201 and 296 newly diagnosed cases of (primary) squamous cell hypopharyngeal
and laryngeal cancers in men, respectively, reported in 15 French hospitals
between January 1989 and April 1991. Information on demographic
characteristics, alcohol and tobacco consumption, and lifetime occupational
history were obtained through interviews. Occupational exposures were
determined using a job exposure matrix. Controls were patients with (primary)
cancers at different body sites, in the same or nearby hospitals during the same
period and matched by age. After adjustment for potential confounding factors,
such as smoking, alcohol consumption and other occupational exposures
(including asbestos and man made mineral fibres), a statistically significant trend
was seen for hypopharyngeal cancers and the probability of exposure to
formaldehyde (Ptrend <0.005, OR = 3.8, 95% CI 1.5 - 9.5 for the highest
probability of exposure). No significant trend was noted for these cancers,
however, in respect to duration or cumulative exposure to formaldehyde. When
cases with a low probability of exposure to formaldehyde were excluded
increased risks were observed for exposure to formaldehyde, with a statistically
significant trend observed for duration of exposure (P <0.04) and for cumulative
level of exposure (p <0.14). Neither the ORs nor any trend suggested an
association between formaldehyde exposure and laryngeal cancer.
92 Priority Existing Chemical Assessment Report No. 28
Vaughan et al. (2000) investigated occupational exposure to formaldehyde among
196 newly diagnosed cases of nasopharyngeal cancers reported in five US cancer
registries between April 1987 and June 1993. These epithelial cancers were
classified into 3 histological groups: 54 cases of undifferentiated and non-
keratinising, 118 cases of differentiated squamous cell and 24 cases of
unspecified epithelial. A total of 244 community controls were randomly selected
and matched by age, gender and cancer registry. Data were collected for cases
and controls by telephone interviews. Information on a number of confounding
factors, such as history of occupational and chemical exposure, demographic
background, medical history, family history of cancer, smoking and alcohol
consumption, were collected. Estimates of potential exposure to formaldehyde
were carried out on a job-by-job basis by experienced industrial hygienists who
were blinded to the status of the subjects. After adjustment for potential
confounding factors, no increased risk was seen between potential exposure to
formaldehyde and undifferentiated and non-keratinising carcinomas. Excluding
these histological cancer types, a statistically significant trend was seen between
nasopharyngeal cancers and both exposure duration (Ptrend = 0.014, OR = 2.7,
95% CI 1.2 - 6.0 for the top exposure duration of > 18 years) and cumulative
exposure (Ptrend = 0.033, OR = 3.0, 95% CI 1.3 - 6.6 for the greatest cumulative
exposure of > 1.10 ppm years), for 25 and 24 cases, respectively, that were
considered to have had a possible, probable or definitive exposure to
formaldehyde. However, when cases with a low probability of exposure to
formaldehyde were omitted the significance of the trend decreased for both
duration (Ptrend = 0.069) and cumulative exposure (Ptrend = 0.13). While for
definitive exposure to formaldehyde, although highly significant trends were
reported for duration and cumulative exposure (Ptrend <0.001), this is based on
only 10 available cases. These ORs for formaldehyde were essentially unaffected
by adding exposure to wood dust to the models.
Recent cohort studies
The NCI study (Hauptmann et al., 2004)
The National Cancer Institute cohort of industrial workers in the USA was
recently extended by 15 years and a mortality study of solid cancers undertaken
(Hauptmann et al., 2004). Details of the study design and follow up can be found
in Hauptmann et al., (2003) (see Section 11.6.2). Briefly, the cohort consisted of
25 619 workers and standardised mortality ratios (SMRs) were derived using the
person-years method and compared with the expected numbers of deaths for the
national population. Additionally, relative risks (RR), stratified by cumulative
exposure, average exposure intensity, highest peak exposure, and duration of
exposure, compared to workers in the low exposure category were calculated.
Potential confounding was evaluated for duration of exposure to 11 other
substances and for duration of work as a chemist or laboratory technician.
Mortality from all causes, all cancers, and all solid malignant neoplasms was
significantly less than expected, regardless of exposure status. Compared to the
national population a significantly increased risk was seen for nasopharyngeal
cancers (SMR = 2.1, 95% CI 1.1 4.2). Additionally, the relative risk based on
an internal comparison group for nasopharyngeal cancers increased with average
exposure intensity, cumulative exposure, highest peak exposure, and duration of
exposure to formaldehyde (Ptrend = 0.066, 0.025, 0.001 and 0.147, respectively).
93
Formaldehyde
Among the 10 deaths for nasopharyngeal cancer, 2 were not exposed to
formaldehyde and never exposed to particulates, whereas 7 were exposed to
formaldehyde and particulates. This prevented an analysis of formaldehyde
exposure separating those workers exposed, and not exposed, to particulates. A
slight non-significant increased risk was seen for cancers of the nose and nasal
cavity (SMR = 1.2, 95% CI 0.4 3.7). No increased risk was seen for the larynx
or lung.
An original mortality study by Marsh et al. (1996), of the plant that reported the
greatest excess risk of nasopharyngeal cancers in the US National Cancer
Institute cohort reported above was recently extended by 14 years (Marsh et al.,
2002). In this update of the plastic producing plant, the cohort consisted of 7328
men employed from 1 January 1945 to 31 December 1998 analysed for malignant
cancers of the upper and lower respiratory tract. For this 1998 update, work
histories and exposures were not updated beyond that of the previous assessment
(up to 1995). Exposure estimates were determined from available sampling data,
job descriptions and personal communications. The median average intensity of
exposure to formaldehyde was 0.138 ppm, and the majority of workers had
worked less than 1 year at the plant. SMRs were derived using the person-years
method for several exposure measures and compared with the expected numbers
of deaths for the national population and the local two counties area, adjusted for
race, sex, age, calendar time, year of hire, duration of employment and time since
first employment. Mortality from all cancers was close to the national and local
rate. A statistically significant increased risk was seen for death from cancers of
the buccal cavity and pharynx when compared with national (SMR = 1.8, 95% CI
1.2 2.6) and local rates (SMR = 1.53, 95% CI 1.03 - 2.15), and for pharyngeal
cancer (total of 22 deaths) when compared with the national (SMR=2.6, 95% CI
1.7 4.0) and local rates (SMR = 2.2, 95% CI 1.4 3.4). An analysis of these
pharyngeal cancers showed a statistically significant increased risk for the
nasopharynx (SMR = 4.9, 95% CI 2.0 10.2 compared to national rates, and
SMR = 5.0, 95% CI 2.0 10.3 compared to local rates), though this was based on
only 7 such deaths.
Local rate based SMRs for pharyngeal and nasopharyngeal cancers were then
determined according to selected work history and formaldehyde exposure
measures. A statistically significant increased risk of pharyngeal and
nasopharyngeal cancers was seen in workers employed during the 1947 1956
period (SMR = 3.2, 95% CI 1.9 5.1 and SMR = 8.1, 95% CI 3.0 17.7,
respectively), but not the 1941 1946 or 1957+ period. Similarly, for time since
first employment a statistically significant increased risk was seen for
nasopharyngeal cancers and 20 29 years (SMR = 8.7, 95% CI 1.8 25.5) but
not for greatest time since first employment (> 30 years). For pharyngeal cancers
a statistically significant increased risk was seen for the greatest time since first
exposure (SMR = 2.8, 95% CI 1.4 4.9). A statistically significant increased risk
was seen for both pharyngeal and nasopharyngeal cancers for exposure durations
of > 0 - < 1 year (SMR = 2.4, 95% CI 1.2 4.2 and SMR = 5.8, 95% CI 1.6
14.9, respectively) and > 10 years (SMR = 3.7, 95% CI 1.2 8.5 and SMR =
12.5, 95% CI 1.5 45.0, respectively) but not for 1 9 years. Furthermore,
analysis of the median average intensity of exposure revealed a statistically
significant increased risk for exposures of 0.03 0.159 ppm formaldehyde for
pharyngeal (SMR = 3.8, 95% CI 1.5 7.9) and nasopharyngeal cancers (SMR =
15.3, 95% CI 4.2 39.1) but not for > 0 - < 0.03 ppm and > 0.16 ppm
94 Priority Existing Chemical Assessment Report No. 28
formaldehyde for either cancer. For cumulative exposure a statistically significant
increased risk was seen for 0.004 0.219 (SMR = 5.9, 95% CI 1.2 17.2) and
> 0.22 ppm-years (SMR = 7.5, 95% CI 1.6 21.9) for nasopharyngeal cancers
only.
Analysis of exposure to > 0.2 or > 0.7 ppm formaldehyde and duration of
exposure was also undertaken. Although a statistically significant increased risk
was seen for pharyngeal and nasopharyngeal cancers and duration of exposures of
> 10 years for > 0.2 ppm, no statistically significant increased risk was seen for
the greatest duration of exposure with > 0.7 ppm formaldehyde, while a
statistically significant increased risk was seen for unexposed workers and
pharyngeal cancers (SMR = 2.1, 95% CI 1.2 3.5).
In this study (Marsh et al., 2002), a nested case-control study was conducted on
the 22 reported pharyngeal cancer deaths. Each case was matched on race, sex,
age and year of birth to four controls from the cohort. An attempt was also made
to obtain information on smoking history and exposures outside of work through
telephone calls or a knowledgeable informant (usually a surviving family
member). When analysis was adjusted for smoking and year of hire no
statistically significant increased risk of pharyngeal cancers was seen for duration
of exposure, cumulative exposure, median average intensity of exposure and the
time since first employment. Indeed, long-term workers (> 1 year) showed a
reduced or nearly equal risk for pharyngeal cancers compared to short-term
workers. As for the cohort study, workers hired during the 1947 1956 period
were at greater risk. The authors concluded that the pattern of findings suggest
that the observed nasopharyngeal cancers are not associated with formaldehyde
exposure, and may reflect the influence of non-occupational risk factors or
occupational risk factors associated with employment outside the plant.
The complete NCI cohort data were recently reanalysed by Marsh and Youk
(2005). SMRs were derived for the US national and regional rates and internal
cohort-based RR for four formaldehyde exposure metrics (highest peak, average
intensity, cumulative and duration) using both the Hauptmann et al. (2003)
categories and an alternative categorization based on tertiles of all
nasopharyngeal deaths among exposed subjects. SMRs and RRs were determined
for each of the 10 study plants and by two plant groups (Plant 1 vs Plants 2 10).
As reported by Marsh et al. (2002) the majority (6 of 10) of the nasopharyngeal
cancers were observed in plant 1 of the 10 plants forming the NCI cohort. Since
Marsh et al. (2002) previously reported on nasopharyngeal cancers in plant 1 and
the pattern observed for such is similar in this later evaluation, only a brief
overview of the analysis by Marsh and Youk (2005) is presented below, which
focuses on the findings in plants 2 10.
In contrast to the findings in plant 1, a deficit in nasopharyngeal deaths was seen
among formaldehyde-exposed workers in plants 2 10 combined (regional rate
based SMR = 0.65, 95% CI 0.08 2.33) and all non-baseline highest peak
exposure categories were less than 1 with no evidence of an exposure-response
relationship observed. Furthermore, none of the corresponding exposure-response
relationships was statistically significant for plants 2 10 combined. The authors
also found that reanalysis of the nasopharyngeal findings seen by Hauptmann et
al. (2004) for the highest exposure category, was driven entirely by the excess
risk in plant 1 at highest peak exposure. Overall, the authors concluded that the
95
Formaldehyde
nasopharyngeal findings in the NCI cohort were not associated with
formaldehyde exposure.
The NIOSH study (Pinkerton et al., 2004)
The follow up of an existing cohort of garment workers exposed to formaldehyde
(Stayner et al., 1988) was recently extended by 16 years in a retrospective cohort
mortality study by Pinkerton et al. of the National Institute of Occupational
Safety and Health (Pinkerton et al., 2004). The cohort consisted of 11 030
workers employed after 1955 at 3 garment facilities in the USA and followed
through to December 1998. Subjects had been identified from employment
records and their vital status was determined. Personal and static air monitoring
data were available from 1981 in one plant and 1984 in the others, and showed
mean 8 hour time-weighted average levels of formaldehyde exposure ranging
from 0.09 to 0.2 ppm. The authors considered it likely that formaldehyde levels
were substantially higher in earlier years. SMRs were derived using the person-
years-at-risk method and compared with the expected numbers of deaths for both
the national population and local population. The SMRs were stratified by
duration of exposure, time since first exposure and year of first exposure.
Results were only presented using national rates though it is stated that results
with local rates were similar. Mortality from all causes and from all cancers was
significantly less than expected, and mortality for pharyngeal, laryngeal and
trachea, bronchus and lung cancers were also less than expected. No cancers of
the nasopharynx or nose were observed. In addition to analysis of underlying
cause of death, this study also analysed all causes on the death certificate using
multiple cause mortality methods. No cancers of the nasal cavities or
nasopharynx were identified in the MCOD (multiple cause of death) analysis.
The MRC study (Coggon et al., 2003)
The follow up on an existing cohort of British chemical workers exposed to
formaldehyde (Gardener et al., 1993) was recently extended by 11 years by
Coggon et al. of the Medical Research Council's Environmental Epidemiology
Unit at the University of Southampton (Coggon et al., 2003). The cohort
consisted of 14 014 men employed after 1937 at six British chemical factories
and followed through to December 2000. Subjects had been identified from
employment records, and their jobs had been classified for potential exposure to
formaldehyde using a job-exposure matrix, as no measurements to formaldehyde
had been taken before 1970. Subjects were placed into one of 5 determined
exposure categories ranging from background levels to > 2 ppm formaldehyde.
Subjects' vital status were determined and SMRs derived using person-years
method and compared with the expected numbers of deaths for the national
population. It was observed that mortality among the cohort for all cancers was
slightly, though significantly, higher (SMR = 1.10, 95% CI 1.04 1.16) and the
increase was greater in men with high exposure (> 2ppm) to formaldehyde (SMR
= 1.3, 95% CI 1.2 1.4). The increase in all cancers arose principally from an
increase in cancers of the stomach and lung. SMRs were determined for these
cancers for each formaldehyde exposure category. After adjustment for local
variations in mortality, a statistically significant increase was only seen for lung
cancer in men with high formaldehyde exposure (SMR = 1.3, 95% CI 1.1 1.4).
The risk was highest in men exposed before 1965 when occupational hygiene was
less developed and the highest exposures to formaldehyde would be expected to
96 Priority Existing Chemical Assessment Report No. 28
have occurred (SMR = 1.3, 95% CI 1.1 1.5). However, a statistically non-
significant inverse trend was seen for the number of years worked in high
exposure jobs (Ptrend = 0.13) and showed no trend to increase with time since first
employed in such a job (Ptrend = 0.93). According to the authors, the observation
that mortality was highest in those who had worked in jobs with high levels of
exposure for less than 1 year suggests confounding by non-occupational factors,
such as smoking. In this study mortality from nasopharyngeal and sino-nasal
cancers in the cohort were less than expected.
Summary
Many epidemiology studies have investigated formaldehyde exposure and cancer
of the respiratory tract. The strongest evidence of an association has been
observed for nasopharnygeal cancers. The most recent meta-analysis (Collins et
al., 1997) concluded that although there was an increased, non-significant risk of
nasopharyngeal cancers, overall, the data did not provide sufficient evidence to
establish a causal relationship between nasopharyngeal cancers and formaldehyde
exposure. Studies published since the meta-analysis provide mixed results for
both case-control studies and cohort studies. Three large industrial cohort studies
with a long follow-up have been recently published (Hauptman et al., 2004;
Pinkerton et al., 2004; Coggon et al., 2003). The study by Hauptman et al. (2004)
found that compared to the national population, there was a significantly
increased risk of nasopharyngeal cancer. In addition, the relative risk increased
with average exposure intensity, cumulative exposure, highest peak exposure and
duration of exposure to formaldehyde. However, no such cancers were seen in the
study by Pinkerton et al. (2004), while no increased risk was seen by Coggon et
al. (2003). Similarly, mixed results have been observed in recent case-control
studies of formaldehyde exposure and nasopharyngeal cancer.
It is noted that, as with all epidemiology studies, the epidemiological
investigations for formaldehyde have study limitations, such as the absence of
direct exposure measurements and the potential of confounding factors, such as
co-exposure to other chemicals and/or wood dust. However, the numerous
findings of increased risk of nasopharyngeal cancers cannot be entirely attributed
to such potential limitations in study design. Therefore, although it cannot be
definitely concluded that occupational formaldehyde exposure results in the
development of nasopharyngeal cancer, there is some evidence to suggest a
causal association between formaldehyde exposure and nasopharyngeal cancer.
Follow-up of the National Cancer Institute cohort continues and the findings
should assist in further elucidating the strength of the association between
formaldehyde and nasopharyngeal cancer.
There are several case-control studies that indicate an increased risk for sinonasal
cancer and formaldehyde exposure, but this has not been observed in cohort
studies. The most recent meta-analysis (Collins et al., 1997) concluded that the
data did not support an association between formaldehyde and sinonasal cancer.
There is limited and inconsistent evidence with respect to laryngeal and lung
cancers. Overall, the available data do not support an association between
sinonasal, laryngeal and lung cancers and formaldehyde exposure.
97
Formaldehyde
11.6.2 Non-respiratory tract cancers
Lymphohematopoietic cancers
Meta-analysis
Collins and Lineker (2004) conducted a meta-analysis of 18 epidemiological
studies1 (12 cohort mortality studies, 4 proportionate mortality and 2 case-control
studies) published between 1975 2004, that reported leukaemia and
occupational exposure to formaldehyde. Criteria were applied in the selection of
studies and, consequently, not all studies reporting leukaemia in formaldehyde-
exposed workers published between the dates stated were included in this
analysis. For all 18 studies analysed a very slight increased risk for leukaemia
was observed (mRR = 1.1, 95% CI 1.0 1.2) in the absence of heterogenicity
across studies (p = 0.07). When analysed by occupation, increased risks were
seen for embalmers (mRR = 1.6, 95% CI 1.2 6.0) and pathologists/anatomists
(mRR = 1.4, 95% CI 1.0 1.9) with consistency seen across studies (p = 0.97 and
p = 0.96, respectively). No increased risk was seen for industrial workers, whom
the authors report may have had higher average daily exposures and peak
exposures than embalmers, pathologists and anatomists. The authors concluded
that this meta-analysis does not provide reliable evidence of an association
between formaldehyde exposure and leukaemia, due to the absence of consistent
findings across study types and inconsistent findings of small increased
leukaemia rates across job types (that suggest the possibility of confounding
factors).
In a previous meta-analysis conducted by Blair et al. (1990a) of 32 case-control
and cohort studies2 a statistically significant increase in mortality from leukaemia
was reported in professionals: embalmers, anatomy technicians and pathologists
(mRR = 1.6, confidence intervals not reported). A slight and non-statistically
increased risk was seen among industrial workers (mRR = 1.1, confidence
intervals not reported). No increased risk was observed for Hodgkin's lymphoma
among professional or industrial workers.
Case-control studies
A population-based case-control study was conducted in Iowa and Minnesota
(United States) to evaluate associations between occupational exposures
(including formaldehyde) and leukaemia in 513 cases identified from the cancer
registry of Iowa between March 1981 and October 1983, and from Minnesota
hospitals between October 1980 and September 1982 (Blair et al., 2001). Cases
(confirmed by pathology diagnosis) were matched to 1087 controls, for age, vital
status and geographical residence. Data were collected through interviews, with
surrogates where necessary. In addition to occupational history, information was
also collected on residential history, drinking water sources, smoking, alcohol
use, medical history, family history of cancer, education and other demographic
1
Harrington and Shannon, 1975; Linos et al., 1980; Walrath and Fraumeni, 1983; Harrington and
Oakes, 1984; Levine et al., 1984; Walrath and Fraumeni, 1984; Stroup et al., 1986; Edling et al.,
1987; Ott et al., 1989; Hayes et al., 1990; Hall et al., 1991; Matanoski et al., 1991; Dell and Teta,
1995; Andjelkovich et al., 1995; Hansen and Olsen, 1995; Coggon et al., 2003; Hauptmann et al.,
2003; Pinkerton et al., 2003.
2
A listing of the studies included in this meta-analysis can be found in the foot note in Section
11.6.1.
98 Priority Existing Chemical Assessment Report No. 28
variables. Exposures were determined using a job exposure matrix and
probability and intensity of exposure determined. ORs were adjusted for use of
pesticides, postsecondary education, use of hair dyes, first degree relative with a
haematolymphopoietic cancer and smoking, and determined by histologic type of
leukaemia: acute myeloid; acute lymphocytic; chronic myeloid; chronic
lymphocytic; and myelodysplasia. For formaldehyde exposure there were no
cases of acute lymphocytic leukaemia, while no increased risks were seen for
acute myeloid leukaemia and myelodysplasia. Small increased risks, not
significant, were only seen for chronic myeloid leukaemia (OR = 1.3, 95% CI 0.6
3.1) and chronic lymphocytic leukaemia (OR = 1.2, 95% CI 0.7 1.8) to
low/medium exposure of formaldehyde. Results for high exposure are not
presented here as they are of limited value being based on only one case for each
cancer type.
Nisse et al. (2001) investigated the association between occupational (including
formaldehyde) and environmental factors, and myelodysplastic syndromes
diagnosed among 204 patients from September 1991 to February 1996 in Lille,
France. These cases were matched on sex, age and geographical residence to 204
population controls. Data were collected by interviews and questionnaires. The
OR for formaldehyde exposure was not reported, suggesting that there was no
increased risk and/or the number of cases with exposure to formaldehyde was so
few to allow a meaningful analysis of the data.
Tatham et al. (1997) investigated the relationship between occupational exposures
(including formaldehyde) and three subgroups of non-Hodgkin's lymphoma
(small cell diffuse, follicular and large cell diffuse) in 1048 men diagnosed with
such cancers between December 1984 and November 1988. Cases (confirmed by
pathology diagnosis) were identified from cancer registries in Atlanta,
Connecticut, Iowa, Kansas, Miami, San Francisco, Detroit and Seattle (United
States) and matched to 1659 controls for age and geographical residence. Data
were collected for cases and controls by telephone interviews on background
characteristics, medical, work and military history, and life-style. Consequently,
exposure was self-reported. ORs were adjusted for the following potential
confounding factors: age at diagnosis/case selection, education, ethnicity, year
entered study, Jewish religion, having never married, AIDS risk behaviours, use
of seizure medication, service in Vietnam (i.e. potential exposure to Agent
Orange), and smoking. A small non-significant increased risk was seen for all
cases of non-Hodgkin's lymphoma (OR = 1.2, 95% CI 0.9 1.5). Similar results
were seen for small and large cell diffuse lymphoma, while no increased risk was
seen for follicular lymphoma.
West et al. (1995) investigated the association between `newly' diagnosed cases
of myelodysplastic syndromes in 400 patients from South Wales, Wessex and
West Yorkshire (UK) and exposures through occupation, environment and hobby.
Controls (number not reported) were selected from outpatient clinics and
inpatient wards of medicine, ear nose and throat, orthopaedics and geriatrics, and
matched to cases for age, geographical residence, hospital and year of diagnosis.
Data on lifetime exposures through occupation, environment or hobby were
collected by questionnaire, structured and semi-structured interview. ORs were
determined for duration of exposure and for formaldehyde and were 1.2, 2.3 and
2.0 for > 10 hours lifetime exposure of low intensity (14 cases), > 50 hours
lifetime exposure of medium or high intensity (7 cases) and > 2500 hours lifetime
99
Formaldehyde
exposure of medium or high intensity (4 cases), respectively. Confidence
intervals were not reported, though it is stated that these ORs were not
statistically significant.
Partanen et al. (1993) investigated occupational exposure among 7307 male
production workers employed in the wood industry in Finland between 1945 and
1963 and traced through the Finnish cancer registry. From this cohort 4 cases of
Hodgkin's disease, 8 cases of non-Hodgkin's lymphoma and 12 cases of
leukaemia diagnosed between 1957 and 1982 were matched by age and vital
status to 152 controls from the same cohort free of cancer in 1983. Exposures
were determined using a job exposure matrix. Cases were interviewed or
questionnaires sent to their next of kin. A non-statistical increased risk was seen
for leukaemias and lymphomas combined and exposure to formaldehyde (OR =
2.5, 95% CI 0.8 7.6). Only 3 of the 7 cases were not co-exposed to wood dust
and, consequently, a meaningful analysis of exposure to formaldehyde alone
could not be undertaken. Adjusting the analysis for exposure to wood dust (or
solvents) did not substantially alter the results. For analysis of cancer type,
increased risks were seen for leukaemia (OR = 1.4, 95% CI 0.3 7.9) and non-
Hodgkin's lymphoma (OR = 4.2, 95% CI 0.7 26.6), however, this analysis was
based on a small number of cancers (2 and 4, respectively), which limited the
statistical power of these analyses.
A population-based case-control study of leukaemia (n = 578) and non-Hodgkin's
lymphoma (n = 622) in white males in Iowa and Minnesota (United States) was
briefly reported in the `letters section' of a published journal (Linos et al., 1990).
A non-significant increased risk was seen for total non-Hodgkin's lymphoma (OR
= 3.2, 95% CI 0.8 13.4) and total leukaemia (OR = 2.1, 95 % CI 0.4 10.0)
among embalmers and funeral directors following adjustment for age and state. A
significantly increased risk was seen specifically for follicular non-Hodgkin's
lymphoma (OR = 6.7, 95% CI 1.2 37.1) and acute myeloid leukaemia (OR=6.7,
95% CI 1.2 36.2) in these professions. Limited methodological details were
presented and the estimates were based on only 3 exposed cases for each cancer
type, so statistical power was limited.
A case-control study was conducted in Montreal Canada to investigate possible
associations between occupational exposures (including formaldehyde) and cases
of cancer diagnosed from September 1979 to December 1985 (Gerin et al., 1989).
A total of 53 cases of Hodgkin's lymphoma and 206 cases of non-Hodgkin's
lymphoma were compared with 2599 controls diagnosed with cancers of other
organs and 533 population controls from the Montreal area. Data were obtained
through interviews or questionnaires and used to determine potential occupational
exposures. ORs were adjusted for the following potential confounding factors:
age, ethnicity, socio-economic status, smoking, `dirtiness' of the job (to
distinguish white collar work histories from blue-collar ones), and other potential
occupational and non-occupational confounders. No increased risk was seen for
non-Hodgkin's lymphomas and exposure to formaldehyde for less than, and over,
10 years exposure at estimated medium or high levels of exposure. Similarly, no
increased risk was seen between formaldehyde exposure and Hodgkin's
lymphoma. Analysis of exposure subgroups was not conducted for this cancer, as
there were only 8 exposed cases.
The case-control group described above by Gerin et al. (1989) was also evaluated
by Fritschi and Siemiatycki (1996) for possible associations between
100 Priority Existing Chemical Assessment Report No. 28
occupational exposures (including formaldehyde) and cases of Hodgkin's
lymphoma, non-Hodgkin's lymphoma (for which there was a small increase in
cases with n = 54 and n = 215, respectively) and myeloma. As for the previous
analysis, this study provides no evidence of an association between formaldehyde
exposure and non-Hodgkin's lymphoma. Results for Hodgkin's lymphoma and
myeloma were not presented due to either a lack of prior evidence of an
association or fewer than 4 exposed cases.
Cohort studies
A number of cohort studies are also available. Several of these cohorts have
recently been updated and only the most recent updates are presented below.
The follow up of an existing cohort of garment workers exposed to formaldehyde
(Stayner et al., 1988) was recently extended by 16 years in a retrospective cohort
mortality study (Pinkerton et al., 2004). Details of the study design can be found
in Section 11.6.1. Briefly, the cohort consisted of 11 030 workers employed after
1955 at 3 garment facilities in the USA and followed through to December 1998.
Subject's vital status was determined and SMRs derived and compared with the
expected numbers of deaths for both the national population and local population.
The SMRs were stratified by duration of exposure, time since first exposure and
year of first exposure.
Results were only provided using national rates, though it is reported that results
with local rates were similar. Mortality from all causes and from all cancers was
significantly lower than expected, and mortality for all lymphatic and
haematopoietic cancers was slightly lower than expected. Additional analysis for
more detailed subgroups (i.e. mortality since 1960) for leukaemia showed a very
small non-significant increased risk (SMR = 1.1, 95% CI 0.7 1.6) that was due
to a non-significant increased risk for myeloid leukaemia (SMR = 1.4, 95% CI
0.8 2.4). After results were stratified by duration of exposure and time since
first exposure an increased risk was seen for myeloid leukaemia (SMR = 2.4,
95% CI 1.0 to 5.0) among workers with both 10 or more years of exposure and 20
years or more since first exposure. In addition to analysis of underlying cause of
death, this study also analysed all causes on the death certificate using multiple
cause mortality methods (MCOD). After results were stratified by duration of
exposure and time since first exposure, a significantly increased excess was seen
for leukaemia deaths, specifically myeloid leukaemia (SMR = 2.55, 95% CI 1.10
5.03, for workers with both 10 or more years of exposure and 20 years since
first exposure).
The follow up on an existing cohort of British chemical workers exposed to
formaldehyde (Gardener et al., 1993) was recently extended by 11 years (Coggon
et al., 2003). Details of the study design and follow up can be found in Section
11.6.1. Briefly the cohort consisted of 14 014 men employed after 1937 at six
British chemical factories and followed through to December 2000. Subjects'
vital status were determined and SMRs derived and compared with the expected
numbers of deaths for the national population. It was observed that the mortality
among the cohort for all cancers was very slightly, though significantly, higher
(SMR=1.10, 95% CI 1.04 1.16). Mortality from leukaemia and other lymphatic
and haematopoietic cancers was generally lower than expected for the full cohort
and in men with high exposures to formaldehyde.
101
Formaldehyde
The National Cancer Institute cohort of industrial workers in the USA was
recently updated, 15 years from the original study by Blair et al. (1986), to
evaluate the association between formaldehyde exposure and
lymphohaematopoietic cancers (Hauptmann et al., 2003). The cohort consisted of
25 619 workers employed before January 1966 at 10 industrial plants and
followed through to December 1994. Exposure to formaldehyde was estimated
from work histories collected through to 1980 based on a job-exposure matrix and
some monitoring data. No information on formaldehyde exposure was collected
after 1980. SMRs were derived using the person-years method and the expected
numbers of deaths were derived from the national population. Relative risks
(RR), stratified by cumulative exposure, average exposure intensity, highest peak
exposure, and duration of exposure, and compared to workers in the low exposure
category, were also determined. The low exposure categories were 0.1-1.9 ppm
for peak exposure, 0.1-0.4 ppm for average exposure intensity, 0.1-0.4 ppm-year
for cumulative exposure and 0.1-4.9 years for duration of exposure. It was
assumed that the exposure rate for all jobs, and over time, was constant. Peak
exposure was estimated from knowledge of the job tasks and a comparison with
8-hour time-weighted averages. Potential confounding was evaluated for duration
of exposure to 11 other substances (including benzene) and for duration of work
as a chemist or laboratory technician.
Mortality from all causes, all cancers, and all solid malignant neoplasms was
significantly less than expected, regardless of exposure status. Similar results
were found for lymphatic and haematopoietic cancers in general and for specific
cancer types including non-Hodgkin's lymphoma, multiple myeloma and
leukaemia. For Hodgkin's disease, there was a slight increase, not statistically
significant (SMR 1.3, 95%CI 0.8 to 2.0), amongst exposed workers. However, a
statistically significant increased risk was seen for lymphohaematopoietic cancers
with peak exposure of 2-3.9 ppm (RR = 1.7, 95% CI 1.1 2.6) and > 4.0 ppm
(RR = 1.9 95% CI 1.3 2.8), and for an average exposure intensity of 0.5 0.9
ppm (RR = 1.6, 95% CI 1.1 2.4) and > 1.0 ppm (RR = 1.5, 95% CI 1.01 2.2).
A statistically significant exposure response relationship was seen between peak
exposure to formaldehyde and all lymphohaematopoietic cancers (Ptrend = 0.002).
This was primarily due to an exposure response relationship for myeloid
leukaemia (Ptrend = 0.009, with a RR = 3.5, 95% CI 1.3 - 9.4 for the highest peak
exposure category of > 4 ppm). For average exposure intensity and myeloid
leukaemia a statistically significant increased risk was seen for the highest
exposure category of > 1ppm (RR = 2.5, 95% CI 1.03 - 6.0), although the
exposure response relationship was only of borderline significance (Ptrend =
0.088). For both duration and cumulative exposure only slightly increased risks,
not statistically significant, were seen for lymphohematopoietic cancers and
myeloid leukaemia specifically. The exposure response relationship for these
endpoints was not statistically significant. For Hodgkin's lymphoma, a
statistically significant increased risk was seen in workers with average exposure
intensity of 0.5-0.9 ppm (RR 4.7, 95% CI 1.6 - 13.8) but not > 1 ppm.
Additionally, a statistically significant exposure response relationship was seen
for both peak and cumulative exposure and Hodgkin's disease (Ptrend = 0.042 and
Ptrend = 0.045, respectively). Generally, slight non-significant increased risks were
seen for multiple myeloma and lymphatic leukaemia for all the analyses
undertaken.
102 Priority Existing Chemical Assessment Report No. 28
In summary, Hauptman et al. (2003) found a significant trend and association for
myeloid leukaemia with both peak and average exposure intensity to
formaldehyde, a weak association with duration of exposure, and no association
with cumulative exposure.
The NCI cohort was recently reanalysed by Marsh and Youk (2004). SMRs were
derived for the US national and regional rates and internal cohort-based RR for
formaldehyde exposure metrics (highest peak, average intensity, cumulative and
duration) using both the Hauptmann et al. (2003) categories and an alternative
categorization based on tertiles of deaths from all leukaemia among exposed
subjects. Additionally, for highest peak exposure, RRs were determined by the
duration of time worked in the highest peak category and the time since highest
exposure, while for average intensity of exposure RRs were determined by the
duration of exposure and the time since first exposure. Similar to Hauptmann et
al. (2003), no association was seen for cumulative and duration of formaldehyde
exposure. However, the comparison using external groups revealed that the
elevated leukaemia and myeloid leukaemia RRs and associated trends reported by
Hauptmann et al. (2003) for highest peak exposure and average exposure
intensity occurred because null (or slight) to moderate mortality excesses were
compared with statistically significant baseline category deficits in death.
Furthermore, the alternative analysis of duration of time worked in the highest
peak exposure category did not indicate an association or higher increased risk
among those workers who had experienced high peaks for a longer time.
Similarly, no consistent evidence was seen that leukaemia or myeloid leukaemia
risks increased for average exposure intensity and duration of exposure in a given
average exposure intensity category, time from the first exposure, highest peak
exposure, and for combined average exposure intensity and first exposure.
Marsh et al. (1996) studied 1 of the 10 industrial plants included in the National
Cancer Institute cohort. However, since this study is included in the Hauptmann
et al. (2003) studies and the results for `all lymphopoietic tissues' are briefly
reported, a detailed summary of this study is not provided.
A recent analysis of the above 3 recent cohorts (Pinkerton et al., 2004, Coggon et
al., 2003, and Hauptman et al., 2003) was undertaken to evaluate the evidence for
causality (Cole and Axten, 2004), based on epidemiologic criteria modified and
updated by Cole (1997) from the criteria advanced in 1965 by Hill (Hill, 1965).
Cole and Axten (2004) point out that the recent analyses of leukaemia findings in
the NCI cohort by Hauptman (2003) that address dose-response relationships are
not based on SMRs and the attendant comparison with general population rates,
but internal comparisons expressed as RRs. Cole and Axten (2004) state that it is
unlikely that there is any excess of myeloid leukaemias among NCI exposed
workers, as the SMR for all leukaemia is < 1.00 based on 65 deaths of which 43%
are myeloid leukaemias, while in the US, among white males 20 years of age and
over, the corresponding percentage based on deaths in 1979 - 1981 is 46%. Using
the NCI observed number of 43% for myeloid leukaemias and the same approach,
Cole and Axten (2004) estimated that, from the deaths for all leukaemia, the
maximum likely SMR for myeloid leukaemias among the high exposure group in
the study by Coggon et al. (2003) would be < 1.00.
Cole and Axten (2004) applied four criteria for determining causation. They
report that the first criteria `replicability' was not met, as the study by Coggon et
103
Formaldehyde
al. (2003), which probably involved the highest exposure, is negative. Also the
study reported by Pinkerton et al. (2004) `is less positive' than the NCI cohort,
which was not highly consistent within itself. The second criteria `strength' of
association was not met, as the SMR as a whole for the collective body of data is
< 1.00 for leukaemia. Even if the Coggon et al. (2003) study is ignored, the SMR
for myeloid leukaemia for the other two studies combined was estimated to be
< 1.00 by the authors (data not presented). The third criteria `coherence' was not
met as the available data indicates that inhaled formaldehyde is rapidly
metabolised, does not reach the bone marrow and is, therefore, unlikely to induce
leukaemia. The fourth criteria `response to manipulation' was not met for the NCI
cohort, as the long-term trend in reduction of formaldehyde exposure in the plants
has not been followed by a reduction in the previously observed risk of leukaemia
or myeloid leukaemia (i.e. only the recent report and not earlier ones suggest a
myeloid leukaemia excess). Therefore, the formaldehyde-leukaemia hypothesis
failed each of the four criteria of general causation applied by the authors, who
concluded that the increased incidence of leukaemia reported in these three large
cohort studies was not plausible.
Mortality was investigated in workers who were exposed to wood and enrolled in
the American Cancer Society's Cancer Prevention Study-II in 1982 (Stellman et
al., 1998). The cohort was followed up for 6 years and consisted of 363 823 men.
Information on exposure to formaldehyde was obtained through self-reporting.
Incidence density ratios were used to determine RR which were adjusted for age
and smoking. The comparison group was men exposed to formaldehyde but not
employed in a wood-related job and who reported no exposure to wood dust. An
increased risk was seen for woodworkers exposed to formaldehyde for all
lymphatic and haematopoietic cancers (RR = 3.4, 95% CI 1.1 10.7) and
specifically leukaemia (RR 5.8, 95% CI 1.4 23.3). In contrast, in men not
employed in a wood-related job but exposed to formaldehyde, a non-significant
increased risk was seen for all lymphatic and haematopoietic cancers (RR = 1.2,
95% CI 0.8 1.8), with no increased risk seen specifically for leukaemia or non-
Hodgkin's lymphoma.
A standardised proportionate cancer incidence study was undertaken of workers
in Denmark born between 1897 and 1964 whose cancer was diagnosed between
1970 and 1984 (Hansen & Olsen, 1995). The cohort consisted of 91 182 men
identified from the Danish cancer registry and for whom work histories were
obtained using the Supplementary Pension Fund. The Danish Product Register
was used to determine potential formaldehyde exposure. Standardised
proportionate incidence ratios were determined for specific cancers and adjusted
for age and calendar time. For non-Hodgkin's lymphoma, Hodgkin's lymphoma
and leukaemia the observed number of cases was either close to, or less than,
expected.
A mortality study of workers exposed to formaldehyde at an iron foundry in the
US was undertaken (Andjelkovich et al., 1995). The cohort consisted of 3929
men employed during the period from January 1960 through to May 1987. SMRs
were derived using the person-years-at-risk method and the mortality of this
group was compared with the US population and 2032 workers at the foundry
with no exposure to formaldehyde during the same time period. After reviewing
work histories exposures were determined to be 0, 0.05, 0.55 or 1.5 ppm
formaldehyde. Mortality from all cancers was close to the national rate for both
104 Priority Existing Chemical Assessment Report No. 28
the exposed and unexposed population. For the exposed population, mortality
from each of lymphosarcoma and reticulosarcoma, Hodgkin's lymphoma and
leukaemia was less than expected.
A mortality study of workers at a formaldehyde resin plant in Italy was
undertaken (Bertazzi et al., 1986; 19891). The cohort consisted of 1332 men
employed at the plant for at least 30 days between 1959 and 1980 and followed
up for a further 6 years (up to 1986) in the second study. The only exposure data
available for formaldehyde were airborne measurements taken between 1974 and
1979. Mean levels were 0.2 to 3.8 mg/m3 formaldehyde with maximum values up
to 9.8 mg/m3 reported. Work histories were reconstructed for past employees.
SMRs were derived using person-years-at-risk method, and the mortality of this
group compared with the local and national population, and adjusted for gender,
age and calendar time. Mortality for all cancers was slightly higher compared to
local rates and significantly higher compared to the national rate (SMR = 1.5,
95% CI 1.1 2.1). A non-significant increased risk was seen for haematologic
cancers (SMR = 1.7, confidence intervals not reported) when compared with the
national rate, which was reported to become `very modest' when compared with
the local rate. Additionally, it was reported that analysis by latency and duration
of employment failed to suggest an association.
A nested case-control study of non-Hodgkin's lymphoma (52 cases), multiple
myeloma (20 cases), nonlymphocytic leukaemia (39 cases) and lymphatic
leukaemia (18 cases) was conducted within a cohort of 29 139 men from two
chemical manufacturing facilities and a research and development centre (Ott et
al., 1989). Cases that had died between 1940 and 1978 were each matched with
five controls from the total employee cohort employed in the same decade with
the same survival period. Exposure to 21 chemicals (including formaldehyde)
was determined based on workplace area and activities. ORs for formaldehyde
were 2.0, 1.0, 2.6 and 2.6 for non-Hodgkin's lymphoma, multiple myeloma,
nonlymphocytic leukaemia and lymphocytic leukaemia, respectively (based on
only 1 2 cancers of each type). Confidence intervals were not reported. It was
reported that the age adjusted analysis did not significantly change the ORs (data
not presented).
Cancer mortality and incidence were investigated among workers exposed to
formaldehyde at a Swedish plant manufacturing abrasive materials (Edling et al.,
1987). The cohort consisted of 911 workers employed between 1955 and 1983.
Exposure to formaldehyde was reported to be 0.1 1.0 mg/m3 (no further details
provided). Expected numbers were calculated using the person-years-at-risk
method for the national population and stratified for age, calendar year and
gender. Mortality from all cancers was close to the expected rate. A non-
significant increased risk was observed for non-Hodgkin's lymphoma (SMR =
2.0, 95% CI 0.2 7.2) and multiple myeloma (SMR = 4.0, 95% CI 0.5 14.4).
This analysis was based on the presence of only 2 cancers of each type in the
exposed group. No other lymphohaematopoietic cancers were observed.
Information is also available from a number of cohort studies in professionals,
such as embalmers, funeral directors and pathologists. While it would be
anticipated that occupational exposure would include formaldehyde among such
1
Only the abstract was available in English
105
Formaldehyde
professionals, no information on occupational exposure was reported in these
studies and, hence, the etiologic agent could not be identified.
A study of the mortality of pathologists and medical laboratory technicians in the
UK by Harrington and Shannon (1975) was followed up by Harrington and Oakes
(1984), and new entrants added to the cohort. A further, and most recent, follow
up of this cohort was by Hall et al. (1991) who also included additional entrants
to the cohort. In this most recent study, vital status was determined in a cohort of
4512 members of the Royal College of Pathologists followed from December
1973 to December 1986. Only 3068 male pathologists and 803 female
pathologists were analysed and it is not transparent from the article why the 740
unaccounted individuals were not included in the analysis. SMRs were derived
and compared with rates in the general population of England, Wales or Scotland
adjusted for gender, age and calendar time. Mortality from all cancers was
significantly below the expected rate for males in England and Wales (SMR =
0.4, 95% CI 0.3 0.6) but was close to that expected for females in England and
Wales. Increased risks, not statistically significant, were seen for lymphatic and
haematopoietic cancers, and specifically leukaemia, in male (SMR = 1.4, 95% CI
0.7 2.7 and SMR = 1.3, 95% CI 0.3 3.7, respectively) and females (SMR =
1.8, 95% CI 0.04 9.8 and SMR = 4.3, 95% CI 0.1 24.2) in England and
Wales. No information on lymphatic and haematopoietic cancers or leukaemia
was reported for male pathologists in Scotland.
The causes of mortality of 3649 white and 397 non-white male US embalmers
and funeral directors, who had died between 1975 and 1985 were examined
(Hayes et al., 1990). Subjects had been identified through licensing boards and
state funeral directors' associations from 32 states and the District of Columbia,
the National Funeral Directors Association and nine state offices of vital
statistics. The proportionate mortality ratio (PMR) and the proportionate cancer
mortality ratio (PCMR) were determined and compared with the national
population adjusted for sex, race, age and calendar year. For PMRs the mortality
for all cancers was significantly greater than expected for whites and non-whites.
A statistically significant excess was seen for embalmers and funeral directors for
lymphatic and haematopoietic cancers (PMR = 1.3, 95% CI 1.1 1.6 for whites,
and PMR = 2.4, 95% CI 1.4 4.0 for non-whites). The PCMR for these cancers
was also significantly elevated (PCMR = 1.3, 95% CI 1.1 1.6). When analysis
of cell-type-specific mortality was undertaken a borderline statistically significant
excess was seen in white males only for myeloid leukaemia (PMR = 1.6, 95% CI
1.0 2.4) and other unspecified leukaemia (PMR = 2.1, 95% CI 1.2 3.3).
Additionally, when lymphatic and haematopoietic cancers were examined by
occupation, a statistically significant excess was seen for funeral directors (PMR
= 1.6, 95% CI 1.2 1.9) but not embalmers.
A mortality study of male pathologists listed in the US Radiation Registry of
Physicians and the American College of Pathologists was conducted (Logue et
al., 1986). The cohort consisted of 5585 members enrolled from January 1962 to
December 1977 and followed to December 1977. Age adjusted mortality rates
were compared with a cohort of 7942 male radiologists. Additionally, SMRs were
determined using the person-years method and compared with deaths in white
males for the national population in 1970. SMRs were adjusted for age and
calendar time for many causes of death. The age-adjusted mortality for all cancers
was slightly lower in pathologists compared to radiologists, as was mortality for
106 Priority Existing Chemical Assessment Report No. 28
each of lymphatic and haematopoietic cancers, and leukaemia. The SMRs for
lymphatic and haematopoietic cancers and leukaemia in pathologists were 0.48
and 1.06, respectively. Confidence intervals were not reported, but neither of
these values was statistically significant.
A mortality study of members of the American Association of Anatomists was
conducted (Stroup et al., 1986). The cohort consisted of 2317 men who joined the
association between 1888 and 1969. Vital status was determined between 1925
and 1979. SMRs were derived for the US white male population for the period
1925 to 1979 and for the male members of the American Psychiatric Association
(APA) who joined between 1900 and 1969 as reference groups. SMRs, also
adjusted for age and time-specific mortality rates, were compared with the
national population. Mortality from all cancers was significantly less than
expected (SMR = 0.6, 95% CI 0.5 0.8). An increased risk, not statistically
significant, was seen for leukaemia (SMR = 1.5, 95% CI 0.7 2.7) in anatomists
compared to the US white male population. Cell-type-specific mortality rates for
US white males were available beginning 1969, and for the period 1969 to 1979.
An increased risk was seen for chronic myeloid leukaemia (SMR = 8.8, 95% CI
1.8 25.5) though this increase was based on only 3 cases. In contrast, when
members of the APA were used as the reference group no increased risk was seen
for leukaemia, though this analysis was only up to 1969 and did not undertake
cell-type-specific mortality for leukaemia.
A study of the mortality of Ontario (Canada) undertakers was conducted (Levine
et al., 1984). The cohort consisted of 1477 men licensed during 1928 through to
1957 and followed up until the end of 1977. Because mortality rates were not
available before 1950, person years and deaths in the cohort were not analysed
prior to this date. Therefore, SMRs adjusted for age and calendar year were
derived and compared with men in Ontario between 1950 and 1977. Mortality
from all cancers was slightly lower than expected. SMRs were not consistently
reported for the various cancers. For lymphatic and haematopoietic cancers, 8
were observed compared to 4 expected, and specifically for leukaemia 4 were
observed compared to 2.5 expected. However, these observed increases were not
statistically significant.
A cohort study of the mortality of embalmers licensed in California (US)
consisted of 1007 white males licensed between 1916 and 1978 and who died
between 1925 and 1980 (Walrath & Fraumeni, 1984). PMRs and PCMRs were
determined and compared with the national population adjusting for age, race and
calendar year. The PMR for mortality from all cancers was significantly greater
than expected (PMR 1.2). The PMR for cancers of the lymphatic and
haematopoietic system was 1.2 and specifically for leukaemia 1.75, which was a
statistically significant excess. Among embalmers licensed for 20 years or more
the PMR for leukaemia was also statistically significant (PMR 2.2). Additionally,
for leukaemia, 6 of the 12 observed cases were myeloid (4 expected). Confidence
intervals were not reported in this study. The number of observed lymphosarcoma
and reticulosarcoma cancer deaths was not elevated.
A study of the mortality of embalmers licensed in New York State (US) was
conducted (Walrath & Fraumeni, 1983). The cohort consisted of 1132 white
males and 79 non-white males licensed between 1902 and 1980 and who died
between 1925 and 1980. PMRs and PCMRs were determined and compared with
the national population adjusting for age, race and calendar year. The PMR for
107
Formaldehyde
mortality from all cancers was slightly greater than expected for white males and
significantly elevated in non-white males (PMR 1.4). The PMR for lymphatic and
haematopoietic cancers, lymphoma and reticulosarcoma, other lymphatic cancers
and leukaemia was 1.2, 1.1 (PCMR 0.8), 1.2 and 1.4 (PCMR 1.2), respectively,
for white males. Confidence intervals were not reported but none of these values
was statistically significant. For leukaemia, of the 12 observed cases 6 were
myeloid (4.1 expected). For non-white males it was reported that mortality from
cancers of the lymphatic haematopoietic system was significantly increased (data
not provided, but stated to be on the observation of only 3 such cases). There was
no significant difference in PMRs for white males when analysed by time from
first licence and by age at first licence.
Summary
Several epidemiology studies have shown a small increased risk for
lymphohaematopoietic cancers, particularly myeloid leukaemia, in workers who
may have been exposed to formaldehyde at work. This has been observed
principally in studies of professional workers. In these studies, no information on
occupational exposures was available and it cannot be excluded that the observed
increases were due to occupational exposures other than formaldehyde. Until
recently, these findings have not been supported by studies of industrial workers.
However, 2 of 3 recent updates of cohort studies of industrial workers provide
some evidence for increased risk. An association was seen in an analysis of the
largest cohort of US industrial workers by Hauptmann et al. (2003) between peak
exposure to formaldehyde and leukaemia, with a stronger association for myeloid
leukaemia. However, a reanalysis of the data by Marsh and Youk (2004), using
additional analysis, provided little evidence to support the suggestion of a casual
association. An increased risk for leukaemia was also seen in a large cohort of US
garment workers (Pinkerton et al., 2004), while no such increased risk was
observed in a large cohort of UK industrial workers (Coggon et al., 2003).
Overall, it is considered that the epidemiology data are insufficient to establish a
causal association between occupational exposure to formaldehyde and
leukaemia. This conclusion is supported by a recent evaluation of the substantial
biological evidence on the disposition and toxicity of inhaled formaldehyde in
experimental animals and humans, particularly as it pertains to effects on the
blood and bone marrow (Heck and Casanova, 2004). The authors of this review,
which did not include an evaluation of the available epidemiology evidence,
concluded that a leukemogenic effect of inhaled formaldehyde is not biologically
plausible. Heck and Casanova (2004) give several reasons for drawing this
conclusion, including rapid metabolism at the site of deposition, no measurable
effects on bone marrow tissues in several species following inhalation exposure,
and failure of formaldehyde to induce leukaemia in several long-term bioassays.
Pancreatic cancer
Collins et al. (2001) conducted a meta-analysis of 14 epidemiological studies (8
cohort mortality studies1, 4 proportionate mortality2 and 2 case-control studies3),
published between 1983 1999, that reported pancreatic cancers and
1
Levine et al., 1984; Blair et al., 1986; Stroup et al., 1986; Stayner et al., 1988; Matanoski, 1991;
Hall et al., 1991; Gardener et al., 1993; Andjelkovich et al., 1995
2
Walrath and Fraumeni, 1983; 1984; Hayes et al., 1990; Hansen and Olsen, 1995
3
Gerin et al., 1989; Kernan et al., 1999
108 Priority Existing Chemical Assessment Report No. 28
occupational exposure to formaldehyde. Direct exposure measurements were
provided in some studies, for others information on job titles was used to
determine exposure levels. Overall, a very slight increased risk was seen for
pancreatic cancer and formaldehyde exposure (mRR = 1.1, 95% CI 1.0 - 1.3) with
no substantial heterogenicity seen across studies (p = 0.12). When studies were
stratified by occupation the greatest risk was seen in embalmers (mRR = 1.3, 95%
CI 1.0 -1.6) and pathologists and anatomists (mRR = 1.3, 95% CI 1.0 - 1.7) with
a greater heterogenicity seen (p = 0.90 and p = 0.30, respectively), indicating a
greater consistency among studies when stratified by job type. No increased risk
was seen for industrial workers (mRR = 0.9, 95% CI 0.8 - 1.1), who the authors
reported were likely to have had higher average exposure and higher peak
exposures to formaldehyde. Additionally, in the only two studies that evaluated
pancreatic cancer risk with exposure levels (Blair et al., 1986; Kernan et al., 1999
both in industrial workers), no linear trend was seen for pancreatic cancer and
increasing exposure to formaldehyde. Thus, it cannot be excluded that exposures
other than formaldehyde may have attributed to the very small increased risk
observed among embalmers, and pathologists and anatomists, while the exclusion
of studies with no reported cases of pancreatic cancer among formaldehyde
workers may have biased the review towards a positive result.
Ojajarvi et al. (2000) conducted a meta-analysis of 92 epidemiological studies
published between 1969 and 1998 that reported cases of pancreatic cancer and
occupational exposure(s) and/or job categories. These 92 studies, which were not
clearly identified, presented data for 161 different exposed populations, with
exposure assessed in 57 populations through job titles, in 25 through expert
assessments, in 15 through job exposure matrices, and in 60 through other, mixed,
or unexplained methods. Industrial hygiene measurements were available for only
4 populations. Data were organised and analysed by populations rather than
studies. A total of 5 populations were identified that had received exposure to
formaldehyde. It is not reported how exposure was assessed in these five
populations. No increased mRR was seen for formaldehyde exposure and
pancreatic cancers overall. Similarly, stratification of studies by sex and
diagnostic quality (i.e. whether histological diagnosis was conducted) or study
type did not result in an increased mRR.
A population-based case-control study based on death certificates from 24 US
states was conducted to determine if occupations/industries or work-related
exposures to solvents (including formaldehyde) were associated with pancreatic
cancer deaths (Kernan et al., 1999). A total of 63 097 deaths from pancreatic
cancer were identified between 1984 - 1993, and matched by state, race, gender
and age to 252 386 controls who died from causes other than cancer in the same
time period (excluding deaths due to pancreatic diseases). Data on occupation and
industry were obtained from death certificates, and exposure determined using a
job-exposure matrix. After adjustment for potential confounding factors, such as
age, race, gender, marital status, metropolitan and residential status, a
significantly increased risk was observed between low and medium levels of
formaldehyde exposure and pancreatic cancers in white males (OR = 1.2, 95% CI
1.1 1.4 and OR = 1.2, 95% CI 1.1 1.3, respectively) and low, medium and
high levels of formaldehyde exposure in white females in the absence of a dose
response (OR = 1.3, 95% CI 1.1 1.5, OR = 1.4, 95% CI 1.2 1.7 and OR = 1.3,
95% CI 1.0 1.7). Similarly for probability of exposure, a significantly increased
risk was only seen between low and medium probabilities of formaldehyde
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Formaldehyde
exposure and pancreatic cancers in white males. For white females, a significant,
dose-related, increased risk was seen for low, medium and high probabilities of
formaldehyde exposure (OR = 1.3, 95% CI 1.1 - 1.6, OR = 1.4, 95% CI 1.2 - 1.7
and OR = 1.5, 95% 1.3 - 1.9, respectively). No significantly increased risks of
pancreatic cancer were seen in black males and black females between
formaldehyde exposure intensity and probability of exposure. When sex and
racial type were pooled together and analysed according to probability of
exposure a significantly increased risk was seen for low (OR = 1.2, 95% CI 1.1 -
1.3), medium (OR = 1.2, 95% CI 1.1 - 1.3) and high (OR = 1.4, 95% CI 1.2 - 1.6)
probabilities. In contrast, when cases were analysed according to intensity of
exposure, a significant increase was only seen for low (OR = 1.2, 95% CI 1.1
1.3) and medium exposure levels (OR = 1.2, 95% CI 1.1 1.3). Although a dose-
response pattern was not apparent for intensity of exposure, the dose-response
relationship for probability of exposure was usually consistent across each level
of exposure intensity, though this is attributed to incidences observed in white
females and not white males, black males or black females.
Overall, these studies do not support an association between formaldehyde
exposure and pancreatic cancers.
11.7 Reproductive toxicity
Only limited information is available for this endpoint in humans. A Finnish
retrospective study examined fertility among female woodworkers exposed to
gaseous formaldehyde between 1985 and 1995 (Taskinen et al., 1999). Data on
pregnancy history, time to pregnancy, occupational exposure and previous
gynaecological diseases were obtained by self-reported questionnaires. From a
total of 1094 women who had delivered at least one child since working in the
wood industry 602 (55%) responded to a mailed questionnaire. This total
contained 235 women who were exposed to formaldehyde. For women exposed
to formaldehyde, workplace exposure measurements were obtained. If such
information was not available a judgement was made to obtain exposure
information from a "comparable" workplace. Women were assigned into low
(119 cases), medium (77 cases) and high (39 cases) dose groups, for which mean
exposure levels were determined to be 0.07, 0.14 and 0.33 ppm formaldehyde,
respectively. Time to pregnancy data were used to determine the fecundability
density ratio (FDR) of women exposed to formaldehyde compared to those who
were not exposed. Following adjustments for potential confounders, such as
employment, maternal smoking and alcohol consumption, irregular menstrual
cycles and number of children, the FDR was significantly decreased in the high
dose group only (0.64, 95% CI 0.43-0.92). FDR values in the medium and low
dose groups were 0.96 (95% CI 0.72-1.26) and 1.09 (95% CI 0.86-1.37),
respectively. Exposure to other workplace chemicals, such as organic solvents
and phenols, was not associated with decreased FDR.
However, limitations are present in the design of this study, such as the use of
judgement or self-reports of workplace exposure to gaseous formaldehyde. This
could have introduced recall bias into the study. When workplace exposure data
were obtained, it is unclear what type of monitoring data were used (e.g. personal
or area exposure data). Failure to clinically diagnose an effect on fertility in
women who reported increased time to pregnancy is also a study limitation.
Furthermore, as the degree of fertility is related to both partners, fathers should
110 Priority Existing Chemical Assessment Report No. 28
have been interviewed to determine any confounding factors, and if required,
examination of paternal exposure conducted. Overall, the limitations in study
design prevent any reliable conclusions to be drawn from the data on the potential
reproductive toxicity of formaldehyde.
In a Russian cross-sectional study of female workers exposed to gaseous
formaldehyde through use of urea-formaldehyde resins by Shumilina (1975)
(reported in Russian, summary from IPCS, 1989), though an increased incidence
of menstrual disorders and problems with pregnancy were reported, there was no
difference in fertility between the exposed and control groups. However, the
limited details reported together with the presence of possible confounding
factors that were not evaluated mean that no reliable conclusions can be drawn
from this study.
A cross-sectional study investigated sperm count and morphology in 11 autopsy
workers exposed to formaldehyde for between one month and "several" years
(Ward et al., 1984). Time-weighted exposures of 0.61-1.32 ppm gaseous
formaldehyde (weekly exposure range 3-40 ppm/hour) were obtained from
personal and area monitoring. Exposed workers were matched for age and
customary use of alcohol, tobacco and marijuana to controls. No effects on sperm
count or morphology were observed in formaldehyde-exposed workers. However,
the small study size limits the significance that can be attached to this result.
11.8 Developmental toxicity
A number of epidemiology studies are available investigating the effects of
occupational exposure to a number of chemicals, including formaldehyde, on
spontaneous abortions. These surveys have reported conflicting results on the
relative risk (RR) of spontaneous abortion among women occupationally exposed
to formaldehyde.
In a cross-sectional study of female workers in university laboratories in Sweden,
the RR was calculated to be 2.6 (95% CI 0.9-7.4) among 10 women exposed to
formaldehyde (Axelsson et al., 1984). In an American case-control study, the RR
was calculated to be 2.1 (95% CI 1.0-4.3) in 51 cosmetologists (e.g. hairdressers
and beauticians) exposed to formaldehyde after adjustment for potential
confounders (John et al., 1994). In a Finish case-control study of female workers
in laboratories the RR was calculated to be 3.5 (95% CI 1.1-11.2) in 11 women
exposed to formaldehyde (Taskinen et al., 1994). A Finnish cohort study
evaluated spontaneous abortions in 52 female wood workers and calculated the
RR to be 3.2 (95% CI 1.2-8.3), 1.8 (95% CI 0.8-4.0) and 2.4 (95% CI 1.2-4.8) in
the high, medium and low formaldehyde exposure groups, respectively, after
adjustment for potential confounders (Taskinen et al., 1999).
In contrast, no increased RR of spontaneous abortion and occupational exposure
to formaldehyde was seen in a Finish cohort study of 50 hospital sterilising staff
(Hemminki et al., 1982), a Finish case-control study of 30 nurses (Hemminki et
al., 1985), a French cohort study of 139 nurses (Stucker et al., 1990), and a Finish
population-based case-control study of 1808 women (Lindbohm et al., 1991) who
all reported exposure to formaldehyde. Additionally, no increased RR was seen
between occupational exposure to formaldehyde and malformations in those
studies that assessed this outcome (Hemminki et al., 1985; Taskinen et al., 1994).
111
Formaldehyde
A comprehensive review of all the available data, including the meta-analysis
data evaluating the relationship between spontaneous abortions and occupational
exposure to formaldehyde, was conducted by Collins et al. (2001). For studies
that showed an increased RR, some important limitations in study design were
highlighted, such as the use of self-reported data or judgement on the level of
exposure with no attempt to validate the exposure estimates with measurements.
Furthermore, only the studies by John et al. (1994) and Hemminki et al. (1982)
made adjustments to RR estimates for important confounding factors, such as
age, heavy lifting or prolonged standing, though none of the studies examined
other exposures that may have contributed to the risk of spontaneous abortions.
For the meta-analysis, when occupation was considered, an increased mRR for
spontaneous abortions was only observed among laboratory workers. However,
this only occurred in those studies that relied on self-reports of exposure,
suggesting a potential recall bias. Additionally, no increased mRR was seen in
studies that used evaluation of work tasks to determine exposure. Furthermore,
evidence of publication bias was found, as increased mRRs were limited to small
studies. When these biases were taken into account no association was seen
between spontaneous abortions and exposure to formaldehyde (mRR= 0.7 [95%
CI 0.5-1.0]).
A Lithuanian population-based case-control study investigating low birth weight
is available (Grazulevicine et al., 1998). Data were obtained from self-reported
questionnaires and geographic air pollution data. No statistically significant
association between low birth weight and formaldehyde exposure was seen after
adjustment for confounding factors, such as education, smoking status, maternal
hazardous work, parity and infectious diseases. Axelsson et al., (1984) and
Taskinen et al. (1994) also found no association between low birth weight and
formaldehyde exposure. Low birth weight of offspring, anaemia and toxaemia
were more frequent in the formaldehyde-exposed group than controls in a study
by Shumilina (1975). The limited details reported, together with the presence of
possible confounding factors that were not evaluated, means that no reliable
conclusions can be drawn from this study (reported in Russian, summary from
IPCS, 1989).
112 Priority Existing Chemical Assessment Report No. 28
12. Hazard Classification
This section discusses the classification of the health effects of formaldehyde
according to the NOHSC Approved Criteria for Classifying Hazardous
Substances (the Approved Criteria) (NOHSC, 2004). The Approved Criteria are
cited in the NOHSC National Model Regulations for the Control of Workplace
Hazardous Substances (NOHSC, 1994c) and provide the mandatory criteria for
determining whether a workplace chemical is hazardous or not.
Where adequate human data were unavailable and/or inappropriate, the
classification for health hazards has been based on experimental studies (animal
and in vitro tests). In extrapolating results from experimental studies to humans,
consideration was given to relevant issues, such as quality of data, weight of
evidence, metabolic and mode of action/mechanistic profiles, inter- and intra-
species variability and relevance of exposure levels.
Classification of formaldehyde in accordance with the OECD Globally
Harmonized System of Classification and Labelling of Chemicals (GHS)
(UNSCEGHS, 2005) can be found in Appendix 4.
Formaldehyde is currently listed in the OASCC's Hazardous Substances
Information System (DEWR, 2004) with classification of R23/24/25 (toxic by
inhalation, in contact with skin, and if swallowed), R34 (causes burns), R43 (may
cause sensitisation by skin contact) and R40 (limited evidence of a carcinogenic
effect, Category 3 carcinogen).
12.1 Acute toxicity
Although there are old reports of human deaths following ingestion of
formaldehyde solution, no reliable quantitative data are available on the doses
consumed. Recent cases reported ulceration and damage along the aero-digestive
tract, with a feeding jejunostomy performed following ingestion of approximately
700 mg/kg bw of formaldehyde solution, and a tracheostomy and gastrectomy
performed following ingestion of an unquantifiable dose. In animal studies, oral
LD50 values of 800 and 260 mg/kg bw are available in the rat and guinea-pig,
respectively. A dermal LD50 of 270 mg/kg bw in the rabbit, and 4-hour
inhalation LC50 values of 480 and 414 ppm (0.578 and 0.497 mg/L) in the rat
and mouse, respectively, are also available.
The LC50 value in rats, the preferred species, equates to `toxic' by inhalation
while the value in mice is almost at the cut-off value for toxic/very toxic. Thus, it
is proposed that the classification as `toxic' be retained. The oral LD50 values
support classification as `harmful'. However, although no deaths occurred in
recent cases of ingestion in humans they are considered to represent a potentially
lethal dose given the significant toxicity observed, and drastic medical procedures
undertaken. Consequently, it is considered appropriate to regard formaldehyde as
`toxic' by the oral route and retain its current classification as such. The dermal
LD50 value in rabbits supports classification as `toxic'.
Classification: Based on the human and animal data, formaldehyde meets the
Approved Criteria for classification as `Toxic by inhalation' (risk phrase R23),
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Formaldehyde
`Toxic in contact with skin' (risk phrase R24) and `Toxic if swallowed' (risk
phrase R25).
12.2 Irritation
Skin reactions have been reported in humans, however, because formaldehyde
solution is a known skin sensitiser it is difficult to determine whether observed
reactions are due to irritation or sensitisation.
In animals, although formaldehyde solution is reported to be a primary skin and
eye irritant, this is based on old anecdotal evidence rather than robust animal
studies. Data are available from a recent rabbit low-volume eye test (LVET)
where 10 ”l of 37% formaldehyde solution produced irritation of the cornea,
conjunctiva and iris three hours post-instillation. Additionally, `necrosis/loss' of
corneal keratocytes was reported in eyes from animals sacrificed one day post-
instillation, and corneal injury was determined to extend at times to 93.2% of
corneal thickness. In a repeated dermal study in mice, skin irritation was reported
following application of > 0.5% formaldehyde solution, 5 days/week for 3 weeks.
A single 6-hour exposure to 15 ppm (18 mg/m3) gaseous formaldehyde produced
histological changes to the nasal tract of rats indicative of a direct irritant effect.
Data are also available in Alarie assays in mice. Although the reliability of this
assay has been questioned (i.e. non-reproducibility of results and species variation
in RD50 values) the data supports the histological findings that gaseous
formaldehyde causes irritation to the respiratory tract.
Thus, there are sufficient data to show formaldehyde is a skin, eye and respiratory
irritant. The observations of severe irritation in the rabbit LVET and
comprehensive injury to the cornea with 10 ”l of 37% formaldehyde solution,
along with skin irritation at concentrations > 0.5% in a mouse repeat dermal
study, raise concerns that corrosivity could be observed if animal studies were
conducted to OECD Test Guidelines, i.e., at higher concentrations in skin studies
and with 0.1 ml in eye studies. Additionally, corrosive injuries to the oesophagus
and stomach were observed in humans following ingestion of formaldehyde
solution. Consequently, it is considered appropriate to regard formaldehyde
solution as corrosive.
Classification: Based on the human and animal data, including observations in
cases of human ingestion, formaldehyde meets the Approved Criteria for
classification as `causes burns' (risk phrase R34).
12.3 Sensitisation
Formaldehyde solution is a known skin sensitiser and is included in standard
series for patch testing. In addition to skin sensitisation being clearly observed in
numerous clinical trials and case reports in humans, positive results have been
observed in a large number of animal studies in guinea-pigs and mice.
When determining whether a chemical is a respiratory sensitiser immunological
mechanisms do not have to be demonstrated, and for human evidence it is
necessary to take into account the size of the population and the extent of
exposure. Although large numbers of people are exposed to gaseous
formaldehyde, there are very few reported cases of well-conducted bronchial
114 Priority Existing Chemical Assessment Report No. 28
challenge tests in humans giving a positive response to formaldehyde.
Conversely, several studies have reported negative bronchial challenge tests.
However, limited evidence indicates that formaldehyde may elicit a respiratory
response in some very sensitive individuals with bronchial hyperactivity,
probably through irritation of the airways. Additionally, studies determining the
effect on lung function following workplace exposure to formaldehyde in air,
along with epidemiology studies, do not indicate formaldehyde to be a respiratory
sensitiser. There is generally little correlation between the presence of
formaldehyde-specific antibodies and respiratory symptoms in humans. Similarly,
in animals, the results of immunoglobulin-E tests and cytokine profiles do not
provide evidence that formaldehyde can induce respiratory sensitisation, though
there is limited evidence available indicating that it may enhance allergic
responses to other respiratory sensitisers. Thus, the available human and animal
data indicates formaldehyde in air is unlikely to induce respiratory sensitisation.
Classification: Based on the human and animal data formaldehyde meets the
Approved Criteria for classification as `May cause sensitisation by skin contact'
(risk phrase R43) but not for sensitisation by inhalation.
12.4 Repeat dose toxicity
Effects on pulmonary function, histological changes within the nasal epithelium,
and neurobehaviour were investigated in populations exposed to gaseous
formaldehyde in occupational and/or community environments. Though transient
decreases in lung function across a work shift have been observed in some
studies, overall, the data do not provide conclusive evidence that formaldehyde
exposure induces major changes in pulmonary function. Conflicting results for
histological changes within the nasal epithelium have been observed for workers
occupationally exposed to formaldehyde. Although histological changes were
observed in the most extensive and well conducted study (Holmstrom et al.,
1989), the weight of causality is weak, due primarily to the limited number of
investigations of relatively small populations that do not permit adequate
investigations of exposure response. Additionally, it is not reported whether these
studies examined other exposures that may have contributed to the observed
histopathological changes. This is also true for the observance of
histopathological changes in a community study. Consequently, the
histopathological findings cannot be attributed to formaldehyde exposure.
Likewise, there is presently no convincing evidence that indicates formaldehyde
is neurotoxic.
In animals, no evidence of systemic toxicity was seen in rat inhalation and oral
studies up to approximately 2 years duration, or in the only dermal study
available, a 2- to3-week rat study. Toxicity in response to irritation was restricted
to the site of contact: skin irritation in the dermal study, histological changes in
the nasal tract in inhalation studies, and stomach in oral studies.
Classification: Based on the available human and animal data formaldehyde
does not meet the Approved Criteria for classification as causing serious damage
to health by prolonged exposure through inhalation, ingestion or dermal contact.
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Formaldehyde
12.5 Genotoxicity
Overall, epidemiology data from occupational studies investigating cytogenetic
effects in nasal and buccal cells are suggestive of formaldehyde having a weak
localised genotoxic activity, while the evidence for a systemic activity, including
peripheral lymphocytes, is equivocal. Small group sizes and the often limited
details reported, limit the significance that can be attached to the observed effects.
The main concern is that there was co-exposure to other chemicals in these
studies (e.g. phenol in embalming fluid and resins, and wood dust in paper
production) whose contribution to the observed effects cannot be precluded.
Consequently, no reliable conclusions can be drawn from human data on the
genotoxic potential of formaldehyde.
In vitro, formaldehyde was clearly genotoxic in bacterial and mammalian cells:
Ames test (+/- S9); gene mutation (-S9); chromosome aberration (+/-S9); SCE
(+/-S9); and produced DNA single strand breaks and DNA protein cross-links (-
S9). In vivo, several ip and inhalation studies are available in rodents
investigating the genotoxicity of formaldehyde in somatic cells. Negative results
were seen in bone marrow cytogenetic and micronuclei studies conducted to
validated test methodology. A statistically significant increase in chromosomal
aberrations (chromatid or chromosome breaks) in the bone marrow was reported
in a single study that used a prolonged exposure period (4 months) and for which
only limited details are available. Similarly, a positive result was seen in only one
of several studies investigating tissues other than the bone marrow; a marginal,
but statistically significant, increase in chromosomal aberrations (chromatid or
chromosome breaks) in pulmonary macrophages. In the only oral study, which
used a non-validated test method, a statistically significant increase in the
proportion of cells with micronuclei and nuclear anomalies was seen in cells from
the stomach, duodenum, ileum and colon of rats. However, the observed effects
clearly correlated with severe local irritation (hyperaemia and haemorrhage), and
are thus considered a likely consequence of cytotoxicity. Formaldehyde exposure
did induce DPX in the nasal tract of rats and monkeys. In ip studies in germ cells
in vivo, effects on sperm morphology and dominant lethal findings were seen in a
single study that employed a 5-day exposure period. Although negative studies
for germ cells used only a single administration, much higher dose levels were
employed.
Thus, the limited positive results in somatic cells in vivo are from cytogenetic
studies that employed non-validated test methodology and, as such, neither study
is considered to provide conclusive evidence of genotoxicity as uncertainty exists
in interpreting the reliability of the data. In contrast, negative findings were
observed in several studies conducted to validated test methodology. Similarly,
the positive result in a single study in germ cells is not considered to provide
conclusive evidence that formaldehyde is a germ cell genotoxicant, as negative
results were seen in other studies at higher dose levels. The only other finding
was the formation of DPX in the nasal tract following inhalation.
Formaldehyde is genotoxic in vitro, and it appears that the chemical is weakly
genotoxic at the site of contact in vivo. The relevance of the finding that
formaldehyde is capable of producing DPX formation is unclear.
Classification: Based on the human and animal data formaldehyde dose not
meet the Approved Criteria for classification as a mutagenic substance.
116 Priority Existing Chemical Assessment Report No. 28
12.6 Carcinogenicity
There are a large number of epidemiology studies available (case-control and
cohort) in industrial workers and professionals, investigating the incidence of
cancers in the nasal tract, pharynx or lungs. Conflicting results have been
observed in these studies. To consolidate the findings, meta-analysis of the data
was conducted by Blair et al. (1990), Partanen (1993) and Collins et al. (1997).
No association was seen in any meta-analysis for gaseous formaldehyde exposure
and lung cancer. In contrast to earlier meta-analyses, the most comprehensive
evaluation of the data by Collins et al. (1997) found no association (all studies
combined) between sinonasal cancers and exposure to formaldehyde. An
association was observed for nasopaharyngeal cancers in this meta-analysis,
however, this was considered to be due to non-reporting of expected numbers in
some industrial cohort studies. Following an adjustment for non-reporting of
expected numbers, a non-significant increased risk was observed for
nasopharyngeal cancers. Mixed results (i.e. occasional associations) have been
observed for nasopharyngeal cancers in recent (post-1997) case-control and
cohort studies. Consequently, it is considered that although the human data do not
provide strong evidence of a causal association, it is acknowledged that there is
some human evidence that occupational exposure to gaseous formaldehyde may
result in the development of nasopharyngeal cancer.
Increased risks of various non-respiratory cancers have occasionally been seen in
some studies, with the most evidence being for leukaemia, particularly myeloid
leukaemia. A recent update of a major cohort study of industrial workers reported
an association for myeloid leukaemia and peak exposures to formaldehyde in air
(Hauptmann, 2003). However, a reanalysis of the data, using additional analyses,
provided little evidence to support the suggestion of a casual association (Marsh
& Youk, 2004). In recent updates of two other major cohort studies of industrial
workers, an increased risk of leukaemia was seen in US garment workers
(Pinkerton, 2004), while no such increased risk was seen in UK industrial
workers (Coggon, 2003). Furthermore, conflicting results were seen in earlier
epidemiology studies investigating leukaemia in industrial workers (i.e. a slight
increased risk or no risk). Increased risks for leukaemia have been observed in
several studies of professional workers (e.g. embalmers), however, data on
exposure to formaldehyde is not available for these studies. Overall, the data is
considered insufficient to clearly establish an association between formaldehyde
exposure and leukaemia. This conclusion is consistent with the present
toxicokinetic profile and animal carcinogenicity data for formaldehyde.
In inhalation carcinogenicity animal studies, a significantly increased incidence in
nasal squamous cell carcinomas was observed in rats at concentrations > 6 ppm
formaldehyde. Nasal polyploid adenomas were also observed in a single study at
15 ppm formaldehyde, however, the non-reproducibility of these findings at
similar concentrations (14-14.3 ppm) in other studies indicates that they are not
treatment related. In contrast, an absence or no significant increased incidence in
nasal tumours was observed in mice and hamsters at equivalent or greater
exposure concentrations that produced such tumours in rats. In oral
carcinogenicity studies, no significant tumour findings were seen in the most
comprehensive study available up to the top dose of 82 and 109 mg/kg bw/day in
male and female rats, respectively (Til, 1989). Although an increase in
`haemolymphoreticular tumours' was seen in male and female rats at the top dose
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Formaldehyde
of 75 and 100 mg/kg bw/day, respectively, in another study, this study was
criticised for its `pooling' of tumour types whose incidence has been
inconsistently reported. Similarly, although an increase in papillomas of the
forestomach was seen in an initiation/promotion study where rats were
administered 0.5% in drinking water for 32 weeks, the study has been questioned
over its histological diagnosis of benign tumours. In contrast, no leukaemias or
stomach tumours were seen in the most comprehensive study to date, which
employed comparable or higher dose levels of formaldehyde solution. No skin
tumours were seen in mouse initiation/promotion studies, the only dermal data
available. Therefore, the available data in animals do not support formaldehyde
being carcinogenic by the dermal or oral routes.
The International Programme on Chemical Safety (IPCS) developed a conceptual
framework in 2001 based on the general principles involved in considering the
chemical induction of a specific tumour in animals (Sonich-Mullin et al., 2001).
The data for nasopharyngeal cancers and leukaemia and formaldehyde exposure
have been evaluated using this framework (Appendix 5). The postulated mode of
action for nasopharnygeal cancers is that inhalation of formaldehyde causes
inhibition of mucociliary clearance, followed by nasal epithelial cell regenerative
proliferation resulting from cytotoxicity and DPX that leads to mutation, and
consequent tumour formation. By considering the available data in the IPCS
framework, it was concluded that the postulated mode of action for
formaldehyde-induced tumours in the nose is likely to be relevant to humans, at
least qualitatively. In contrast, a mechanism by which formaldehyde may induce
leukaemia has not been identified and the framework highlights the low degree of
confidence that may be ascribed to the hypothesis that formaldehyde induces
leukaemia.
Overall, it is considered that the available epidemiology data are not sufficient to
establish a casual relationship between formaldehyde exposure and cancer. For
nasopharyngeal cancers there are several epidemiological studies that show an
increased risk, whereas other studies do not. There is also clear evidence from
inhalation studies of nasal squamous cell carcinomas in the rat, though not the
mouse and hamster. The postulated mode of action for these tumours is
considered likely to be relevant to humans. Therefore, based on the available
nasopharyngeal cancer data, formaldehyde should be regarded as if it may be
carcinogenic to humans following inhalation exposure. There are also concerns
for an increased risk for formaldehyde-induced myeloid leukaemia, however, the
available data are not considered sufficient to establish an association and there is
currently no postulated mode of action to support such an effect.
IARC concluded that formaldehyde is carcinogenic to humans (Group 1), on the
basis of sufficient evidence in humans and sufficient evidence in experimental
animals. IARC's conclusion is as follows:
`Nasopharyngeal cancer mortality was statistically significantly increased
in a cohort study of United States (US) industrial workers exposed to
formaldehyde, and was also increased in two other US and Danish cohort
studies. Five of seven case-control studies also found elevated risk for
formaldehyde exposure. The Working Group considered it was
"improbable that all of the positive findings...could be explained by bias
or by unrecognised confounding effects" and concluded that there is
sufficient evidence in humans that formaldehyde causes nasopharyngeal
118 Priority Existing Chemical Assessment Report No. 28
cancer. Leukaemia mortality, primarily myeloid-type, was increased in
six of seven cohorts of embalmers, funeral-parlour workers, pathologists,
and anatomists. These findings had previously been discounted because
an increased incidence of leukaemia had not been seen in industrial
workers. Recent updates, however, report a greater incidence of
leukaemia in two cohorts of US industrial workers and US garment
workers, but not in a third cohort of United Kingdom chemical workers.
The Working Group concluded that there is "strong but not sufficient
evidence for a causal association between leukaemia and occupational
exposure to formaldehyde". Several case-control studies have associated
exposure to formaldehyde with sinonasal adenocarcinoma and squamous-
cell carcinoma. However, no excess of sinonasal cancer was reported in
the updated cohort studies. The Working Group concluded that there is
limited evidence in humans that formaldehyde causes sinonasal cancer.
In rats, several inhalation studies have shown that formaldehyde induces
squamous-cell carcinoma of the nasal cavity. Four drinking-water studies
gave mixed results. Formaldehyde also shows cocarcinogenic effects
when inhaled, ingested, or applied to the skin of rodents.
Formaldehyde is genotoxic in in-vitro models, animals and humans.
Increased numbers of DNAprotein crosslinks have been found in
peripheral blood lymphocytes of exposed workers, in the upper
respiratory tract of monkeys, and in the rat nasal mucosa. Cell
proliferation increases substantially at formaldehyde concentrations
higher than six parts per million in rats, amplifying the genotoxic effects.
The Working Group concluded that, "both genotoxicity and cytotoxicity
have important roles in the carcinogenesis of formaldehyde in nasal
tissues". By contrast, the Working Group could not identify a mechanism
for leukaemia induction, and this tempered their interpretation of the
epidemiological evidence.' (IARC, 2004b).
The available data do not support formaldehyde being carcinogenic by the dermal
or oral routes.
Classification: Based on the above, formaldehyde meets the Approved Criteria
for classification as a Category 2 carcinogen with risk phrase R49 `May cause
cancer by inhalation'. This is a different category with the IARC classification
which is Category 1, (known human carcinogen), principally due to differences in
the carcinogen classification criteria and also consideration of the weight of
evidence.
12.7 Reproductive effects
Only a few epidemiology studies are available. A retrospective investigation of
fertility reported a significant increase in the time to pregnancy (i.e. decrease in
the fecundability density ratio) in female workers exposed to formaldehyde.
However, limitations in study design prevent any reliable conclusions being
drawn from the data. Similarly, in cross-sectional studies, although no difference
was seen in female fertility or male sperm count and morphology between
formaldehyde exposed workers and controls, study limitations restrict the
significance that can be attached to the data.
119
Formaldehyde
In the only fertility study available in animals, formaldehyde did not produce an
adverse effect on fertility in minks, though there are concerns that formaldehyde
was not robustly tested in this oral study. No effect on epididymal sperm
morphology was seen in an oral mouse study at the only dose tested, and no
effects on the testes have been reported in rodents in a chronic repeat oral study
and chronic inhalation studies. In contrast, although effects have been seen on
epididymal sperm following intraperitoneal administration this is not a relevant
route of human exposure.
Classification: Based on the human and animal data formaldehyde does not
meet the Approved Criteria for classification as a reprotoxicant.
12.8 Developmental toxicity
There is no human evidence to indicate occupational exposure to formaldehyde is
associated with low birth weight or malformations. For studies investigating
spontaneous abortions, the inconsistent findings observed in epidemiological
studies and limitations in study design, including the potential for recall and
publication bias, mean the findings cannot be attributed to occupational exposure
to formaldehyde.
In animal studies, the only effect observed following inhalation was a reduction
in foetal body weight that was a secondary non-specific consequence of severe
maternal toxicity. No effects on development were seen in an oral study though
dose levels were not maximised. No robust dermal study is available that allows
the developmental toxicity of formaldehyde to be reliably determined.
Classification: Based on the human and animal data formaldehyde does not
meet the Approved Criteria for classification as a developmental toxicant.
120 Priority Existing Chemical Assessment Report No. 28
13. Environmental Exposure
13.1 Ambient air concentrations
In this section, the predicted environmental concentration (PEC) of formaldehyde
is calculated for various environmental compartments using modelling
techniques. The modelling results are presented as annual averages and maximum
24-hour averages. Annual averages are relevant for long-term (chronic) exposure,
whereas 24-hour averages are more representative of acute exposure. An
averaging time of 24 hours is also specified for formaldehyde in the Air Toxics
National Environmental Protection Measure (NEPC, 2004) with the monitoring
investigation level set at 40 ppb (see Section 18.1.1 for details). First, a PEC
value for each of the point and diffuse sources of release is calculated, and then
these values are combined to determine a final PEC. Where available, published
monitoring studies are also summarised and used to verify the PEC values.
The formaldehyde release estimates are primarily from the NPI emission database
(NPI database at www.npi.ea.gov.au). Most of the NPI emissions data are
themselves estimations, determined by a range of techniques, including mass
balance calculations, use of emissions factors, and sampling and direct
measurement. As such, the PEC predictions should be interpreted cautiously
owing to uncertainties in the initial release estimates.
A number of different approaches have been adopted to calculate PECs,
depending on the type of source. The modelling was carried out by
Commonwealth Scientific and Industrial Research Organisation (CSIRO)
Atmospheric Research Division and details of the modelling techniques and
results are provided in Appendix 6.
13.1.1 Point source emissions from industry
Emissions of formaldehyde resulting from industrial activities are difficult to
assess owing to the high diversity in use patterns and the high number of both
small and large companies using formaldehyde or manufacturing products
containing formaldehyde. While the NPI estimates are a reasonably good
indicator of the major contributors, the data are incomplete. Data from the
Australian Bureau of Statistic (ABS) suggest that from 5000 to 10 000 companies
should be reporting emissions (although not all of these companies necessarily
emit formaldehyde), but only about 3000 facilities reported emissions in the
20012002 reporting year and 3400 for the 2002-2003 reporting year.
Figure 13.1 provides a breakdown by industry category of point source emissions
from the 34 industries and 196 facilities reporting formaldehyde emissions to the
NPI in the financial year 2001-2002 and 38 industries and 257 facilities for the
2002-2003 financial year. These emissions are combined and appear as industry
emissions in Figure 8-1. Some of the original NPI industry categories have been
changed or combined for this report.
The major industrial contributors of atmospheric point source emissions of
formaldehyde are the mining, wood and paper industries, and electricity supply.
In the following summaries of point source data, the average emissions are used
121
Formaldehyde
to represent emissions and potential exposure concentrations owing to the wide
variability in releases from each industrial facility including some facilities
reporting no emissions. The minimum and maximum emissions are also reported.
The detailed emission data for a number of major industries are tabulated in
Appendix 7.
The details of modelling for PEC values, such as source configuration and
modelling techniques are presented in Appendix 6, Section A2. Only results are
reported here. The release estimates used in the modelling are primarily from
emissions data listed in the NPI database for the 2001-2002 reporting year. The
2002-2003 NPI data reported in this section became available after the modelling
was conducted, therefore, were not used in the PEC estimations. However, it is
expected to be directly proportional to those estimated for 2001-2002.
All PEC values are calculated using the conversion factor 1 ppb = 1.20 ”g/m3,
which is appropriate for ambient conditions of 25 șC.
Figure 13.1: Formaldehyde emissions (NPI database) for each industry
category for (a) 2001-2002 and (b) 2002-2003. The figure in brackets
indicates the number of facilities reporting in each category
(a) Formaldehyde Emisions by Industry 2001-2002
Petrol, Oil and Gas
Chemical
[6]
Manufacturing [25] Electricity Supply
2%
Materials 2% [27]
Manufacture [26] 16%
9%
Miscellaneous [68]
<0.3%
Wood and Paper
Manufacturing [20]
15%
Mining [50]
56%
(b) Formaldehyde Emisions by Industry 2002-2003
Petrol, Oil and Gas
Chemical
[10] Electricity Supply
Manufacturing [27]
5% [41]
1%
Materials 16%
Manufacture [36]
8% Miscellaneous [68]
2%
Wood and Paper
Manufacturing [27]
19%
Mining [51]
49%
122 Priority Existing Chemical Assessment Report No. 28
Mining operations
The average and maximum formaldehyde emission rates derived from the NPI
database from the various types of mining operations are given in Table A7-1 in
Appendix 7.
Metal ore mining activities (iron, gold, silver-lead, or nickel) contributed the
highest emissions, although some facilities in this category reported no emissions
of formaldehyde. The average emission rate for mining activities was 12 203
kg/year with a maximum of 401 112 kg/year for a nickel mining activity in
Western Australia in the 2001-2002 reporting year. For the 2002-2003 reporting
year the average emission rate was 7254 kg/year with a maximum of 363 769
kg/year for an iron mining activity in Western Australia.
Emissions of formaldehyde from mining operations are expected to occur mainly
via vehicle exhaust from mining equipment and transport, cleaning and site
maintenance activities, power generation using fossil fuels, combustion in boilers,
and blasting.
The calculated annual average PEC at 100 m from the edge of the activity was
1.8 ppb and the maximum 24-hour average was 8.1 ppb based on the average
source emissions for the 2001-2002 reporting year. These results are
approximately inversely proportional to the diameter of the area source (for a
given emission rate). (see Appendix 6, A2.1 for details)
Given that the main sources of emissions from mining operations are distributed
surface sources, the area of emissions is likely to be approximately proportional
to the emissions rate, so that PECs from the largest emitter are expected to be
similar to those from the average emitter.
Wood and paper product manufacturers
Release estimates from the NPI database for the years 2001-2002 and 2002-2003
indicate the wood and paper manufacturing industry contributed the second
highest proportion of point source emissions of formaldehyde from industrial
facilities. The average emission rates were 8195 and 7061 kg/year for the 2001-
2002 and 2002-2003 reporting years, respectively, with a maximum of 51 844
kg/year (2002-2003 data) for an individual wood products activity (Table A7-2,
Appendix 7). This is not surprising considering that one of the primary uses of
formaldehyde is in the production of urea formaldehyde and phenol formaldehyde
resins, which are used mainly as adhesives in the manufacture of particleboard,
fibreboard, and plywood.
Emissions of formaldehyde from the wood and paper industries are expected to
occur mainly through fugitive and point source emissions of vapours from
process and storage areas, and with some emissions of formaldehyde from
combustion activities. The processes emitting vapours will differ with the type of
industry, but may include gluing and veneering, steam heating, wood preservation
treatment, and drying activities. Combustion sources include wood and paper
drying, incinerating, and boiler operations.
The calculated annual average PEC 100 m from a facility with average emission
rates was 4.8 ppb and the maximum 24-hour average was 36 ppb. The highest
estimated PECs from the largest emitter were 16 ppb (annual average) and
119 ppb (maximum 24-hour average) (see Appendix 6, A2.2 for details). A
123
Formaldehyde
sensitivity analysis showed that the PECs are much more sensitive to the
configuration of the source of the fugitive emissions than the stack emissions All
of the wood and paper product industries in the NPI database are located outside
major urban areas.
To refine the estimates, further modelling of formaldehyde emissions from the
highest emitter for wood and paper manufacturing industries was undertaken by
EML Air Pty Ltd. EML included the typical facility layout, including
configuration of the sources of formaldehyde emissions as inputs into the model.
The revised estimates for the highest emitter of wood and paper facilities were 2
ppb (annual average PEC) and 37 ppb (maximum 24-hour average PEC) (see
Appendix 17). CSIRO reviewed the EML Air Pty Ltd estimates and confirmed
that the model had been correctly applied (see Appendix 18).
Limited boundary data for ground formaldehyde levels around wood
manufacturing plants were provided by AWPA and PAA. In total, 37 samples
were collected around 5 plants between 1999 and 2005. No details on test
methods were provided. About half the number of samples (18 out of 37) showed
concentrations of formaldehyde < 10 ppb. Two samples of 66 ppb were measured
around a plant that emits formaldehyde at 20 000 kg/year. There is no
indication whether the plant is one of the largest formaldehyde emitters.
Electricity supply
Most electricity generated in Australia is produced in steam cycle plants, with
over 90% of plants using fossil fuel combustion to drive the steam turbines
coupled to the electricity generators. Coal and natural gas are the main fossil fuel
sources (ESAA, 1997). Thus, emissions of formaldehyde from the electrical
supply industry result primarily from coincidental production during fuel
combustion. Discharges are mainly into the air via stacks.
In the NPI reporting years 2001-2002 and 2002-2003, the electrical supply
industry reported total emissions of 177 303 and 163 918 kg/year of
formaldehyde, respectively, with averages of 4792 and 3998 kg per facility.
However, only a small proportion of the electrical supply companies in Australia
actually reported emissions to the NPI. In 2001-2002, the majority (33 of 37) of
companies reporting emissions were small isolated facilities operating throughout
QLD and using diesel internal combustion to generate power. The range of
emissions from these facilities varied between 0.92-70 kg/year. The remaining
four facilities (3 in NSW, 1 in QLD) reported significantly higher emissions,
between 29 012 and 85 614 kg/year, with two of these facilities generating power
from coal seam methane. Emissions from combustion of coal-bed gas are likely
to be high due to formation of formaldehyde by oxidation of methane.
The calculated PECs are 0.11 ppb (annual average) and 1.12 ppb (maximum 24-
hour average). For the largest emitter using different source configuration (see
Appendix 6, A2.3 for details), similar PECs of 0.10 ppb (annual average) and
0.98 ppb (maximum 24-hour average) were produced. These PEC estimates are
conservative because buoyant plume rise was ignored by setting the efflux
temperature to 25șC.
124 Priority Existing Chemical Assessment Report No. 28
Materials manufacture
Release estimates from NPI for the years 2001-2002 and 2002-2003 indicate that
emissions vary widely with the type of material being manufactured (Table A7-3,
Appendix 7). The average emission rates were 3664 and 2293 kg/year,
respectively.
Basic non-ferrous metal manufacturing contributed the highest emissions with the
bulk of emissions from this category being discharged from alumina production
facilities (maximum emission rate 35 000 kg/year, in 2001-2002). Emissions from
alumina production facilities occur primarily through combustion of fossil fuels
in furnaces and boilers during bauxite processing, vent emissions from bulk
storage of hydrocarbons, and vapour emissions during certain stages of
processing.
The estimated PECs from modelling are 2.1 ppb (annual average) and 16 ppb
(maximum 24-hour average). For the largest emitter (an aluminium refinery),
PECs of 0.78 ppb (annual average) and 8.2 ppb (maximum 24-hour average) were
calculated (see Appendix 6, A2.4 for details).
Petroleum refining, oil and gas extraction
Release estimates from NPI for the years 2001-2002 and 2002-2003 indicate the
petroleum refining, and oil and gas extraction industries contributed a total of 21
700 (1085 tonnes x 2%) and 51 000 kg (1022 tonnes x 5%) of point source
emissions of formaldehyde (from 6 and 10 reporting facilities), respectively.
Emissions ranged between about 5 and 8883 kg per year (average 3162 kg/year)
in 2001-2002 and between 14 and 36 150 kg per year (average 5488 kg/year) in
2002-2003, with petroleum refining contributing the highest emissions.
Emissions of formaldehyde from petroleum refining are expected to occur mainly
through combustion activities during the refining process (catalytic cracking,
fluid coking, blowdown systems, VDU condensers, sulfur recovery), and fugitive
emissions from process and storage areas.
For the average emitter, the estimated PECs of 0.07 ppb (annual average) and
0.74 ppb (maximum 24-hour average) are calculated. For the largest emitter
(8883 kg/year), the estimated PECs are 0.20 ppb (annual average) and 2.1 ppb
(maximum 24-hour average) (see Appendix 6, A2.5 for details).
Chemical industry
Release estimates of formaldehyde to air reported to NPI by the chemical
manufacturing industry for the years 2001-2002 and 2002-2003 indicate average
emissions of 651 kg from 25 facilities and 399 kg from 27 facilities, respectively,
with individual facility emissions ranging between 0 and 6960 kg (Table A7-4,
Appendix 7).
Not surprisingly, formaldehyde manufacturing facilities contributed the bulk of
emissions reported by the chemical industry (13 445 kg). Emissions estimates to
air from formaldehyde manufacturing for 2001-2002 are shown separately in
Table A7-5, Appendix 7.
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Formaldehyde
Most of the formaldehyde consumed in Australia each year (~50 000 tonnes) is
manufactured here by four chemical manufacturing companies at five sites
(Section 7.1 and 7.3).
Formaldehyde emissions from the manufacturing process fall into three main
categories: vapour emissions derived from processing and storage (majority, see
Section 8.1), liquid effluent contaminated with formaldehyde, and solid wastes
containing formaldehyde. Most air emissions occur via stacks, although some
fugitive vapour emissions (for example, from storage tanks and discharge areas)
may be released directly into the air.
One formaldehyde manufacturer conducted monitoring of stack emissions at
discharge points in 2001. It is indicated that process emissions were released from
2 stacks on-site, one for tail gas fed from boilers, and the other for exhaust from
the resin distillation process. Tail gas is used as boiler fuel and is discharged only
during start-up. The gas passes through two process absorbers prior to release to
the atmosphere to remove water, formaldehyde, and methanol from the
hydrogen/nitrogen gas mixture. Discharges from the resin distillation process pass
through scrubbers prior to release to the atmosphere. It was reported that the only
significant stack emissions were 0.72 kg/day from the Resin Reactor 1 (efflux
velocity 5.9 m/s). All other sources had emission rates at least 35 times lower
than this.
For the average facility (651 kg/year), the maximum estimated annual average
PEC was 0.05 ppb and the maximum 24-hour average was 0.41 ppb. For the
largest formaldehyde manufacturing plant (6960 kg/year), the maximum
estimated annual average PEC was 0.57 ppb and the maximum 24-hour average
was 4.4 ppb (see Appendix 6, A2.6 for details).
Miscellaneous industries
A number of miscellaneous industries including food manufacturing, farming,
textile manufacturing, hospitals and nursing homes, and waste disposal facilities
reported formaldehyde emissions to air in 2001-2002. For most of these
industries, emission rates were low. The total annual emissions of formaldehyde
from all facilities in this category were 3255 kg (i.e. 1085 tonnes x 0.3%, refer to
section 8.1.1 and Figure 13.1), and the average for an individual facility was 79
kg. The highest emissions reported for this category were from waste disposal
services, with one company reporting 1099 kg/year emissions.
For an average emitter, the estimated PECs were 0.14 ppb (annual average) and
1.2 ppb (maximum 24-hour average). For the largest emitter, the estimated PECs
were 2.0 ppb (annual average) and 17 ppb (maximum 24-hour average). (see
Appendix 6, A2.7 for details)
Summary
Based on the NPI emissions estimates for formaldehyde, point source emissions
contributed between 14% to 16% of the total yearly emissions reported to NPI
from all sources in 2001-2003. Most emissions from industry were incidental
emissions arising from combustion process. Of the industry emissions, the
formaldehyde manufacturing industry contributed about 1.2% (13445 kg out of
1085 tonnes) of the total in 2001-2002.
126 Priority Existing Chemical Assessment Report No. 28
The estimated maximum annual average and maximum 24-hour average PECs for
each industry category are shown in Table 13.1. It should be remembered that
these PEC predictions have been derived using data from the NPI database in
which most of the data has been estimated. As such, the PEC predictions should
be interpreted cautiously owing to uncertainties in the initial release estimates. In
addition, not all industrial sources report to the NPI.
Table 13.1: Annual estimated average and maximum 24-hour average PECs
for point source emissions of formaldehyde for each industry category (in
ppb)
Type of industry Maximum Annual Maximum 24-hour Average
Average PEC PEC
Average Largest Average Largest
emitter emitter emitter emitter
1.8 8.1
1.8 8.1
Mining
(expected)
(expected)
4.8 16 (2*) 36 119 (37*)
Wood & paper
0.11 0.10 1.12 0.98
Electricity supply
2.1 0.78 16 8.2
Materials
manufacture
0.07 0.20 0.74 2.1
Petroleum
0.05 0.57 0.41 4.4
Chemical
manufacture
0.14 2.0 1.2 17
Miscellaneous
* refined estimates by EML Pty Ltd
13.1.2 Diffuse source emissions
Urban air
Urban levels of formaldehyde due to diffuse urban emissions were determined by
CSRIO from a re-analysis of detailed urban airshed modelling of ambient
pollutant concentrations in Melbourne previously undertaken by CSIRO for EPA
Victoria (Hurley et al., 2001). The details are provided in Appendix 6, Section
A3. The re-analysis generated 24-hour averages to supplement the original
modelling of annual average concentrations. The results provide the best
available estimate of urban concentrations away from significant local sources,
such as industry or large roads. The estimated maximum annual average
formaldehyde concentration is 1.6 ppb (Hurley et al., 2001) and the maximum 24-
hour average is 13 ppb (see Table 13.2).
When determining the impact of an industrial source located in an urban area, it is
common practice (EPA Victoria, 1985) to add the maximum PEC for the
industrial source to a typical urban background concentration, represented by the
70th percentile, rather than the maximum 24-hour average urban background,
which is unlikely to occur at the same time as the maximum source impact.
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Formaldehyde
Analysis of the cumulative probability distribution from the PPCR modelling
indicated that the 70th percentile 24-hour average PEC was 2.2 ppb
Table 13.2: PECs of formaldehyde for Melbourne from urban airshed
modelling
70th percentile PEC
Averaging time Maximum PEC
Annual average 1.6 ppb -
13 ppb 2.2 ppb
24-hour average
Roads
Maximum formaldehyde concentrations due to roadway emissions were
determined by CSIRO from modelling of emissions from a 6-lane dual
carriageway freeway. The details are provided in Appendix 6, Section A4. The
modelling results at three distances from the edge of the freeway are listed in
Table 13.3. They show a rapid decrease in concentrations with distance from the
edge of the freeway.
Table 13.3: Formaldehyde PECs for typical large urban freeway (150 000
cars per day) modelled using AUSROADS
Maximum annual Maximum 24-hour average
Location average PEC PEC
At edge of freeway 0.77 ppb 2.3 ppb
20 m from edge of freeway 0.37 ppb 1.06 ppb
100 m from edge of 0.15 ppb 0.50 ppb
freeway
13.1.3 Natural background concentrations
Formaldehyde is formed naturally in the atmosphere and biosphere by a variety of
processes, the most important of which are oxidation of methane and isoprene. As
such, background concentrations also need to be incorporated in calculation of the
PECs. Assuming natural methane oxidation is the only source, Lowe et al. (1980)
predicted natural background concentrations of formaldehyde in the atmosphere
in the order of 0.4 ppb at the ground surface, decreasing to about 0.1 ppb at an
altitude of 5 km. This agrees with measurements in clean marine air at Cape Grim
(northern Tasmania) by Ayers et al. (1997), who reported a 24-hour average of
0.4 ppb in summer.
The US EPA (1993) predicted that in remote areas, oxidation of methane
combined with oxidation of biogenic hydrocarbons, such as isoprene, produced
background concentrations of about 0.6 ppb during daylight hours. In contrast,
measurements in the Latrobe Valley in Australia from rural sampling sites
showed 2-hour average concentrations between 2 and 3 ppb with a recommended
representative summer regional background concentration of 2 ppb (Carnovale &
Ramsdale, 1988). This result indicates a significant contribution from the
oxidation of isoprene, which is much smaller in the non-summer months. This
would reduce the annual average below 2 ppb. Thus, for the purpose of this
128 Priority Existing Chemical Assessment Report No. 28
assessment, it is assumed that natural background formaldehyde concentrations
are 2 ppb (maximum 24-hour average) and 1 ppb (annual average).
13.1.4 Combining PECs from all sources
Table 13.7 summarises the contribution from the various sources modelled and
the estimated natural background concentration. The PECs from the wood and
paper industries have been separated from the other industries because they are all
located away from major urban centres.
The total PECs (without the wood and paper industries) represent an expected
extreme worst-case formaldehyde concentration in an urban area. It includes the
70th percentile PEC due to diffuse urban sources, the natural background
concentration, the worst-case contribution from an urban freeway, and the worst-
case contribution from a nearby industry. The total PECs are 5.5 ppb (annual
average) and 23.5 ppb (maximum 24-hour average).
13.1.5 Measured data
Monitoring data are available from a number of locations and environments in
Australia, predominantly Victoria, Queensland, South Australia and Western
Australia.
Table 13.4 provides ambient formaldehyde levels (24 h average) measured at two
sites in Brisbane, which have been monitored for over two years by the
Queensland EPA (Pattearson, 2002).
Table 13.4: Ambient formaldehyde concentrations in the Brisbane CBD and
at Wynnum, QLD (in ppb)
Location Season Minimum Maximum Median Mean
Wynnum Summer 1.5 10.6 4.5 4.6
Brisbane CBD 1.4 5.9 2.7 2.9
Wynnum Autumn 1.2 10.7 5.5 5.6
Brisbane CBD 0.8 7.1 2.6 2.8
Wynnum Winter 3.0 17.8 7.5 7.7
Brisbane CBD 0.9 7.7 3.0 3.5
Wynnum Spring 1.8 13.5 4.9 5.3
Brisbane CBD 1.2 6.9 3.0 3.2
Wynnum All data 1.2 17.8 5.3 5.7
Brisbane CBD 0.8 7.7 2.8 3.1
CBD, central business district
The data indicate consistently higher formaldehyde concentrations at the
Wynnum monitoring site than in the central business district (CBD) of Brisbane.
The Wynnum site is situated in a residential area adjacent to a petroleum refinery.
The predominant source of formaldehyde in the CBD is motor vehicle emissions.
The data in Table 13.4 show that formaldehyde concentrations are highest in
winter. The higher pollution levels in winter are a feature peculiar to Brisbane,
owing to its geographical position. The city is surrounded by mountain ranges on
129
Formaldehyde
thre