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EC number: 222-720-6
CAS number: 3586-55-8
No long-term carcinogenity study using the
test substance in experimental animals is available. However, it is
assumed that test substances hydrolyses rapidly in body fluids.
Sufficient data on this endpoint are available for both hydrolysis
products. For formaldehyde it is referred to additional information
,where the effects are summarised. The carcinogenic potential of
ethylene glycol has been investigated in 2 year oral combined chronic
toxicity and carcinogenicity bioassays in rats and in mice (DePass et
al., 1986). The studies were non-GLP and non-guideline but were based on
similar methodology to OECD Test Guideline 453. In a 2 year oral
bioassay in rats, groups of 26 male and female animals (F344 strain)
received ethylene glycol ad libitum via the diet at either 0, 40, 200 or
1000 mg/kg bw/day. No evidence of the occurrence of treatment-related
neoplastic lesions was observed in the study. On this basis it was
concluded that ethylene glycol is not carcinogenic in male or female
rats and that the NOAEL for carcinogenicity was considered to be >1000
mg/kg bw/day (i.e. > the highest dose tested). In a 2 year oral bioassay
in mice, groups of 16 male and female animals (CD 1 strain) received
ethylene glycol ad libitum via the diet at either 0, 40, 200 or 1000
mg/kg bw/day. No evidence of the occurrence of treatment-related
neoplastic lesions was observed in the study. On this basis it was
concluded that ethylene glycol is not carcinogenic in male or female
mice and that the NOAEL for carcinogenicity was considered to be >1000
mg/kg bw/day (i.e. > the highest dose tested). No studies are available
in the public domain that have investigated the carcinogenic potential
of ethylene glycol via the dermal or the inhalations routes. Taking into
account observations from long-term oral bioassays, ethylene glycol is
unlikely to be carcinogenic via the dermal or the inhalation routes.
For the test substance no information is
available. However, for the hydrolysis products data are available.
Ethylene glycol is considered to be not carcinogenic based on the
available data. A huge data set is available for formaldehyde. The final
conclusion was laid down in a harmonised classification as Carc. 1b.
Data on formaldehyde
Several long-term drinking water
studies on rats are documented in Doc III A6.5.1 and are included in the
evaluation of carcinogenicity. No data are available on other species.
The main effects in chronic drinking
water studies on rats with concentrations up to 5000 mg/L (ca. 300 mg/kg
bw/day) are local lesions of the forestomach and the glandular stomach
at a dose level of 50-100 mg/kg bw. In the most valid study of Til et
al. (1989), the NOAEL is 15 mg/kg bw/day in males and 21 mg/kg bw/day in
females. Other effects were due to decreased water consumption and/or
secondary to lesions of the stomach. Neither treatment-related systemic
carcinogenic effects nor local carcinogenic effects in the
gastrointestinal tract were reported (Til et al. 1989, Tobe et al. 1989)
(cf. Table 3 3). In the drinking water study presented by Soffritti et
al. (1989, 2002) increased incidences of tumours in the gastrointestinal
tract of Sprague-Dawley rats were found at doses up to 2500 mg/L without
dose response. Furthermore increased incidences of leukaemia were
reported. However, the leukaemia incidence was not significantly
different from methanol controls and within the range of historical
controls. There are several deficiencies in this study: the leukaemia
tumour types were pooled, there was a lack of statistical analysis and
findings for non-neoplastic endpoints were not reported (BfR 2006).
In an initiation-promotion study with
rats, 5000 mg/L formaldehyde showed promoting effects in the glandular
stomach (Takahashi et al. 1986) 32 weeks after initiation with
methyl-N-nitrosoguanidine. In this study also papillomas of the
forestomach were found in animals treated only with formaldehyde
In summary, the weight of evidence
that formaldehyde induces systemic or local carcinogenic effects after
oral exposure is insufficient.
No studies according to current
guidelines are available. Data on this endpoint showed local irritation
but no carcinogenic effects. However, in initiation/promotion
experiments formaldehyde significantly reduced the latency time for the
development of tumours (BfR 2006).
Inhalation exposure - Data on rats
There is clear evidence from chronic
inhalation studies in rats that formaldehyde causes tumours in the nasal
cavity. There is also some evidence for induction of nasal tumours even
after subchronic exposure periods (Feron et al. 1988). The most
prominent tumour type identified in the nasal cavity was the squamous
cell carcinoma. It is shown that in inhalation studies in F344 rats a
sharp increase in tumour incidences was evident at concentrations > 6
ppm indicating a non-linear dose response. The results in Wistar rats
(low incidence at 10 ppm, Feron et al. 1988, Woutersen et al. 1989) are
limited by a small group size or short exposure duration. Nevertheless,
there might exist strain differences in sensitivity. No sex specific
differences were detected in a study using both sexes (Kerns et al.
Occasionally also other tumour types
than the squamous cell carcinoma are found in the nasal cavity: squamous
cell papilloma (3/32 rats at 15 ppm, 3/32 rats; Kamata et al. 1997),
rhabdomyosarcoma (1/90 at 10 ppm, 1/147 at 15 ppm; Monticello et al.
1996), adenosarcoma (1/90 at 10 ppm, 1/147 at 15 ppm; Monticello et al.
1996), fibrosarcoma (1/100 at 15 ppm; Sellakumar et al. 1985), polypoid
adenoma (5/90 rats at 10 ppm & 14/147 rats at ppm; Monticello et al.
1996), undifferentiated carcinoma or sarcoma (2/117 at 15 ppm, Kerns et
The predominant localisation of
tumours (mainly the squamous cell carcinoma) in the nasal cavity was the
anterior portion of the lateral side of the nasal turbinate and the
adjacent lateral wall or the mid-ventral septum (Kerns et al. 1983).
exposure - Data on other species
In repeated dose toxicity studies on
mice it has been shown that the mouse is less sensitive than the rat.
Generally, the lesions in mice were less severe than in rats (Kerns et
al. 1983). This might also be true for carcinogenic effects in long-term
inhalation studies in mice (Kerns et al. 1983). Only 2 squamous cell
carcinomas in the nasal cavity of male mice were detected in the high
dose group (15 ppm) in a carcinogenicity study with B6C3F1 mice.
Location and morphology were similar to those observed in rats. However,
only 25 male mice survived a minimum of 18 months in the high dose group
(reduced survival not treatment-related). In females the survival was
not reduced but no tumour was detected in the nasal cavity.
In addition, hamsters were less
sensitive than rats. In the long-term inhalation study on Syrian
hamsters (Dalbey 1982) at formaldehyde concentration of 10 ppm in 5% of
the animals, metaplasia and hyperplasia in the nasal epithelium was
found but no tumours were detected in the respiratory tract. However,
only one dose level was tested.
Data on carcinogenicity in men
The possible association between
formaldehyde exposure and cancer have been investigated in numerous
epidemiological studies in occupationally exposed humans (e.g.,
pathologists, anatomists, embalmers, or industrial workers). A tabulated
summary from cohort studies published before 1996 is available as well
as new data on risk measures from cohort studies on cancers.
Epidemiological data are also available from case-control studies. With
regard to toxicokinetic data and the results in long-term laboratory
animal studies most epidemiological studies focused on carcinogenic
effects in the respiratory tract, the site of first contact. In
addition, in three out of four recent cohort studies all cancer types
are investigated (Coggon et al. 2003, Hauptmann et al. 2003 & 2004,
Pinkerton et al. 2004). The overall results suggested an increased risk
of cancer only at two tumour sites: the upper respiratory tract and the
Indication for an excess of death from
nasopharyngeal tumours in industrial workers (Blair et al. 1986, Collins
et al. 1988, Marsh et al. 1996; all three studies refer to the same
study population) and embalmers (Hayes et al. 1990) was presented in
former cohort studies and a proportionate incidence study (Hansen &
Olsen 1995), however, no increased risk was detected in others. Some
evidence for an association between nasopharyngeal tumours and
formaldehyde exposure was also reported in Marsh et al. (2002). Although
the SMR for all pharyngeal cancer and nasopharyngeal cancer were
significantly increased, no clear relation to the level of exposure was
found when different exposure categories were considered. Most
pharyngeal cancer (PC) and nasopharyngeal cancer (NPC) occurred in
workers hired between 1947 and 1956 (higher exposure levels presumed).
But short-term workers showed a higher death rate of PC or NPC than
workers employed for > 1 year. Neither PC nor NPC were associated with
duration of employment but SMR (as well as number of deaths) increased
with time since first employment. Only little evidence of increasing
mortality risks with increasing duration of exposure, cumulative
exposure or AIE was seen. There is some evidence for increasing risks
for PC with increasing duration of exposure with average exposure >0.2
or 0.7 ppm. Concerning especially the NPC data it should be noted that
subgroup size of 1-3 cases resulted in limitation of the statistical
Evidence for an association between
formaldehyde exposure and nasopharyngeal tumours came from a recent
publication of Hauptmann et al. (2004). The cohort study of Hauptmann et
al. (2004) is the largest study in industrial workers concerning the
number of study subjects in the cohort. It includes as Plant 1 the
cohort analyzed by Marsh et al. (2002). The authors have shown a
statistically significant exposure-response relationship for peak
exposure and cumulative exposure compared with an internal control
group. In comparison with the general population the SMR for
nasopharyngeal tumour was also increased. The cohort from Hauptmann et
al. (2004) has been re-evaluated by Marsh and Youk (2005). They point
out that 6 of the 10 deaths due to nasopharyngeal cancer occurred only
in Plant 1, while the remaining four cases occurred individually in four
of the other nine plants. Furthermore a comprehensive exposure analysis
for the cases in Plant 1 showed no clear relation to exposure as had
already been pointed out in Marsh et al. (2002). Only three of the cases
were exposed to formaldehyde longer than one year and each has had low
average intensity of exposure. Marsh and Youk (2005) concluded that the
increased risks for nasopharyngeal cancer in Plant 1 are due to
occupational or non-occupational exposure to risk factors outside Plant
1. Similar criticism came from Tarone & McLaughlin (2005). In their
re-evaluation of the data presented by Hauptmann et al. (2004) the
calculated SMR for nasopharyngeal cancer in exposed workers in Plant 1
was 9.1 (95% CI: 3.3-19.8) (unexposed workers SMR 0.0) but in Plant 2-10
the SMR in exposed workers was 0.6 (95% CI: 0.1-2.3) (unexposed workers
SMR 1.9). They argued that the absence of an increased risk in exposed
workers of Plant 2-10 and the magnitude of the differences in SMRs
raises serious questions about the interpretation of the results.
However, Tarone and McLaughlin focussed on ever/never exposure
comparison (all exposure categories combined) and compared with external
rates. In their reply Hauptmann et al. (2005) suggested the internal
comparison (used in Hauptmann et al. 2004) for comparison which is more
informative without a healthy worker bias. However, even the comparison
with an external group resulted in increased SMR for Plant 1 and Plant
2-10 at the highest level for all four exposure categories (Hauptmann et
al. 2005). Furthermore, the homogeneity of SMR for Plant 1 versus Plant
2-10 was not rejected, except peak exposure indicating no clear pattern
of risk heterogeneity between Plant 1 and Plant 2-10 (Hauptmann et al.
2005). The authors stated that all six workers with nasopharyngeal
cancer in Plant 1 had been in the highest peak exposure category of ≥ 4
ppm (compare with criticism presented by Marsh & Youk (2005)). Marsh and
coworkers (Marsh et al. 2006) substantiated their criticism in a recent
re-evaluation of the Hauptmann study (Hauptmann et al. 2004). They
performed two types of re-analyses with focus on peak exposure and NPC
mortality and in their sensitivity analysis uncertainties in the risk
estimates were demonstrated and pointed to instability problems
particularly related to Plant 1. The authors stated that their results
do not support a causal association with formaldehyde exposure and
A slight but statistically not
significant increase in pharyngeal cancer was found in the study of
Coggon et al. (2003). No nasal or nasopharyngeal tumours were found in
the cohort studied by Pinkerton et al. (2004) and only 3 deaths were
related to cancer of the pharynx limiting the statistical power.
Indication for an association between
formaldehyde exposure and nasopharyngeal tumours was presented in
case-control studies. Several studies on nasopharyngeal cancer found an
increased risk for an exposure to formaldehyde, mainly in subjects with
the highest probability, level or duration of exposure (Vaughan et al.
1986b & 2000, Roush et al. 1987, West et al. 1993, Hildesheim et al.
2001); two studies did not show such an association (Vaughan et al.
1986a, Armstrong et al. 2000).
In most cohort studies, no association
between exposure and lung cancer was found. However, in two recent
studies (Coggon et al. 2003, Marsh et al. 2002) some evidence for an
association was provided. No excess in mortality from lung cancer was
recorded by Pinkerton et al. (2004) and also by Hauptmann et al. (2004),
the most detailed and informative investigation concerning this tumour
site. In conclusion: there is no convincing evidence on exposure-related
increase in tumours of the lung.
Furthermore, in most case-control
studies there has been no increase in lung cancer. Only one study (Gerin
et al. 1989) reported an association between lung adenocarcinoma and
Most studies published ≤ 1996 focused
on cancer of the respiratory tract (biologically plausible). No or only
weak evidence for an association between formaldehyde exposure and
increased mortalities from systemic cancer in humans was found. In two
out of three recent studies evidence for an association between
formaldehyde exposure and leukaemia has been reported (Hauptmann et al.
2003, Pinkerton et al. 2004, Coggon et al. 2003).
A valid and informative cohort study
was published by Hauptmann et al. (2003). For all leukaemia the authors
reported a significant increase in the relative risk (RR, referent
group: low exposure level) for peak exposure, the trend was highly
significant. Especially for myeloid leukaemia the RR for peak exposure
and average intensity was increased and reached significance. For
Hodgkin’s disease an increased (but not significant) RR for peak
exposure and average intensity (significant at the mid exposure level,
not significant at the high dose level) was found; however, the trend
was significant for both exposure categories. For the other two exposure
categories, cumulative exposure and duration, no statistical
significance was observed except a significant trend for Hodgkin’s
disease at the category cumulative exposure. These results could not be
explained by obvious biases or confounding factors. In summary, the data
suggested an increased risk for leukaemia, especially myeloid leukaemia,
from peak and average exposure to formaldehyde.
In a recent update of garment workers
(Pinkerton et al. 2004), leukaemia (all types) and myeloid leukaemia
related deaths were not increased. However, investigating the parameters
duration of exposure or time since first exposure there was an
exposure-related increase in deaths due to these cancer types (not
statistically significant) but significant among workers exposed the
first time more than 20 years ago (shorter latency period expected).
Using the multiple causes of death (MCOD) analysis a significant
increase in multiple cause mortality was found for workers exposed for ≥
10 years to formaldehyde concerning leukaemia and especially myeloid
leukaemia: workers exposed for more than 10 years and ≥ 20 years since
first exposure the MCOD analysis revealed for leukaemia and myeloid
leukaemia significantly increased multiple cause mortality. In summary,
the study of Pinkerton et al. (2004) supported the results of Hauptmann
et al. (2003), although some differences in methodology are obvious
(e.g., category peak exposure not determined, comparison with general
In the study presented by Coggon et
al. (2003) the results of the Hauptmann study (2003) were not confirmed.
Instead, the authors reported fewer leukaemia-related deaths than
expected in the high exposure group (standard mortality ratio 0.71, 95%
confidence interval 0.31-1.39). However, the category peak exposure was
not evaluated, the high average exposure group was not stratified for
high peak exposure, and no adjustment was done for co-exposure with
A meta-analysis of formaldehyde
exposure and leukaemia has been performed by Collins and Lineker (2004).
Based on the examination of 18 epidemiology studies (including recent
cohort studies) they concluded that the data do not provide consistent
support for a relationship between formaldehyde exposure and leukaemia
risk. This conclusion was based on lack of dose response in the studies
finding an association. Furthermore the long latency for leukaemia
deaths observed was not consistent with the experience on latency for
other chemicals inducing leukaemia.
In contrast to nasopharyngeal tumours,
a site of first contact, no plausible mechanism for the induction of
leukaemia in humans is found. According to Golden et al. (2006), there
is no evidence that formaldehyde reaches the bone marrow or has toxic
effects in the bone marrow and there is no credible evidence that
formaldehyde causes leukaemia in experimental animals.
In a pooled analysis of 12 case
control studies conducted in 7 countries and adjusted for age, study and
other occupational exposure an exposure related increase in the risk of
sinonasal cancer, particularly adenocarcinoma, was reported (Luce et al.
2002). Similar results were presented by T’Mannetje et al. (1999). In a
Danish study, the odds ratios for squamous cell carcinoma in the nasal
cavity or paranasal sinus were increased (Olsen & Asnaes 1986). In
contrast to these case-control studies, the recently published cohort
studies (Coggon et al. 2003, Pinkerton et al. 2004), and Hauptmann et
al. 2004) reported no excess of this cancer type.
1) Statistically increased
risk for nasopharyngeal cancer in workers exposed to formaldehyde has
been detected in one cohort but not in others.
2) A correlation between
formaldehyde exposure and leukaemia, especially myeloid leukaemia, was
seen in some studies but not all. This tumour type is biologically not
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