Registration Dossier

Toxicological information

Carcinogenicity

Currently viewing:

Administrative data

Description of key information

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.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
carcinogenicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
The hydrolysis studies demonstrate that the test substance "reaction product ethylene glycol and para-formaldehyde” hydrolyses rapidly and completely. Therefore, data from the hydrolysis products are regarded sufficient to fulfill the data requirements.
Reason / purpose:
read-across source
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
body weight and weight gain
histopathology: non-neoplastic
Remarks on result:
other: no adverse effects observed up to highest dose level tested; no effects observed, study limited to clinical signs, body weight and histopathology
Key result
Critical effects observed:
no
Endpoint:
carcinogenicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
The hydrolysis studies demonstrate that the test substance "reaction product ethylene glycol and para-formaldehyde” hydrolyses rapidly and completely. Therefore, data from the hydrolysis products are regarded sufficient to fulfill the data requirements.
Reason / purpose:
read-across source
Key result
Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
urinalysis
gross pathology
histopathology: non-neoplastic
Dose descriptor:
LOAEC
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
urinalysis
gross pathology
histopathology: non-neoplastic
Remarks on result:
other: Nephrotoxic effects, more pronounced in males
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
200 mg/kg bw/day (nominal)
System:
urinary
Organ:
kidney
Treatment related:
yes
Dose response relationship:
not specified
Relevant for humans:
not specified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Data on formaldehyde

Experimental animals

Oral exposure

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 (limited validity).

In summary, the weight of evidence that formaldehyde induces systemic or local carcinogenic effects after oral exposure is insufficient.

Dermal exposure

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. 1983).

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 al. 1983).

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).

Inhalation 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 haematopoietic system.

Nasopharyngeal cancer

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 power.

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 nasopharyngeal cancer.

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).

Lung

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 formaldehyde exposure.

Leukaemia

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 population).

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 other substances.

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.

Sinonasal cancer

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.

Conclusion

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 plausible.

Justification for classification or non-classification

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.