Furfuryl alcohol

Carcinogenicity

Description of key information

Two-year inhalation carcinogenicity studies with furfuryl alcohol are available, plus rat and mouse oral (gavage) carcinogenicity studies with furfural, the proximate metabolite. These provide limited evidence of carcinogenicity at dose levels associated with systemic toxicity and only in tissues which exhibit significant tissue damage (i.e. nose and kidney for furfuryl alcohol, liver for furfural). As tumours were associated with tissue damage and furfuryl alcohol is assessed to be not genotoxic, it may be concluded that the tumours are induced by a non-genotoxic mechanism.  The reported LOAEC for nasal tissue non-neoplastic lesions was 2 ppm (8 mg/m3), however the changes at this concentration may be viewed as adaptive and non-adverse.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Dose descriptor:

NOAEL

53 mg/kg bw/day

Carcinogenicity: via inhalation route

Endpoint conclusion

Dose descriptor:

LOAEC

8 mg/m³

Justification for classification or non-classification

The classification for carcinogenicity laid down in Annex I ATP TC C&L is: Carc. Cat 3. Although limited evidence of carcinogenicity was seen as an increase in the incidence of tumours at toxic dose levels and associated with tissue damage a classification of Carc Cat 3 R40 is considered appropriate based on the avalable data. Under Reg(EC) 1272/2008 the appropriate classification is Cat 2 H351 “Suspected of causing cancer”.

Additional information

Two-year inhalation carcinogenicity studies with furfuryl alcohol are available, plus rat and mouse oral (gavage) carcinogenicity studies with the proximate metabolite, furfural.

Inhalation

In the two year rat inhalation study with furfuryl alcohol (NTP, 1999) all male rats at 32 ppm died by week 99. There were no exposure related clinical findings and mean body weights of 32 ppm males were reduced. Increased severity of nephropathy was noted in both males and females at 32 ppm. Local toxicity including non-neoplastic lesions in nasal tissue was noted at all dose levels (LOAEC 2 ppm, equivalent to 8 mg/m³). Neoplastic effects in males included an increased incidence of adenoma, carcinoma or squamous cell carcinomas in nasal tissue at 32 ppm, and of renal tubule adenoma at 32 ppm. In females, no clear neoplastic effects were seen. The NOAEC for systemic toxicity was 8 ppm (32 mg/m³).

In the mouse inhalation carcinogenicity study with furfuryl alcohol there was an increased incidence of renal tubule neoplasms at 32 ppm. There was no evidence of carcinogenic activity of furfuryl alcohol in females. Exposure of mice to furfuryl alcohol was associated with increased incidences of non-neoplastic lesions of the nose at 2, 8 or 32 ppm in both sexes, increased severities of nephropathy at 32 ppm in males and corneal degeneration at 32 ppm in females. The reported LOAEC for local toxicity was 2 ppm (8 mg/m³) and the NOAEC for systemic toxicity was 8 ppm (32 mg/m³).

The 'adversity' of the furfuryl alcohol induced pathological changes in the nose in both rats and mice in the NTP study are considered below using the criteria described by ECETOC (ECETOC, 2002).

In the rat some changes, in particular a low incidence of combined malignant tumours in males at the high dose (128 mg/m³) are clearly adverse. In contrast, at the low dose (8 mg/m³) most of the nasal changes observed at the high (effect) dose have either a zero incidence (hyperplasia of glands, squamous metaplasia of respiratory epithelium, adenoma and carcinoma of respiratory epithelium) or an incidence and severity similar to that in the unexposed control group (suppurative inflammation, lateral wall squamous metaplasia, hyperplasia / fibrosis of olfactory epithelium). The exceptions to the above are hyperplasia of the lateral wall, atrophy and metaplasia of olfactory epithelium, and hyperplasia of respiratory epithelium where the incidences at 8 mg/m³ were statistically significantly increased compared to the control rats. Although the incidences were increased, the severity was similar to the controls. Atrophy of olfactory epithelium with metaplasia to a respiratory type epithelium is a common defensive (adaptive) response to inhaled irritants. The only neoplastic diagnosis at 8 mg/m³ is an adenoma of the lateral wall in a male rat. Although the historical control incidence of this tumour type is not recorded in the report, the absence of similar tumours in the 16 and 128 mg/m³ groups indicates that this is an incidental finding and the tumour is not related to furfuryl alcohol exposure.

In mice, the nasal findings are similar to the rat.  Lesions considered to be adverse e.g. necrosis of respiratory epithelium, are not present in the 8 mg/m³ group. There are no neoplastic findings at any dose level. Treatment related findings at 8 mg/m³ e.g. metaplasia of olfactory epithelium, hyaline degeneration of respiratory epithelium are of minimal severity.

In summary, in both sexes of rats and mice, there are some changes in the nasal epithelium which are statistically significantly increased compared to the corresponding controls and are treatment related.   However the nature and severity of the treatment related changes indicates that they were not adverse, but rather adaptive changes that are considered not toxicologically relevant. The furfuryl alcohol study report notes that the hyperplasia and squamous metaplasia represent conversion of highly specialised nasal tissue into a more resistant type of epithelium, representing an adaptive response to chronic irritation (NTP, 1999). In addition to the type of lesion, the limited severity of the changes (ECETOC, 2002) is a very important consideration in reaching the conclusion that they are non-adverse.

All the treatment related changes at 8 mg/m³ were consistently in the minimal/slight range of severity i. e. below a threshold of concern when compared with controls.

It is concluded that the treatment related nasal tissue findings in both rats and mice exposed to 8 mg furfuryl alcohol/m³ were of minor severity and considered to be adaptive in nature. Hence 8 mg/m³may be regarded as a 'NOAEC' for assessment of a DNEL for long term local effects.

Oral

Oral carcinogenicity studies with furfural in rats and mice (NTP, 1990) showed some evidence of carcinogenic activity for male rats, based on the occurrence of uncommon cholangiocarcinomas in two animals and bile duct dysplasia with fibrosis in two other animals at the high dose of 60 mg/kg bw/day. In mice there was an increased incidence of hepatocellular adenoma at the highest dose (175 mg/kg bw/day). These carcinomas were associated with hepatotoxicity (chronic inflammation and pigmentation) which was also seen at 100 mg/kg bw/day

Conclusion

These studies provide limited evidence of carcinogenicity at dose levels associated with systemic toxicity and only in tissues which exhibit significant tissue damage (i.e. nose and kidney for furfuryl alcohol, liver for furfural). The kidney tumours seen in the inhalation studies were at an incidence similar to the overall background range and are considered likely to have arisen as an exacerbation of the common rodent specific age-related phenomenon of chronic progressive nephropathy and thus not to be relevant to human risk assessment. As tumours were associated with tissue damage and there is no evidence of genotoxicity it may be concluded that the tumours are induced by a non-genotoxic mechanism. This interpretation is supported by the final Risk Assessment Report on Furfural published by the EU in 2008 (EU RAR, 2008) which concluded “Therefore, it is assumed that the observed liver tumours were induced via some mechanism involving liver toxicity, and that at levels at which no liver toxicity is induced, tumours will not arise. Hence, as starting point for the risk characterisation for carcinogenicity the oral NOAEL for liver toxicity by the relevant route of administration … is taken”. Therefore, the oral NOAEL of 53 mg/kg bw/day from the dietary repeated dose toxicity study (Jonker, 2000a,b) is used as the starting point for both oral and inhalation DNEL determination.

Reference:

ECETOC (2002) Recognition of, and differential between, Adverse and Non-Adverse effects in toxicology studies. Technical Report No 85, Brussels

Carcinogenicity: via oral route (target organ): digestive: liver

Carcinogenicity: via inhalation route (target organ): respiratory: nose