Furfuryl alcohol

Endpoint summary

Key value for chemical safety assessment

Skin sensitisation

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

Furfuryl alcohol is considered negative for skin sensitisation based on the OECD toolbox. A UK classification proposal for furfuryl alcohol submitted in April 2004 stated that with regard to skin sensitisation ‘no data are available on which to base a classification. The chemical does not contain any structural alerts for possible sensitising potential’. On that basis a proposal for no classification (R43) was made.

However, there are now data that require consideration.

Non-human

There are test results from a local lymph node assay (LLNA) conducted in 2003 and reported in 2004 by Burleson Research Technologies (Burleson 2004). Test material ST 16 C 03 (furfuryl alcohol) was tested at 5 concentrations (1%, 5%, 10%, 20% and 40%) using 4:1 acetone:olive oil (AOO) as the vehicle. A positive control, isoeugenol (a known skin sensitiser), was tested concurrently (0.5%, 1% and 5% in AOO). Control animals were treated with AOO alone.

The LLNA was conducted in compliance with GLP using a standard procedure. There was an induction of draining lymph node cell proliferation by furfuryl alcohol that was to some extent dose-related. The data are consistent with a positive response in the LLNA, insofar as at 3 test concentrations (10%, 20% and 40%) stimulation indices of 3 or greater were recorded (8.8, 9.2 and 21.0, respectively). In the same animals increases in ear thickness associated with exposure to furfuryl alcohol were less than 3% (compared to 2.9% with vehicle control). The interpretation is that the changes in lymph node cell proliferative activity observed with the higher test concentrations of furfuryl alcohol were not to be attributable to elicitation of a strong skin irritant response at the point of contact.

In the same study responses observed with isoeugenol, a positive control, were as expected. That is, a clear positive response (SI = 18.3) was observed with 5% of the chemical. The response to isoeugenol in this study translates into an EC3 value of 0.75%. This is not dissimilar to a previously reported EC3 value for isoeugenol of 1.8% (Gerberick et al., 2004). These data suggest that the LLNA conducted in this study was not of abnormal sensitivity.

A second LLNA (Franko et al., 2012) used a relatively standard assay and also measured skin irritancy. Furfuryl alcohol (10%, 2%, 50% and 75%) was applied using acetone as a vehicle. A dose-related increase in lymph node cell proliferation was observed. The SI values were 1.3, 2.9, 4.3 and 5.9 at 10%, 20%, 50% and 75%, respectively. Statistically significant increases in proliferative activity were recorded with 50% and 75% furfuryl alcohol, concentrations that provoked positive responses (SI values of 3 or greater). Only 75% furfuryl alcohol caused significant skin irritation, measured as a function of induced increases in ear thickness. Using the LLNA data the investigators derived an EC3 value of 25.6%, on which basis skin sensitising activity would be categorised as ‘weak’.

Although at face value the results obtained with two independent LLNA indicate that furfuryl alcohol does have the potential to induce skin sensitisation, it is important to view this in a wider context.

There have been suggestions that certain classes of chemical are associated with false positive reactions in the LLNA (Kreiling et al., 2008).

Human

In a NIOSH (US National Institute for Occupation Safety and Health) review of occupational exposure to furfuryl alcohol (NIOSH, 1979) it was noted that, despite skin contact with furfuryl alcohol in the workplace, including in some instances what was described as ‘extensive skin contact’, there were no associated medical histories, and examination of workers revealed no significant findings. These views apparently derive from an unpublished report of work conducted by the Quaker Oats Company in 1969 and submitted to NIOSH in 1978. This is cited as reference 26 (Sanders LW) in the NIOSH review (NIOSH, 1979). In the same review reference is made to a report that describes dermatitis in two workers associated with the handling of acid-resistant cement that probably contained liquid furfuryl alcohol (Mastromatteo, 1965). However, there is no indication that this was allergic contact dermatitis, nor is it certain that the skin effects resulted from contact with furfuryl alcohol rather than other irritant agents contained within the material (Mastromatteo, 1965; NIOSH, 1979).

At the date of preparation of this report no reports of allergic contact dermatitis to furfuryl alcohol were found.

The 1979 NIOSH review draws attention to a study of furfuryl alcohol published (in Russian) by Chernousov (1974). That article described a very unconventional assessment of skin sensitisation to furfuryl alcohol in guinea pigs in which it was found that topical exposure to some concentrations of the chemical resulted in the appearance of anti-hapten antibodies. It is not possible to interpret that observation in the context of skin sensitisation potential.

In conclusion, therefore, the results of 2 independent LLNA assays suggest that furfuryl alcohol has some potential to cause skin sensitisation, although the level of activity observed in the assays was different. Furfuryl alcohol does not have a clear structural alert for skin sensitisation, and, despite opportunities for significant skin exposure, there are no reported cases in humans of allergic contact dermatitis caused by furfuryl alcohol. It is concluded that furfuryl alcohol is not a skin sensitiser.

 

Additional References

Gerberick GF, Ryan CA, Kern PS, Dearman RJ, Kimber I, Patlewicz GY and Basketter DA (2004) A chemical dataset for evaluation of alternative approaches to skin-sensitization testing. Contact Dermatitis 50: 274-288.

Kreiling R, Hollnagel HM, Hareng L, Eigler D, Lee MS, Griem P, Dreessen B, Kleber M, Albrecht A, Garcia C and Wendel A (2008) Comparison of the skin sensitizing potential of unsaturated compounds as assessed by the murine local lymph node assay (LLNA) and the guinea pig maximization test. Food and Chemical Toxicology 46: 1896-1904.

Mastromatteo E (1965) Recent occupational health experiences in Ontario. Journal of Occupational Medicine 7: 502-511

 

Migrated from Short description of key information:
The results of two independent LLNA assays suggest that furfuryl alcohol has some potential to cause skin sensitisation, although the level of activity observed in the assays was different. Furfuryl alcohol does not have a clear structural alert for skin sensitisation, and, despite opportunities for significant skin exposure, there are no reported cases in humans of allergic contact dermatitis caused by furfuryl alcohol. It is concluded that furfuryl alcohol is not a skin sensitiser.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

There is little information available regarding the respiratory sensitisation potential of furfuryl alcohol. There are no structural alerts that suggest that furfuryl alcohol has respiratory sensitising potential. Nor does it share structural homology with classes of chemistry (acid anhydrides, diisocyanates, piperazine, chloroplatinate salts) that are known to be associated with respiratory allergy and occupational asthma.

Non- human

The local lymph node assay (LLNA) was not developed to identify chemicals that are able to cause sensitisation of respiratory tract. However, there is evidence that some chemical respiratory allergens test positive in the assay. Thus, although activity in the LLNA is not necessarily indicative of respiratory sensitisation potential, and only a minority of chemicals that are positive in the LLNA are also respiratory sensitisers, it remains the case that chemicals that test negative in the LLNA are very unlikely to be respiratory allergens.

It has been proposed that topical exposure to chemical respiratory allergens, but not to contact allergens, induces increases in the total serum concentration of IgE in mice. Although not a validated method, it is believed by some to be indicative of respiratory sensitising potential (Kimber et al., 2011). Franko et al (2012) investigated whether furfuryl alcohol has the potential to cause sensitisation of the respiratory tract by examining whether it causes changes in the production of IgE immunoglobulin. He reported that topical exposure of mice to 75% furfuryl alcohol caused a significant increase in the total IgE concentration in plasma. Furthermore 75% and 50% furfuryl alcohol applied topically also resulted in an increase in the number of IgE-bearing B lymphocytes in lymph nodes. A significant increase in total plasma IgE was found also following pulmonary exposure of mice to 2% furfuryl alcohol.

Whilst the ability of high concentrations of furfuryl alcohol to provoke an increase in total concentrations of IgE can be viewed as suggestive of respiratory sensitising potential, these data cannot be considered conclusive, acknowledging that in an international trial of this endpoint (the Mouse IgE Test) there was significant inter-laboratory variation in results (Dearman et al., 1998).

Franko et al. (2012) also describe airway hyperreactivity (AHR) following pulmonary exposure of mice to furfuryl alcohol, either with or without prior dermal exposure to the same chemical. The fact that AHR in response to pulmonary challenge was more pronounced following previous dermal contact is suggestive of allergic sensitisation. However, as the investigators acknowledge, it is not possible to exclude the possibility that airway changes result from irritant effects rather than from allergic hypersensitivity.

Human

There have been isolated reports of respiratory symptoms in moulders and foundry workers using furan-based materials (Low and Mitchell, 1985; Ahman et al., 1991). However, in neither instance was the mechanism of action established, nor was the causative chemical species identified. The only other relevant information available is from a single worker who developed asthma following working with a furan binder. The authors concluded that the symptoms observed were in response to volatile reaction products of furfuryl alcohol following reaction withparaformaldehde, xylene, sulphuric acid, phosphoric acid and butyl alcohol (Cockroft et al., 1980). However, a direct relation could not be clearly established, since humans were exposed to mixtures and/or reactions products, and not to furfuryl alcohol alone. There are no other case reports on sensitisation for furfuryl alcohol alone despite the wide industrial use of the substance.

In summary, although the results of Franko et al (2012) are suggestive of the possibility that furfuryl alcohol may have some potential to cause respiratory allergy, the data are not conclusive. In the absence of any other evidence implicating furfuryl alcohol as a respiratory allergen it would be premature to classify this chemical as a respiratory sensitiser.

Additional References

Dearman RJ, Basketter DA, Blaikie L, Clark ED, Hilton J, House RV, Ladics GS, Loveless SE, Mattis C, Saistad DM et al (1998) The mouse IgE test: interlaboratory evaluation and comparison of BALB/c and C57BL/6 strain mice. Toxicology Methods 8: 69-85.

Kimber I, Basketter DA, Gerberick GF, Ryan CA and Dearman RJ (2011) Chemical allergy: translating biology into hazard characterization. Toxicological Sciences 120: S238-S268.

Migrated from Short description of key information:
Although data from a murine model suggest furfuryl alcohol may have some potential to cause respiratory allergy, the data were inconclusive. In the absence of any other evidence implicating furfuryl alcohol as a respiratory allergen it would be premature to classify this chemical as a respiratory sensitiser.

Justification for classification or non-classification

Furfuryl alcohol is concluded not to warrant classification under DSD or CLP for potential skin or respiratory sensitisation. This is in accordance with the Annex VI CLP classification for furfuryl alcohol.