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Description of key information

The key study reports the acute oral LD50 in the rat to be 100 mg/kg. A modern reliable dermal toxicity study reports a dermal LD50 value of >2000 mg/kg in rats. A clear NOAEC of 0.54 mg/L is reported for acute inhalation toxicity and the weight of evidence from several other studies indicates an acute inhalation 4 hour LC50 of approximately 1000 mg/m3 (1 mg/L). 

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion
Dose descriptor:
LD50
100 mg/kg bw

Additional information

The acute toxicity data for furfural have been reviewed by the EU (EU-RAR, 2008), Health Canada (2010) and the EPA HED (2010).

Oral

In a reliable acute oral toxicity study in rats, an LD50 of 100 mg/kg bw and 105 mg/kg bw was established for male and female rats, respectively (Mital, 2002). Clinical signs included lethargy, tremors, abdominal breathing, tachypnea, exophthalmos and piloerection. The outcome of this study is consistent with an older acute oral toxicity study where the LD50 of undiluted furfural was 160 mg/kg bw to males rats and 119 mg/kg to female rats and when tested in different vehicles ranged from 145 - 205 mg/kg in males rats and 90 - 119 mg/kg in female rats (Brown, 1982).

These data are further supported by two 28 day studies, the first reported by Chengalis in 1997 where no effects were observed at doses up to 100 mg/kg/day and the second 28 day study reported by Arts et al (2004) which reported a NOAEL of 96 mg/kg/day (see Section 5.6; Repeat dose toxicity).

The acute oral toxicity data reviewed and summarised in the EU RAR in 2008 generally predates the studies summarised in this dossier; however the acute oral LD50 is concluded to be in the same range warranting similar classification under DSD and CLP. 

Dermal

All dermal data summarised in the EU-RAR (2008) were taken from old studies which pre-dated GLP and modern guidelines and were limited in detail. The RAR cites LD50 values of >310 mg/kg in rabbits to <10,000 mg/kg in guinea-pigs and a study in rabbits (Wood and Seevers, 1955) where the LD50 was reported between 500 and 1000 mg/kg (fully occlusive dressing). However, studies to modern guidelines and GLP are now available and are summarised in this dossier.

The key study for the acute dermal toxicity of furfural is by Moore (2004). The acute dermal LD50 of furfural technical in male and female rats was greater than 2000 mg/kg; there were no signs of toxicity.

A second study reported by Joseph in 2003(a) reported a dermal LD50 of 192 mg/kg. However, this study used a fully occlusive dressing which can increase absorption and hence over predict the toxicity. Furthermore the animals were group (rather than single) housed throughout the study; this is a deviation to guideline and would increase the potential for oral exposure through grooming. Therefore this study should not be considered for risk assessment purposes.

An acute MLD of greater than 2000 mg/kg (as reported by Moore, 2004) is further supported by a 28 day dermal study cited in the EPA HED review of 2010 where furfural was applied to the clipped skin of groups of 5 male and female rats at 0, 100, 500 and 1000 mg/kg/day, 6 hours per day, 5 days per week for 28 days. The systemic LOAEL was reported as 500 mg/kg/day based on clinical signs in males, an increase in motor activity in males and increased mortality (males and females). The systemic NOAEL was reported as 250 mg/kg/day. 

Inhalation 

In a 4-hour nose-only (aerosol) GLP guideline inhalation study (Merkel, 2003) in the rat, no mortality was observed at the lowest dose concentration of 0.54 mg/L, whereas exposure to 1.63 mg/L resulted in mortality (7/10 animals). Clinical signs included irregular respiration, dyspnea, hypoactivity and/or abnormal posture; surviving animals recovered by day 3. As a result, the acute LC50 of furfural was reported as > 0.54 mg/L and < 1.63 mg/L (>540 mg/m3 and <1630 mg/m3).

A 1 hour LC50 study in rats reported an LC50 of 3910 mg/m3 and 4150 mg/m3 to male and female rats respectively with a combined value of 4075 mg/m3 (4.075 mg/L) (Terrill, 1987). In this study 4 dose concentrations were tested and clinical signs included languid behaviour, prostration, squinted eyes, polypnea, prostration, respiratory distress and increased secretory responses. The data were published by Terrill et al in 1989 as ppm equivalent. In relation to the calculation of a 4 hr LC50 value as relevant for classification, Haber's Law is applied. This equates to a 4 hour LC50 of approx 1000 mg/m3 (1 mg/L).

In the 1989 publication, Terrill cites other studies that report a 4 hour LC50 of 235ppm (equivalent to 924 mg/m3 or 0.924 mg/L) and a 6 hour LC50 of 175ppm (equivalent to 688 mg/m3) for furfural. Wood and Seevers (1955, cited in EU RAR 2008) reported an LC50 of 490 mg/m3 in mice after exposure to furfural vapour for 6 hours.

In summary, the Merkel (2003) study provides a clear NOAEC for systemic toxicity of > 0.54 mg/L and the weight of evidence from the other available data indicates the 4 hour inhalation LC50 appears to be approximately 1000 mg/m3 or 1 mg/L. This value is supported by the study reported by Arts in 2004 (see Section 5.6; Repeat dose toxicity) where exposure of 10 rats (5 males and 5 females) to 1280 mg/m3 for 6 hours resulted in the death of all animals.  

 

Additional references

Health Canada (2010) : Draft Screening Assessment for the Challenge 2-furancarboxaldehyde (Furfural); October 2010

EPA Health Effects Division (2010): Furfural. Human Health Risk Assessment for Use on Golf Course Turf (Tees and Greens) and Sod Farms; 18 February 2010

Terrill JB, van Horn WE, Robinson D, Thomas DL. (1989): Acute Inhalation Toxicity of Furan, 2-Methyl Furan, Furfuryl Alcohol, and Furfural in the Rat

Am. Ind. Hyg. Assoc. J. 50, p. 359 361, 1989

Justification for classification or non-classification

Furfural triggers classification for acute oral toxicity. The LD50 value of 100 mg/kg bw triggers classification with T; R25 and H301 according to the DSD (Directive 67/548/EEC) and CLP (Regulation (EC) No 1272/2008 of the European Parliament) respectively. This is consistent with the conclusion summarised in EU-RAR in 2008.

With regards to dermal toxicity, the EU-RAR (2008) proposed classification as harmful in contact with the skin, Xn;R21 (under Directive 67/548/EEC) and Acute Category 4, H312 according to CLP/GHS. However, this proposal was based on old studies which pre-dated modern guidelines and GLP. A modern, reliable study is now available, the results from which does not trigger classification under DSD (Directive 67/548/EEC) or CLP/GHS (Regulation (EC) No 1272/2008 of the European Parliament).

Furfural triggers classification for acute inhalation toxicity. The weight of evidence from several studies indicate an LC50 of approximately 1mg/L which triggers classification with T; R23 according to the DSD (Directive 67/548/EEC). As a vapour, the corresponding classification is Category 2 H330 according to CLP (Regulation (EC) No 1272/2008 of the European Parliament).