Subacute (28-day) toxicity of furfural in Fischer 344 rats: a comparison of the oral and inhalation route

Introduction:
This article compares the subacute oral and inhalation toxicity of furfural vapor in Fischer 344 rats. The study investigates whether route-to-route extrapolation can be used to derive the limit value for inhalation exposure from oral toxicity data. The study includes groups treated daily for 28 days with furfural by gavage at various dose levels, or exposed by inhalation to different concentrations for 6 hours/day, 5 days/week or 3 hours/day, 5 days/week for 28 days. Control groups received vehicle or clean air.

Key Points:

* The study found that daily oral treatment with furfural at high doses (initially 192 mg/kg bw/day, later reduced to 144 mg/kg bw/day and 120 mg/kg bw/day) resulted in mortality and increased kidney and liver weight in surviving females.
* Exposure to furfural vapor by inhalation for 6 hours/day, 5 days/week for 28 days induced mortality at concentrations of 640 mg/m3 and above within 1-8 days. however, exposure to lower concentrations was tolerated without serious clinical effects.
* histopathological nasal changes were seen in all rats exposed to furfural vapor by inhalation, even at the lowest concentration of 20 mg/m3. The severity and incidence of these changes increased with increasing exposure concentration.
* The no-observed-adverse-effect level (NOaEL) for oral toxicity was 96 mg/kg bw/day. The NOaEL for systemic inhalation toxicity was comparable, i.e. 92 mg/kg bw/day (corresponding to 320 mg/m3(6 h/day) or 640 mg/m3(3 h/day)) assuming 100% absorption.
* however, the presence of histopathological nasal changes at the lowest tested concentration of 20 mg/m3 (corresponding to 6 mg/kg bw/day) proves that for locally acting substances like furfural, route-to-route extrapolation from the oral to the inhalation route is not valid.
* For locally acting substances, the inhalation route can be much more toxic than the oral route, even when applying safety/uncertainty factors.
* Regulatory agencies should consider the unique toxicological properties of locally acting substances and avoid using route-to-route extrapolation for risk assessment.

Main Message:
The study highlights the limitations of route-to-route extrapolation for risk assessment of locally acting substances like furfural. The study found that furfural is much more toxic by inhalation than by oral gavage, even when applying safety/uncertainty factors. Regulatory agencies should consider the unique toxicological properties of locally acting substances and avoid using route-to-route extrapolation for risk assessment.

arts, Josje h.E., hans Muijser, Marko J. appel, C. Frieke Kuper, Jos G.M. Bessems, and Ruud a. Woutersen. “Subacute (28-Day) Toxicity of Furfural in Fischer 344 Rats: a Comparison of the Oral and Inhalation Route.” Food and Chemical Toxicology 42, no. 9 (September 2004): 1389–99. https://doi.org/10.1016/j.fct.2004.03.014.