Safety evaluation of certain food additives - ipcs inchem

490 FURAN-SUBSTITUTED ALIPHATIC HYDROCARBONS
2.1.2 Absorption, distribution and excretion
Data on furan-substituted aliphatic hydrocarbons, alcohols, aldehydes,
ketones, carboxylic acids and related esters, sulfides, disulfides and ethers with an
oxygenated alkyl substituent indicate that the furyl derivatives in this group are
rapidly absorbed, metabolized and excreted from animals. Furfuryl alcohol and
furfural are rapidly absorbed by rodents via common routes of exposure, including
oral (Nomeir et al., 1992), dermal and inhalation routes (Castellino et al., 1963;
National Institute for Occupational Safety and Health, 1979). At doses ranging from
0.1 to 200 mg/kg bw, furfuryl alcohol and furfural were absorbed from the
gastrointestinal tract, metabolized and excreted, primarily in the urine (Rice, 1972;
Nomeir et al., 1992; Parkash & Caldwell, 1994).
More than 86% of the radiolabel from 0.275, 2.75 or 27.5 mg [ 14 C]furfuryl
alcohol/kg bw or 0.127, 1.15 or 12.5 mg [ 14 C]furfural/kg bw given to male Fischer
344 rats (four per group) by gavage in corn oil was rapidly absorbed from the
gastrointestinal tract, with 83–88% of the radioactivity being excreted in the urine
and 2–5% in the faeces (Nomeir et al., 1992). The majority of radioactivity was
excreted within the first 24 h following dosing. Approximately 7% of the 12.5 mg/kg
bw dose of furfural was exhaled as 14 CO2. At 72 h following administration, residual
radioactivity was distributed primarily to the liver and kidney, with tissue radioactivity
levels being generally proportional to the dose.
More than 90% of a single oral dose of 1, 10 or 60 mg [ 14 C]furfural/kg bw
given to male and female Fischer 344 rats or 1, 20 or 200 mg [ 14 C]furfural/kg bw
given to male and female CD1 mice was recovered within 72 h (Parkash & Caldwell,
1994). The major route of elimination was the urine (>76% in rats and >61% in mice
within 24 h). Faecal elimination (1–6% in 72 h for all dose groups of rats and mice)
and expired carbon dioxide (5% in high-dose male mice and 4% in low-dose female
mice after 24 h; no other carbon dioxide measurements were taken) constituted
minor routes of excretion.
A similar pattern of absorption, distribution and excretion has been reported
for alkyl-substituted furfural derivatives. Groups of male Fischer F344 rats and male
B6C3F1 mice were administered 5, 10, 100 or 500 mg [ 14 C]5-hydroxymethyl-2furfural/kg
bw via gavage. In both species, 5-hydroxymethyl-2-furfural-derived
radioactivity was rapidly cleared from all major tissues, with no evidence of
accumulation in any tissues. Tissue concentrations varied with dose in both species
at most time points. Within 48 h, 70–82% of the administered dose was excreted in
the urine of rats, whereas 8–12% was excreted in the faeces. In mice, 61–77% was
excreted in the urine and 15–26% in the faeces within the same period (Godfrey et
al., 1999).
Alkylfuran derivatives also exhibit rapid uptake, metabolism and excretion.
Male Sprague-Dawley rats administered 100 mg [ 14 C]2-methylfuran/kg bw in
sesame oil via intraperitoneal injection showed radiolabelled 2-methylfuran (No.
1487) metabolites in the 12-h urine (Ravindranath & Boyd, 1991). It was reported
that pretreatment of the rats with buthionine sulfoximine (an inhibitor of -glutamyl
cysteine synthetase, a key enzyme in glutathione [GSH] synthesis) at least 1.5 h
prior to [ 14 C]2-methylfuran administration caused a 20% increase in urinary