Safety evaluation of certain food additives - ipcs inchem

498 FURAN-SUBSTITUTED ALIPHATIC HYDROCARBONS
animals suggests that glycine conjugation may be capacity limited, probably by the
supply of endogenous glycine (Gregus et al., 1993).
It is anticipated that the aldehydes in this group will be oxidized to the
corresponding 3-furylpropenoic acid or 3-furylpropanoic acid derivatives. The esters
in this group will be hydrolysed to the same 3-furylpropenoic acid or 3-furylpropanoic
derivatives. The acids will then be conjugated with glycine and excreted. Similarly,
furoic acid formed by ester hydrolysis will be conjugated with glycine and excreted
in the urine.
(c) Furan-substituted ethers (Nos 1520–1522)
The Committee has previously reviewed the metabolic fate of alkylsubstituted
aromatic ethers (Annex 1, references 166 and 167). If the substance is
a methyl (No. 1520) or ethyl (No. 1521) furfuryl ether, O-dealkylation occurs in vivo
to yield the furfuryl alcohol, which subsequently undergoes oxidation to furoic acid.
As discussed above, furoic acid conjugates with glycine and is excreted mainly in
the urine. Difurfuryl ether (No. 1522) is anticipated to undergo CYP-catalysed
hydroxylation to yield the hemiacetal, which readily hydrolyses to yield furfuryl
alcohol and furfural. Both of these substances are then oxidized to furoic acid and
excreted (Nomeir et al., 1992; Parkash & Caldwell, 1994).
(d) Furan-substituted sulfides, disulfides and thioesters
(Nos 1523–1526)
The Committee has previously reviewed the metabolic fate of furansubstituted
sulfides and disulfides (Annex 1, references 160 and 161).
The two thioesters (Nos 1523 and 1526) in the group are anticipated to
undergo hydrolysis to the corresponding thiol (2,5-dimethyl-3-thiofuran, No. 1063)
and furfuryl mercaptan (No. 1072) and simple aliphatic carboxylic acid. The resulting
thiols are highly reactive in vivo, mainly because most thiols are readily oxidized.
Thiols are oxidized to unstable sulfenic acids (RSOH), which are further oxidized to
the corresponding sulfinic (RSO2H) and sulfonic acids (RSO3H). Methylation of
thiols primarily by S-adenosyl methionine yields methyl sulfides, which are then
readily oxidized to sulfoxides and sulfones. Thiols may react with physiological thiols
to form mixed disulfides or form conjugates with glucuronic acid. Oxidation of the
-carbon results in desulfuration and formation of an aldehyde, which oxidizes to
the corresponding acid (McBain & Menn, 1969; Dutton & Illing, 1972; Maiorino et
al., 1989; Richardson et al., 1991).
The labile nature of the S–S bond in furfuryl 2-methyl-3-furyl disulfide
(No. 1524) also presents a variety of metabolic options for detoxication. The
disulfide bond is rapidly reduced to the corresponding thiol (i.e. mercaptan) in a
reversible reaction in vivo. Therefore, the metabolic options available to thiols are
also available to disulfides. Thiol–disulfide exchange reactions are reversible,
nucleophilic substitution reactions that occur in vivo between low relative molecular
mass reduced and/or oxidized thiols (e.g. GSH disulfide or GSH) and cysteinyl thiol
components of proteins, resulting in the formation of mixed disulfides. The disulfide