Safety evaluation of certain food additives - ipcs inchem

564 MISCELLANEOUS NITROGEN-CONTAINING SUBSTANCES (addendum)
accounted for only 2.1% of the 14 C found in the urine. In both animals, a large
percentage of radiolabelled, unidentified, highly polar metabolites were present in
the urine after 48 h. The authors suggested that the majority of the [ 14 C]methyl
isothiocyanate undergoes extensive degradation to formaldehyde and formic acid,
and the radiolabel is then redistributed throughout the tissues (Lam et al., 1993).
A single 50 mg/kg bw dose of 4-(methylthio)butyl isothiocyanate or
sulforaphane (1-isothiocyanato-4-methylsulfinylbutane, a naturally occurring
isothiocyanate present in cruciferous vegetables, such as broccoli) was given to
male Sprague-Dawley rats by intraperitoneal injection (Kassahun et al., 1997). In
bile, the GSH and mercapturic acid conjugates of 4-(methylthio)butyl isothiocyanate
and sulforaphane were identified. Additionally, the urine of sulforaphane-dosed rats
gave metabolites identified as the mercapturic acid conjugates of sulforaphane and
4-(methylthio)butyl isothiocyanate. A third metabolite was assumed to be the
mercapturic acid conjugate of 1 -sulforaphane, a minor (desaturated) metabolite of
sulforaphane (Kassahun et al., 1997). These data support the evidence for
isothiocyanates being metabolized via GSH conjugation and subsequently
eliminated as mercapturic acid conjugates.
The metabolic fates of benzyl isothiocyanate and its conjugates were
investigated in vitro using rat whole-tissue homogenates. The GSH, cysteinylglycine
or cysteine conjugates of benzyl isothiocyanate (6 μmol) were incubated with either
liver or kidney homogenate at 37 ºC for 30 min. Although the GSH conjugate formed
the cysteine conjugate of benzyl isothiocyanate in either homogenate, the
conversion was complete in the presence of kidney homogenate, suggesting that
the formation of the cysteine conjugate from the GSH conjugate occurs more readily
in the kidney. The cysteinylglycine conjugate formed both GSH and cysteine
conjugates in the liver homogenate, but only the cysteine conjugate in kidney
homogenate. The mercapturic acid conjugate was detected when the cysteine
conjugate was incubated with liver or kidney homogenates in the presence of acetylcoenzyme
A (CoA). In the absence of acetyl-CoA, reduced acetylation occurred,
indicating that sufficient acetyl-CoA in the homogenates was available to produce
the mercapturic acid conjugate (Brusewitz et al., 1977).
Collectively, these data support the conclusion that isothiocyanates are
detoxicated primarily via conjugation with GSH and subsequent conversion to the
mercapturic acid conjugate (Barnes et al., 1959; Boyland & Chasseaud, 1967;
Brusewitz et al., 1977).
2.3.2 Toxicological studies
(a) Acute toxicity
No significant new information on the acute toxicity of these agents has been
reported since the preparation of the original monograph (Annex 1, reference 177).
(b) Short-term studies of toxicity
Additional short-term toxicity studies have been reported for several
substances in the group. The results of these studies are provided below and
summarized in Table 3.