Safety evaluation of certain food additives - ipcs inchem

562 MISCELLANEOUS NITROGEN-CONTAINING SUBSTANCES (addendum)
experimental animals. Benzyl isothiocyanate (No. 1562), phenethyl isothiocyanate
(No. 1563) and methyl isothiocyanate (No. 1884) are rapidly absorbed by rodents
following oral exposure (Brusewitz et al., 1977; Lam et al., 1993; Ji et al., 2005).
Isothiocyanates, at doses ranging from 1.7 to 80 mg/kg bw, are rapidly absorbed,
metabolized and excreted, primarily in the urine (Brusewitz et al., 1977; Lam et al.,
1993; Kassahun et al., 1997; Ji et al., 2005).
In experiments that investigated the metabolism of benzyl isothiocyanate,
oral administration of 20 or 80 mg/kg bw of the cysteine conjugate of [7- 14 C]benzyl
isothiocyanate to Wistar rats led to rapid absorption of more than 98% of the
radiolabel from the gastrointestinal tract, followed by excretion of 87–98% of the
radioactivity in the urine and 6% in the faeces. Mean plasma concentrations (43 and
24 μg-equivalent/ml in males and females, respectively) peaked at 45 min and then
dropped rapidly (half-life, 1–2 h), suggesting rapid excretion. After 3 days, less than
0.5% of the radioactivity remained in the carcass. In two rats with cannulated bile
ducts, a mean of 3.9% of the radiolabel was found in the bile, indicating that biliary
secretion was not a primary route for benzyl isothiocyanate excretion (Brusewitz
et al., 1977).
Following an intraperitoneal dose of 0.05 mmol [ 14 CH3]-labelled methyl
isothiocyanate/kg bw (equivalent to 4.0 mg/kg bw) administered to male Swiss-
Webster mice, the radiolabel was broadly distributed in the tissues at 6, 24 and
48 h, with the highest levels of residual 14 C retained in the liver and kidneys. After
48 h, more than 94% of the radiolabel was recovered, with urine (>80%) providing
the major route of elimination and the faeces (5%) and expired carbon dioxide (4%)
constituting minor routes of excretion. Approximately 6% of the radiolabel remained
in the carcass after 48 h (Lam et al., 1993).
Phenethyl isothiocyanate doses of 2, 10, 100 or 400 μmol/kg bw were given
to male Sprague-Dawley rats by intravenous injection. At the lowest dose level of
2 μmol/kg bw (326 μg/kg bw), the pharmacokinetic parameters (area under the
curve [AUC], 2.96 μmol/l per hour; clearance, 0.70 l/h per kilogram; volume of
distribution, 1.94 l/kg; and degradation half-life, 3.52 h) indicated that phenethyl
isothiocyanate was rapidly absorbed, distributed and eliminated. The half-life values
were significantly longer at 100 and 400 μmol/kg bw than at 2 μmol/kg bw (P < 0.05),
suggesting that as the dose increased, metabolic detoxication pathways (i.e.
mercapturic acid) approached saturation (Ji et al., 2005).
Plasma concentrations peaked at 0.44 and 2.0 h after doses of 10 and
100 μmol phenethyl isothiocyanate/kg bw, respectively, were given by oral gavage
to rats. The maximal plasma concentrations were 9.2 and 42.1 μmol/l after doses
of 10 and 100 μmol/kg bw, respectively. The similar AUC values observed for
intravenous and oral administration demonstrate that phenethyl isothiocyanate is
almost completely absorbed after oral administration (Ji et al., 2005).
(ii) Metabolism
Data on the metabolic fate of isothiocyanates indicate that they are
principally detoxicated by conversion to GSH conjugates. Studies on a number of
aromatic, aliphatic and further functionalized isothiocyanates have demonstrated