Safety evaluation of certain food additives - ipcs inchem

MISCELLANEOUS NITROGEN-CONTAINING SUBSTANCES (addendum) 563
that they are conjugated with reduced GSH and eliminated primarily in the urine as
the corresponding N-acetylcysteine (mercapturic acid) conjugate (Brusewitz et al.,
1977; Mennicke et al., 1983, 1988; Ioannou et al., 1984; Eklind et al., 1990).
The metabolic fate of benzyl isothiocyanate and its cysteine conjugate was
investigated in rats utilizing in vivo models. Only the mercapturic acid conjugate was
detected in the urine 20 h after male Wistar rats were given 10 mg doses of benzyl
isothiocyanate by oral gavage. The mercapturic acid conjugate was also detected
following the intraperitoneal and intravenous administration of the cysteine and Nacetylcysteine
conjugates of benzyl isothiocyanate to rats (Brusewitz et al., 1977).
In the same study, starved CFHB Wistar rats were dosed orally with the
cysteine conjugate of [ 14 C]benzyl isothiocyanate (20 mg/kg bw) as a suspension in
aqueous 0.5% weight by volume (w/v) gum tragacanth (2 ml). The radioactivity was
well absorbed and rapidly excreted, with mean peak plasma concentrations of
radioactivity occurring within 45 min. More than 92% of the radioactivity was
excreted in the urine over 3 days. The primary radioactive metabolite (62% of dose)
corresponded to the mercapturic acid of benzyl isothiocyanate (Brusewitz et al.,
1977).
Similar results were found when two Wistar rats were given oral doses of L-
[ 35 S]cysteine hydrochloride for 4 days to enrich their sulfur pool with radiolabelled
cysteine. One rat was then given the non-radiolabelled cysteine conjugate of benzyl
isothiocyanate, and the other was used as the control. Two other rats that had not
been pretreated with the 35 S-enriched cysteine were then administered either a
[ 35 S]cysteine conjugate of benzyl isothiocyanate or the cysteine conjugate of
[7- 14 C]benzyl isothiocyanate. Urinary analysis for either the rat administered
unlabelled benzyl isothiocyanate cysteine conjugate after pretreatment with [ 35 S]cysteine
or the rat administered the [ 35 S]cysteine conjugate of benzyl isothiocyanate
with no pretreatment revealed the same major radioactive metabolite, [ 35 S]mercapturic
acid of benzyl isothiocyanate. These data suggest that the cysteine
conjugate on benzyl isothiocyanate partially reverts to free benzyl isothiocyanate in
vivo, which is then reconjugated with [ 35 S]GSH. Urinary analysis for the rat given
[7- 14 C]benzyl isothiocyanate revealed that some of the cysteine conjugate is
converted directly to the mercapturic acid derivative without prior regeneration of
free benzyl isothiocyanate (Brusewitz et al., 1977).
The metabolic fate of methyl isothiocyanate was investigated in rats and
mice in vivo. Male Sprague-Dawley rats were administered [ 13 CH3]methyl
isothiocyanate at approximately 33 mg/kg bw via oral, intraperitoneal and
intravenous routes. Regardless of the mode of administration, the corresponding
mercapturate and GSH conjugates were the primary metabolites in the urine and
bile, respectively (Lam et al., 1993).
In an attempt to quantify these and other metabolites, male Sprague-Dawley
rats and male albino Swiss-Webster mice were treated intraperitoneally with
[ 14 CH3]methyl isothiocyanate at a dose equivalent to 4.0 mg/kg bw (Lam et al.,
1993). Forty-eight hours after administration, analysis of the urine revealed that the
major metabolite in the rat was the mercapturic acid conjugate of methyl
isothiocyanate (28% of the 14 C in urine). In mice, the mercapturic acid conjugate