Pesticide residues in food — 2006: Toxicological ... - ipcs inchem

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Skin 33.07 61.59 0.5 17.94 17.29 1.0 4.366 1.086 4.0
Total penetrated
+ skin
67.42 66.62 1.0 22.26 21.3 1.0 8.998 2.236 4.0
Surface washings 31.28 31.16 1.0 73.06 73.45 1.0 96.33 95.30 1.0
Donor cell wash 0.635 0.309 2.1 1.014 1.806 0.6 0.376 0.299 1.3
Total 99.34 98.09 1.0 96.33 96.39 1.0 105.70 97.84 1.1
From Thornley & Bryson (2001)
The total amount of radiolabel that fully penetrated the skin membrane (“absorbed radiolabel”)
was recovered in the receptor fluid and in the wash of the receptor cell. At the lowest and highest
concentrations, the amount of absorbed radiolabel was approximately sevenfold and fourfold higher
in specimens from rats than from humans, while at the intermediate concentration, the absorption
ratio was approximately 1. When the amount of radioactivity remaining associated with the skin was
also taken into account, no differences in the “potentially absorbable” percentages of administered
radiolabel were observed between species in the groups at the lowest and intermediate doses, while a
fourfold higher recovery was established in the group at the highest dose.
Therefore, it can be concluded that absorption through rat epidermal membranes in vitro was
the same as through human epidermal membranes at the lowest and intermediate doses (0.01 and
0.1 mg/cm²) and approximately fourfold that at the highest concentration (1.00 mg/cm²). The results
o btained for the lowest and intermediate concentrations were considered to be the most relevant,
because these concentrations fall in the range of the expected operator exposure. Thus, based on
the results of the study of dermal penetration in vitro, is the Meeting concluded that there is no
n otable d ifference between rats and humans in the extent of bioavailability after dermal exposure to
boscalid.
Metabolism
Studies of metabolic transformation (Grosshans & Knoell, 2001) were conducted in rats
given [diphenyl-ring-U- 14 C]boscalid (batch No. 641-2018; radiochemical purity, > 99%, specific
activity, 5.23 MBq/mg) or [pyridine-3- 14 C]boscalid (batch No. 640-1026; radiochemical purity,
> 97%, s pecific activity, 5.81 MBq/mg) or non-radiolabelled boscalid (batch No. 01174-236; purity,
> 99.4%). Male and female Wistar rats were orally dosed with [ 14 C]boscalid at a nominal dose of
50 and 500 mg/kg bw.
Patterns of radioactive metabolites in excreta (urine, faeces, bile), plasma, and tissues (liver
and kidney) were analysed by high-performance liquid chromatography (HPLC). Metabolites were
identified by mass spectroscopy (LC-MS and LC-MS/MS) and, in some cases, nuclear magnetic
resonance analysis of isolated fractions. Metabolite patterns of samples generated in this study were
compared with those obtained in kinetic studies in which rats were given single oral high (500 mg/ kg)
and low (50 mg/kg) doses and repeated high doses (14 × non-radiolabelled, 1 × radiolabelled;
500 mg/ kg). The structures of the identified metabolites recovered from rat excreta, plasma and
tissues are given in Table 19.
After administration of an oral dose of [ 14 C]boscalid to male and female rats, a large number
of metabolites were detected in urine. Predominant metabolites were a 4-hydroxyl diphenyl ring
m etabolite (named M510F01 in the tables) and its glucuronic acid conjugate (named M510F02 in
the tables). The proportion of the 4-hydroxy-diphenyl metabolite excreted via urine ranged from
0.5% to 3% in the group at 500 mg/kg bw and from 10% to 16% in the group at 50 mg/kg bw,
while the proportion of its glucuronyl conjugate was in the range of 0.1–4% of the dose. Two more
BOSCALID X-X JMPR 2006