Pesticide residues in food — 2007: Toxicological ... - ipcs inchem

488
All the pivotal studies met the basic requirements of the relevant Organisation for Economic
Co-operation and Development (OECD) or national test guideline and contained certificates of compliance
with good laboratory practice (GLP).
Evaluation for acceptable daily intake
1. Biochemical aspects
1.1 Absorption, distribution and excretion
(a)
Oral route
Rats
In a GLP-compliant study, the balance and excretion patterns of 14 C- and 13 C-phenyl ringlabelled
zoxamide (Figure 1), and the amount of residual radioactivity in blood, organs and tissues
were determined in male and female Sprague-Dawley Crl:CDBR rats (body weight, 220–426 g)
treated orally.
Groups of three to six males and three to six females were given [ 14 C]zoxamide (radiochemical
purity, 97.6–99.5%; 45.8–90.2 mCi/g or 1.69–3.34 GBq/g) at nominal dose levels of 10 (lower dose)
or 1000 (higher dose) mg/kg bw by gavage—details of the main groups are outlined in Table 1. The
test materials were prepared as suspensions in corn oil and administered in a volume of 5 ml/kg bw.
For all groups, [ 14 C]zoxamide was combined with appropriate amounts of non-radiolabelled zoxamide
(purity, 92.9–94.2%). In addition, 13 C-labelled zoxamide (purity, 96.8%) was added to the dosing
solution for groups A, B, Q and R to assist in metabolite determinations.
The following experiments were conducted:
• Determination of the excretion, distribution and mass balance of radioactivity (up to 120 h after
dosing) in groups A and B (lower dose) and C and D (higher dose);
• Evaluation of the pharmacokinetics of radioactivity in blood (to determine the time to C and max
½ C max
) (groups 1, 2 (also investigated for expired air) (higher dose) and 3 (lower dose);
• Determination of the tissue distribution of radioactivity at C and ½ C (groups I to P; both
max max
dose levels),
• Investigation of effects after repeated doses (groups E, F, G and H). Rats in groups E and F
received diets containing non-radiolabelled zoxamide technical at a concentration of 200 ppm for
2 weeks before receiving [ 14 C]zoxamide as a single oral dose at 10 mg/kg bw. Rats in groups G
and H received [ 14 C]zoxamide as five consecutive daily doses at 10 mg/kg bw/day by gavage.
Figure 1. Structure of zoxamide
O
Cl
NH
Cl
O
Cl
ZOXAMIDE 487–522 JMPR 2007