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

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Evaluation for acceptable daily intake
1. Biochemical aspects
1.1 Absorption, distribution and excretion
Mice
In a study of pharmacokinetics that complied with GLP, groups of 21 male and 21 female
B6C3F 1
mice were given the sodium salt of racemic haloxyfop as a single oral dose at 5 mg/kg bw.
Groups of three mice of each sex were killed at 6, 12, 24, 48, 72, 96 and 168 h after dosing for
measurement of the radioactivity in the plasma, kidney and liver. Urine and faeces were collected
at 24-h intervals for measurement of radioactivity. Peak plasma concentrations of 23 (males) and
24 mg eq/g (females) were attained at 6 h after dosing. The half-life for apparent first-order absorption
into the plasma was 1.5 h for males and 1.9 h for females. Disappearance of radiolabel from the
plasma appeared to follow first-order kinetics with half-lives of 1.7 and 1.9 days in males and females
respectively and volumes of distribution (V d
) of 196 and 194 ml/kg. The half-lives for removal from
the liver and kidneys were respectively 1.7 and 1.8 days in males and 1.9 and 2.0 days in females. At
168 h after dosing, 18% (males) and 24% (females) of the administered radiolabel had been recovered
in urine and 66% (males) and 60% (females) had been recovered in faeces. The proportion of the
excreted radiolabel that was found in the faeces was 79% for males and 71% for females (Smith
et al., 1984).
Rats
In a dose range-finding study, groups of Fischer 344 rats were given racemic haloxyfop methyl
ester (radiochemical purity > 98%) that was labelled with 14 C on the phenyl ring. Males were given
single intravenous or oral doses at either 0.5 mg/kg bw or 50 mg/kg bw, while females were received
doses of 10 mg/kg bw orally or intravenously. Urine and faeces were collected at frequent intervals
throughout the study. Three rats from each group were killed at 1, 2, 4, 6, 8, 12, 24, 36, 48, 60, 72, 96
and 120 h after dosing in order to obtain samples of plasma. The oral doses were rapidly absorbed and
there was little difference between the pharmacokinetic behaviours of oral and intravenous doses. The
clearance of radioactivity from the plasma seemed to follow first-order kinetics. Pharmacokinetics
results for appearance and disappearance of radioactivity in plasma are summarized in Table 1. Most
of the radioactivity remaining in the bodies of male rats at 5 days after dosing was in the carcass
(19.3–25.0% of the administered dose), liver (9.8–18.0%) and skin (10.3–14.6%). The proportion
of the excreted radiolabel that was found in the faeces was 63–73% for males and in females the
proportion in urine was 68–78% (Smith et al., 1982).
Table 1. Pharmacokinetics in a dose range-finding study in mice given a single dose of
r adiolabelled racemic haloxyfop methyl ester
Parameter Males Females Males
0.5 mg/kg
bw, oral
0.5 mg/kg
bw, IV
10 mg/kg
bw, oral
10 mg/kg
bw, IV
50 mg/kg
bw, oral
50 mg/kg
bw IV
Absorption half-life (h) 1.8 — 1.7 — 3.0 —
Plasma clearance half-life (days) 3.6 3.9 1.1 1.0 2.8 4.5
Volume of distribution (ml/kg bw) — 236 194 199 — 179
Peak plasma concentration (μg/g) 1.13 2.22 50 50 213 299
HALOXYFOP X-X JMPR 2006