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

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two animals with whole litter resorption which consisted of early resorptions of 1 and 7 implantation
sites, respectively. This resulted in a corresponding increase (not significant) in postimplantation loss
for the group at the highest dose. No treatment-related external, visceral, or skeletal malformations/
variations were observed in any fetuses.
The NOAEL was 200 mg/kg bw per day, the highest dose tested (Schardein, 1997a).
2.6 Special studies: studies on metabolites
No studies on toxicity of metabolites were available.
3. Observations in humans
A toxicological working paper on bifenazate prepared for the Meeting by Crompton Corporation
stated that “monitoring of production plant personnel following normal safety precautions have not
indicated any significant adverse effects”. It also stated that “a review of incidental reports regarding
bifenazate showed that the incidents were minor in nature and dissipated within a reasonable period
of time. No oral studies have been performed with bifenazate in volunteers”.
Comments
Biochemical aspects
In studies of toxicokinetics, rats were given a single dose of radiolabelled bifenazate (10 or
1000 mg/kg bw) or were pre-treated with unlabelled bifenazate (10 mg/kg bw per day for 14 days)
then given a dose of radiolabelled bifenazate administered by gavage. On the basis of urinary and
biliary excretion, approximately 79–85% and 22–29% of the orally administered dose was absorbed
within 72 h at 10 and 1000 mg/kg bw. A peak in plasma concentrations of radioactivity was observed
5–6 h and 18–24 h after dosing at 10 and 1000 mg/kg bw, respectively. The elimination half-life at
10 and 1000 mg/kg bw was between 11.5 and 15.6 h. Approximately 90% of the administered dose
was eliminated in excreta within 48 h and 96 h at 10 and 1000 mg/kg bw, respectively. Faeces were
the major route of excretion (66–82% of the administered dose), with 8–24% of the administered
dose being recovered in the urine. Approximately 68–73% of the administered dose was excreted
in the bile within 72 h at 10 mg/kg bw and 21–26% of the administered dose at 1000 mg/kg bw.
Approximately 0.5% of the administered dose was detected in the tissues and residual carcass at
168 h, with highest concentrations of radioactivity in the liver, kidney and blood. Systemically
absorbed bifenazate was extensively metabolized. The major metabolites of bifenazate in the faeces
and urine resulted from hydrazine oxidation, demethylation, ring hydroxylation, removal of the
hydrazine-carboxylic acid side-chain, and conjugation of the biphenyl ring moiety with glucuronic
acid and sulfate. A total of eight metabolites and bifenazate were identified in the faeces and three
metabolites were identified in the urine. The primary metabolite(s) in the urine were sulfate and
glucuronide conjugates. Unchanged bifenazate was isolated in the faeces of males and females (5–7%
and 48–61% of the faecal radioactivity at 10 and 1000 mg/kg bw, respectively). In faeces, metabolite
D3598 (a product of oxidation of the hydrazine moiety) was detected (4–5% and 1–2% of the faecal
radioactivity at 10 and 1000 mg/kg bw, respectively). Excretion, distribution and metabolite profiles
were essentially independent of pre-treatment and sex.
Toxicological data
Bifenazate has low toxicity when administered orally, dermally or by inhalation. The LD 50
after oral administration was > 5000 mg/kg bw in mice and rats. The LD 50
in rats treated dermally
BIFENAZATE X-X JMPR 2006