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

392
Females
Relative liver weightt (% bw) 3.1 3.2 3.2 3.4* 5.5*
p-Nitroanisole O-demethylase activity 17 17 19 24* 48*
Alkaline phosphatase activity (IU/l) 283 304 298 285 355*
Bilirubin (mg/dl) 0.06 0.06 0.06 0.12 0.16*
From Weaver (1988)
* p < 0.05.
(b)
Neurotoxicity
(i)
Acute neurotoxicity
In a GLP-compliant study of acute neurotoxicity, groups of 10 male and 10 female Fischer F344
rats received a single dose of quinoxyfen (purity, 97.4%) at 0, 200, 632 or 2000 mg/kg bw by gavage
in 0.5% methyl cellulose. The concentration, homogeneity and stability of quinoxyfen solutions were
analysed. Food, water and housing conditions were controlled and monitored throughout the study. Clinical
observations for acute effects were made before dosing and daily during days 1–4. Body weights were
recorded before dosing and on days 1, 2, 8 and 15. Neurobehavioural assessments, including functional
observational battery (FOB) hand-held and open-field observations, grip performance, landing foot splay
and rectal temperature) and motor activity assay, were conducted before exposure and on days 1, 8 and
15. Ophthalmologic examinations were conducted before dosing and at termination. At necropsy on day
16, organs and tissues from all animals were examined grossly. Five males and five females from each
group were selected for evaluation of neuropathology, and sections of central and peripheral nervous
tissues from perfusion-fixed rats at 0 and 2000 mg/kg bw per day were assessed histopathologically.
Ophthalmology did not reveal any treatment-related change. Treatment with quinoxyfen did
not adversely affect cage-side, clinical, FOB, hand-held and open-field observations, body weights,
hindlimb grip performance, forelimb grip performance, rectal temperature or landing foot splay, at
any dose. No effects were detected in any aspect of motor activity. An apparent increase in level of
activity on a ranking basis on day 8 in males at 632 mg/kg bw per day was not confirmed by motor
activity scores, and a slight variation in rectal temperature at 200 mg/kg bw per day was regarded
as incidental as the findings were within normal variation within the study and there was no dose–
response relationship (Table 14).
Neuropathology evaluation revealed some neural lesions, including focal/multifocal, very slight
degeneration of individual nerve fibres in the trapezoid body of the medulla oblongata, the sciatic
nerve, or the lumbar dorsal root ganglion, very slight mineralization of the nasal olfactory epithelium,
and an epidermal inclusion cyst in the meninges of the lumbar spinal cord. These alterations were
either found in a single rat in the control group or a single rat at the highest dose, or were distributed
within groups in a similar incidence (Table 14).
The NOAEL was 2000 mg/kg bw per day, the highest dose tested (Shankar & Stebbins, 1999).
Table 14. Findings in a study of acute neurotoxicity in rats given quinoxyfen by gavage
Finding
Dose (mg/kg bw per day)
0 200 632 2000
Activity level, day 8, M/F (ranking) 2.2 / 3.1 2.5 / 3.3 2.7* / 3.4 2.5 / 3.3
Motor activity scores, day 8, M/F 10.6 / 11.4 9.9 / 13.0 9.4 / 12.6 10.7 / 11.9
Rectal temperature, day 8, M/F (°C) 36.5 / 37.3 36.9* / 37.3 36.7 / 37.3 36.7 / 37.3
Medulla oblongata slight degeneration, M/F (%) 40 / 80 NA NA 60 / 60
QUINOXYFEN X-X JMPR 2006