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

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before treatment and after 1, 2 and 3 months of treatment. The concentrations of several thyroid
hormones (free-T3, free-T4, total-T3 and total-T4) were measured in the serum taken at 3 months.
Urine was taken at 3 months for urine analysis (specific gravity, pH, glucose, protein, ketones,
occult blood, bilirubin, urobilinogen, colour and microscopy of sediment). All dogs were killed
at the end of the treatment period and autopsied and the weights of adrenals, brain, kidneys, liver,
pituitary, thyroid (including parathyroid), ovaries and testes were recorded. An extensive range of
tissues from all dogs in the control group and the group at the highest dose was examined by
light microscopy, but the histopathology performed on the other dogs was limited to the following
tissues: adrenals, epididymes, kidneys, liver, thyroid, parathyroid, pituitary, prostate, skin, testes,
thymus and tonsils. Samples of liver were taken for measurement of hepatic fatty acid beta-oxidation
(FAOX; by measuring cyanide-insensitive beta-oxidation of palmitoyl-CoA) in vitro and for electron
microscopy.
No dogs died during the treatment period and no treatment-related clinical signs were observed.
Body weights of males and females in the group at the highest dose became statistically significantly
lower (p < 0.05) than the concurrent body weights of controls, but there was no effect on food
consumption. No treatment-related effects were revealed by ophthalmoscopy. Small but statistically
significant (p < 0.05) haematological changes were seen in the groups of dogs at the highest dose,
for males and females: decreases in erythrocyte count, haemoglobin, erythrocyte volume fraction
and platelet count. Clinical chemistry results showed that there were small dose-related decreases in
serum cholesterol in males and females throughout the study that were statistically significant
(p < 0.05) in all treated groups of males and in females at 5 and 20 mg/kg bw per day. The reduction
in serum cholesterol concentrations was considered to be too small to be of toxicological significance.
In addition, significant (p < 0.05) decreases in the serum concentrations of total triiodothyronine
(T3), free T3 and total thyroxin (T4) were found in male and female dogs at 5 or 20 mg/kg bw per
day. Absolute and relative weight of the thyroid/parathyroid was significantly (p < 0.05) decreased
in males and females at 5 and 20 mg/kg bw per day and was associated with slight decreases in
follicular size and hypertrophy of follicular epithelial cells. Relative kidney weights were increased
in males and females in the group at the highest dose, but no renal pathology was seen and this
effect was thought to be due to the loss of body fat by this group (as reflected in their lower body
weight). Absolute liver weight, relative to controls, was significantly (p < 0.05) increased in males
at 5 or 20 mg/kg bw per day and in females at 20 mg/kg bw per day; relative liver weight was
significantly increased in males and females at 20 mg/kg bw per day. Light microscopy showed slight
hepatocellular hypertrophy in males and females at 20 mg/kg bw per day and in females at 5 mg/kg
bw per day that was shown to be due to increased stores of glycogen (vacuoles stained positive for
glycogen but negative for fat). Electron microscopy showed no treatment-related changes. Hepatic
activity of fatty acid beta-oxidation (FAOX) significantly increased in males and females at 5 and
20 mg/kg bw per day, but not at 2 mg/kg bw per day.
The NOAEL was 2 mg/kg bw per day on the basis of various effects seen at 5 and 20 mg/kg bw
per day, including decreased serum thyroid hormone levels with associated morphological changes
to the thyroid and induction of hepatic FAOX (Dietz et al., 1987).
In a GLP-compliant study, groups of six male and six female beagle dogs were given diets
providing racemic haloxyfop acid (purity, 99.6%) at a dose of 0, 0.05, 0.5 or 5.0 mg/kg bw per day
for 12 months. Blood was taken before treatment and after 1, 3, 6, 9 and 12 months of treatment
for haematology (total leukocyte count, differential leukocyte count, erythrocyte count, erythrocyte
volume fraction, haemoglobin, platelets, prothrombin time and reticulocyte count) and clinical
chemistry (glucose, ALT, AST, AP, BUN, cholesterol, total protein, albumin, globulin, total bilirubin
and triglycerides). In addition, liver function was tested by bromosulfthalein retention measurements
at 6 and 12 months. Urine was collected for urine analysis before treatment and at 6 and 12 months.
HALOXYFOP X-X JMPR 2006