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In a 90-day study, groups of five beagles of each sex were given
ethoxyquin (purity, 97.6%) by capsule at 0, 2, 4, 20, or 40 mg/kg bw
per day. Clear signs of toxicity were seen during the first seven
weeks of the study at 40 mg/kg bw per day, including reduced body
weight, staining of the body surface, brown urine, brown sclera, dark
mucoid faeces, and emesis, and these groups received only empty
capsules for the final six weeks of the study, effectively becoming
reversibility groups. Investigations of clinical chemistry (including
thyroid hormones), haematology, and ophthalmoscopy were performed
before treatment and at weeks 4 and 12 or 13. Post-mortem
investigations included microscopic examination of a wide range of
tissues from all animals and special stains for pigment
identification.
One female at the highest dose was sacrificed in extremis on
day 13. Other findings were similar in males and females. Clinical
signs including brown staining of the abdomen and urogenital area,
brown urine, decreased faeces, and emesis were seen regularly at 20
and 40 mg/kg bw per day and occasionally during the 4 h after dosing
at 4 mg/kg bw per day; these signs were still present between weeks 7
and 13 ('recovery') in animals at the highest dose. Body-weight loss
occurred at 40 mg/kg bw per day in weeks 1-7, which reversed when
dosing stopped, but females had a lower (12%) mean body weight than
controls at termination. At 20 mg/kg bw per day, body-weight gain was
reduced (60%) throughout the study. Food consumption was reduced at 20
(20%) and 40 mg/kg bw per day (up to 50%). The only notable change in
haematological parameters was a dose-related decrease in activated
partial thromboplastin times in males at 4 mg/kg bw per day and higher
and in females at the highest dose. Marked increases in total
bilirubin concentration and in alkaline phosphatase, alanine
aminotransferase, aspartate aminotransferase, and gamma-GT activities
in serum, indicative of liver dysfunction, were seen at 20 mg/kg bw
per day in weeks 4 and 12 or 13 and at 40 mg/kg bw per day in week 4
only; alanine aminotransferase and, to a lesser extent, alkaline
phosphatase activities were also increased at 4 mg/kg bw per day. By
week 13, the serum values in animals at 40 mg/kg bw per day
(seven-week treatment, six-week recovery) had returned approximately
to control values. There were no significant changes in absolute or
relative organ weights. Treatment-related gross and microscopic
findings were limited to the liver. At 20 and 40 mg/kg bw per day, a
darkened appearance was associated microscopically with increased
pigment deposition, hepatocellular necrosis, cytoplasmic vacuolation,
and bile-duct hyperplasia; at 4 mg/kg bw per day, occasional findings
of mild or moderate pigmentation, minimal hepatocellular necrosis, and
vacuolation were recorded. The pigments were found to be porphyrin and
bilirubin in most cases, some sections also staining for haemosiderin.
The NOAEL was 2 mg/kg bw per day (Naas, 1996c).
Source:
International Programme on Chemical Safety 
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