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EC number: 700-263-8 | CAS number: 89686-69-1
Wistar rats were treated with Ditetrahydrofurylpropane for 28 consecutive days by daily oral gavage at dose levels up to 500 mg/kg/day.
No signs of toxicity were noted during the in-life phase, except for the first few days during which lethargy, flat posture, uncoordinated movements, abnormal gait and/or ptosis were noted among animals treated at 500 mg/kg/day.
Increased liver weights were noted at necropsy in males at 500 mg/kg/day and females at 150 and 500 mg/kg/day, along with a single occasion of an accentuated lobular pattern of the liver in one of these males. At 500 mg/kg/day, this was supported by midzonal/centrilobular hypertrophy of the liver in both sexes. The location of the hypertrophy in centrilobular and midzonal hepatocytes and absence of any morphological lesions indicative of hepatocytotoxicity was consistent with that of an adaptive change. The lower total bilirubin levels and aspartate aminotransferase activity at 500 mg/kg/day could reflect adaptive changes in the liver. However, considering the magnitude of the increase in liver weight in these animals (i.e. approximately 20 and 43% for males and females respectively), the increased liver weight was considered to be of an adverse nature. In addition, a number of clinical biochemistry parameters were observed that suggest an effect of the test substance on liver function. These parameters included increased total protein, albumin, glucose and cholesterol levels in (individual) females at 150 and 500 mg/kg/day and reduced glucose levels in males at 500 mg/kg/day.
In the kidneys of male rats at 150 and 500 mg/kg/day, an increase in the incidence and severity of cortical hyaline droplets was observed. These droplets were considered to represent alpha-2u-globulin, a normal protein in male rats that undergoes reabsorption in the proximal cortical tubules. A range of chemicals are known to increase hyaline droplet formation beyond the physiological capacity of the tubular epithelium which may then result in tubular epithelial cell damage (hyaline droplet nephropathy) which was evident in this study as an increase in the severity of corticomedullary tubular basophilia in males at 150 and 500 mg/kg/day. Kidney weights were also increased at these dose levels. An increase in the incidence/severity of cortical hyaline droplets is a specific male rat response which is not observed in normal female rats and higher species of either sex, including humans.
Other changes in clinical biochemistry parameters included increased calcium levels in females at 150 and 500 mg/kg/day, increased inorganic phosphate levels in males at 500 mg/kg/day, and an increased inorganic phosphate and potassium level in one female at 500 mg/kg/day.
The increase in calcium levels in females at 150 and 500 mg/kg/day coincides with an increase in albumin levels in these animals. As albumin is a major calcium binding protein and no correlating morphological changes of these animals were observed, this change probably reflects the increase in albumin levels and is considered of no toxicological significance.
From the results presented in this report, a definitive No Observed Adverse Effect Level (NOAEL) for Ditetrahydrofurylpropane of 50 mg/kg/day was established, based on effects on liver and kidneys in animals at 150 mg/kg/day and higher.
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