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EC number: 201-487-4
CAS number: 83-56-7
Based on effects on kidneys and forestomach,
a No Observed Adverse Effect Level (NOAEL)
for naphthalene-1,5-diol of 50 mg/kg/day was established (oral route, 90 days).
Repeated dose 90-Day oral toxicity study
with naphthalene-1,5 -diol by daily gavage in the rat, followed by a
28-day recovery period.
Based on a 28-day range finding study (NOTOX
Project 409556), the dose levels for this 90-day oral gavage study were
selected to be 0, 50, 100 and 300 mg/kg/day.
The study was based on the following
- EC Directive 67/548/EEC, B Repeated
Dose (90 days) Toxicity (oral), 2001.
- OECD 408, Repeated Dose 90-day Oral
Toxicity Study in Rodents, 1998.
- EPA 712-C-98-199, 90-Day Oral
Toxicity in Rodents, 1998.
The test substance was administered daily
for at least 90 days by oral gavage to SPF-bred Wistar rats. One control
group and three treated groups were tested, each consisting of 12 males
and 12 females. An extra 5 animals per sex in the control and high dose
group were allowed 28 days of recovery.
The following parameters were evaluated:
clinical signs daily; functional observation tests; body weight and food
consumption weekly; ophthalmoscopy at pretest and in week 13; clinical
pathology and macroscopy at termination; organ weights and
histopathology on a selection of tissues.
4.1 Discussion and Conclusion
Five high dose animals died during the
treatment phase. Although the cause of death was not established for
three high dose females, a relationship to treatment can not be
Purple discolouration of the urine as noted
in all treatment groups was probably caused by the test substance and/or
a test substance metabolite and was not regarded as adverse.
Necropsy findings at 300 and 100 mg/kg/day
consisted of black discolouration of the kidneys (correlating to
brown/black tubular pigment) and thickening of the limiting ridge in the
stomach (correlating to hyperplasia of the squamous epithelium), the
latter finding being regarded of no relevance to man. No microscopic
correlate was found for the thickened limiting ridge in the stomach in a
single male at 50 mg/kg/day. In addition, higher kidney weights were
recorded in males at 300 mg/kg/day. Other histopathological lesions in
the kidneys consisted of an increased severity of hyaline casts and
corticomedullary basophilia at 300 and/or 100 mg/kg/day. Following
recovery, renal tubular pigment, increased severity of renal
corticomedullary basophilia and squamous hyperplasia of the stomach
remained present only in a few high dose animals.
The clinical biochemistry deviations noted
at the end of the treatment period were probably secondary effects
related to target organ toxicity. These deviations included higher
glucose, total protein, albumin, potassium and bilirubin levels, and
reduced urea levels at 300 mg/kg/day, and had regressed by the end of
the recovery period. At 100 mg/kg/day, increased bilirubin and reduced
urea levels were noted. The higher inorganic phosphate levels recorded
for high dose females at the end of recovery were considered to be of
uncertain significance in view of absence of evidence of kidney
dysfunction at the end of recovery and absence of a similar finding at
the end of treatment.
No concurrent morphologic evidence of liver
dysfunction was obtained for the increased liver weights recorded for
males and females at 300 mg/kg/day at the end of treatment.
Based on effects on kidneys and forestomach,
a No Observed Adverse Effect Level (NOAEL) for naphthalene-1,5-diol of
50 mg/kg/day was established.
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