Naphthalene-1,5-diol

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: only as secondary citation available: guideline study and GLP

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

2010

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Deviations:

yes

Remarks:

4-week recovery period

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Naphthalene-1,5-diol

EC Number:

201-487-4

EC Name:

Naphthalene-1,5-diol

Cas Number:

83-56-7

Molecular formula:

C10H8O2

IUPAC Name:

naphthalene-1,5-diol

Test material form:

other: solid

Details on test material:

content: >99.9 % (HPLC)
batch no. 820211/01

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

no details

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

not specified

Details on oral exposure:

Wistar rats were treated with 1,5-naphthalenediol for at least 90 days by oral gavage at dose levels up to 300 mg/kg bw/day, followed by a 28-day treatment-free recovery period.

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

no data

Duration of treatment / exposure:

90 days

Frequency of treatment:

daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 50, 100, 300 mg/kg bw (in propylene glycol)
Basis:
actual ingested

No. of animals per sex per dose:

12 animals per sex and dose, 5 per sex in recovery groups

Control animals:

yes, concurrent vehicle

Details on study design:

Wistar rats were treated with 1,5-naphthalenediol for at least 90 days by oral gavage at dose levels up to 300 mg/kg bw/day, followed by a 28-day treatment-free recovery period.
Mortality and viability were checked at least twice daily.
Clinical observations were made in all animals once daily.
During week 12-13 of treatment functional observation tests were performed including hearing ability, pupillary, static righting and grip strength reflex test and motor activity test
Ophthalmoscopic examinations were conducted at pre-test with all animals and at week 13 with controls and the 300 mg/kg dose group.
Body weight and food consumption were monitored weekly.
blood samples were collected for clinical laboratory investigations immediately prior to scheduled post mortem examination and the common parameters were determined.

Positive control:

no

Examinations

Observations and examinations performed and frequency:

Mortality and viability were checked at least twice daily.
Clinical observations were made in all animals once daily.
During week 12-13 of treatment functional observation tests were performed including hearing ability, pupillary, static righting and grip strength reflex test and motor activity test
Ophthalmoscopic examinations were conducted at pre-test with all animals and at week 13 with controls and the 300 mg/kg dose group.
Body weight and food consumption were monitored weekly.
blood samples were collected for clinical laboratory investigations immediately prior to scheduled post mortem examination and the common parameters were determined.

Sacrifice and pathology:

at the end of the treatment animals of the main stud groups were sacrificed and examined for organ weight gain and pathological anatomical and microscopical changes in the organs.
4 weeks later the animals of the recovery groups were examined

Other examinations:

no data

Statistics:

yes, but methods were not reported.

Results and discussion

Results of examinations

Details on results:

CLINICAL SIGNS AND MORTALITY
Two males and three females at 300 mg/kg bw died during the treatment phase. Misgavage
was considered the cause of death for one high dose male based on microscopic
assessment and the other high dose male died during blood sampling.
Purple discolouration of the urine was noted in all treatment groups, which resolved immediately after
discontinuation of treatment. This effect was probably caused by the test substance and/or
a test substance metabolite and was not regarded as adverse.

BODY WEIGHT AND WEIGHT GAIN
Body weights and body weight gain of treated animals remained in the same range as
controls over the study period.

FOOD CONSUMPTION AND COMPOUND INTAKE
Food consumption before or after allowance for body weight
was similar between treated and control animals throughout the study period

OPHTHALMOSCOPIC EXAMINATION
There were no ophthalmology findings at pre-test and in week 13.

HAEMATOLOGY and CLINICAL CHEMISTRY
Haematological parameters of treated rats were considered not to have been affected by
treatment. All statistically significant deviations from control mean showed no relationship
to dose and were considered to be incidental in nature. The following statistically significant
deviations in clinical biochemistry parameters that distinguished treated animals from
control animals were considered to be related to treatment:
- increased bilirubin levels in females at 100 mg/kg bw/day and in males and females at
300 mg/kg bw/day
- reduced urea levels in males at 100 and 300 mg/kg bw/day
- increased glucose levels in males and females at 300 mg/kg bw/day
- increased potassium levels in males at 300 mg/kg bw/day
- increased total protein and albumin levels in females at 300 mg/kg bw/day
- reduced aspartate aminotransferase activity in females at 300 mg/kg bw/day

These changes had resolved at the end of the recovery period, whilst increased inorganic
phosphate levels were recorded for high dose females.


URINALYSIS
no data

NEUROBEHAVIOUR
Hearing ability, pupillary reflex, static righting reflex and grip strength were normal in all
animals. Variations were noted in motor activity between treated and control animals but
occurred in the absence of a dose-related response and supportive clinical signs. Therefore,
they were considered to be of no toxicological relevance.

ORGAN WEIGHTS
At the end of treatment, increased absolute kidney weights and kidney to body weight
ratios were measured for high dose males. In addition, absolute liver weights were
increased in high dose females, while liver to body weight ratios were increased in high dose
males and females. These deviations had resolved at the end of the recovery phase.

HISTOPATHOLOGY: NON-NEOPLASTIC
The following microscopic findings were noted at the end of treatment:
- brown/black tubular pigment in the kidneys (minimal to moderate degree) in 11/12
males and 8/11 females at 300 mg/kg bw/day and in 5/12 males at 100 mg/kg
bw/day
- increased severity of hyaline casts was seen in 6/12 males and 2/11 females at 300
mg/kg bw/day and in 2/12 males and 1/12 females at 100 mg/kg bw/day
- increased severity (moderate) of corticomedullary basophilia in 5/12 males at 300
mg/kg/day
- hyperplasia of the squamous epithelium of the limiting ridge in the stomach (minimal
to moderate degree) in 11/12 males and 6/11 females at 300 mg/kg bw/day and in
3/12 males and 3/12 females at 100 mg/kg bw/day.

Following the recovery period slight degree of brown/black tubular pigment in the kidneys
was recorded in 2/5 males at 300 mg/kg bw/day. At 300 mg/kg bw/day one male had
corticomedullary basophilia and slight squamous hyperplasia was recorded in 2/5 females
after the recovery period.

Effect levels

Dose descriptor:

NOAEL

Effect level:

50 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: due to the effects on kidneys and the forestomach

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Executive summary:

According to OECD TG 408 and GLP male and female rats received orally by gavage 1,5 -naphthalenediol for at least 90 consecutive days at doses of 0 (polyehtylene glycol) , 50, 100 and 300 mg/kg bw/day, followed by a 28 -day recovery period. Due to the effects on kidneys (brown-black tubular pigment, increased severity of hyaline casts. corticomedullary basophilia) and forestomach (hyperplasia of the squamous epithelium) a NOAEL of 50 mg/kg bw/day was established.