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Toxicological information

Repeated dose toxicity: oral

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Administrative data

short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions

Data source

Reference Type:
study report
Report date:

Materials and methods

Test guideline
equivalent or similar to guideline
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Functional observations were not conducted
GLP compliance:
Limit test:

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
Test material form:
solid: particulate/powder

Test animals

Crj: CD(SD)
Details on test animals or test system and environmental conditions:
- Source: Charles River Italia S.P.A.
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 27-29 days
- Weight at study initiation: Weight range of 10g for each sex
- Housing: five animals per polycarbonate cages
- Diet: Altromin AT rodent diet ad libitum
- Water: Tap water ad libitum
- Acclimation period: 14 days

- Temperature (°C): 21°C +/- 2°C
- Humidity (%): 55% +/- 10%
- Air changes (per hr): ca. 20 per hr
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
CMC (carboxymethyl cellulose)
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: Prepared daily by addition of the vehicle to the test compound.

- Concentration in vehicle: 5 mg/mL, 15 mg/mL and 45 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg bw
Analytical verification of doses or concentrations:
Details on analytical verification of doses or concentrations:
Samples of the formulations prepared in week 1, 3 and 4 were analysed to check homogeneity and concentration of the preparation.
Duration of treatment / exposure:
4 weeks
Frequency of treatment:
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
50 mg/kg bw/day (nominal)
Dose / conc.:
150 mg/kg bw/day (nominal)
Dose / conc.:
450 mg/kg bw/day (nominal)
No. of animals per sex per dose:
5 animals/sex/group + 5 animals/sex for control and high-dose groups (recovery animals)
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale:
- Fasting period before blood sampling for clinical biochemistry: Yes
- Post-exposure recovery period in satellite groups: 4 weeks


Observations and examinations performed and frequency:
- Time schedule: Twice daily

- Time schedule: Weekly

- Time schedule for examinations: Weekly

- Food consumption: Recorded weekly by cage to calculate mean daily intake per rat.

- Time schedule for examinations: Daily

- Time schedule for examinations: Prior to treatment, during week 4 of treatment and week 4 of recovery.
- Dose groups that were examined: all groups.

- Time schedule for collection of blood: During week 4 of treatment and recovery
- Anaesthetic used for blood collection: Yes (light ether)
- Animals fasted: Yes

- Time schedule for collection of blood: During week 4 of treatment and recovery
- Animals fasted: Yes / No / Not specified

- Time schedule for collection of urine: During week 4 of treatment and recovery
- Metabolism cages used for collection of urine: Not specified
- Animals fasted: Yes


Sacrifice and pathology:

The following tissues were investigated: abnormalities, adrenal glands, aorta, brain, caecum, cervix, colon, duodenum, eyes, harderian glands, head, heart, ileum, jejunum, kidneys, larynx and pharynx, liver, lungs, lymph nodes, mammary glands, oesophagus, ovaries, pancreas, pituitary gland, prostate gland, sciatic nerve, seminal vesicles, skeletal muscle, skin, spinal column, spleen, sternum, stifle joint, stomach, testes, thymus, thyroid, tongue, trachea, urinary bladder, uterus, vagina.
Standard deviations were calculated as considered appropriate. For continuous variables the significance of the differences between group means was assessed by analysis of variance, comparing the treated groups with controls and the intergroup variation. Differences between each treated group and the control group was assessed by Dunnett’s test using a pooled error variance.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
No relevant clinical signs were observed in male rats throughout the study. Amongst female animals, brown staining was apparent in 8/10 animals receiving 450 mg/kg bw/d of test substance. This discoloration usually affected the head, fore limbs and/or dorsal surface of the body, and was observed during the last week of the treatment until week 2 of the recovery period. This is not considered of toxicological significance.
mortality observed, non-treatment-related
Description (incidence):
One animal dosed with 50 mg/kg bw/d died on Day 14, which was attributed to an intubation error during administration by the study director. No other animals died during the study.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No treatment-releated effects were reported.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Food intake for the treated groups was similar to the control groups.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
There were no consistent intergroup differences in water consumption which could be attributed to treatment.
Ophthalmological findings:
no effects observed
Description (incidence and severity):
There were not ophthalmic lesions observed which could be related to treatment. The minor changes recorded during the study are consistent with those occurring frequently in this strain of rats and were without significance.
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Changes were recorded that could not be definitively considered related to treatment. At the end of recovery period, apparent variations were recorded in regards to packed cell volume, haemaglobin and red blood cells in male and female animals from the highest-dose group. Some of these variations were statistically significant but there toxicological significance could be confirmed.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
A significant increase in creatinine, sodium and calcium levels, and a decrease in potassium level were reported in male animals receiving 450 mg/kg bw/d at the end of the treatment period, however, the values were comparable to control animals at the end of the recovery period. Female animals from this same group had a significantly lower level of creatinine both at the end of treatment and recovery periods.
The variation in the level of creatinine would suggest that kidney was affected by the test substance, however, it did not reflected in other relevant clinical indices, during the urinalysis, nor during the histopahtological examination of kidney. Therefore, this change is not considered to be related to a nephrotoxic effect nor as toxicologically significant.
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
At the end of the treatment period, urine specific gravity and osmolarity readings for male animals were slightly increased in all treated groups (significant for mid- and high-dose groups) but decreased in female animals. Toxicological significance of the findings could not be definitively attributed to the test substance.
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
All treated groups showed a slight and not dose-dependent increase in absolute and relative adrenal weights. These values were within Historical Control Data and not considered toxicologically significant.
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
Minimal changes were observed consistent with Historical Control Data for this strain of rats. Consequently, they were not considered relevant.
Histopathological findings: neoplastic:
no effects observed

Effect levels

Dose descriptor:
Effect level:
150 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
clinical biochemistry
clinical signs

Target system / organ toxicity

Critical effects observed:

Applicant's summary and conclusion

A short-term repeated-dose exposure to the test substance resulted in a NOAEL of 150 mg/kg bw/d.
Executive summary:

The toxicity of 2-naphthol following a short-term (4 weeks) repeated oral exposure was investigated using a method similar to the OECD Testing Guideline 407. The study was GLP-compliant.

Groups of five male and female SD rats were exposed to 0, 50, 150 or 450 mg/kg bw/d of test substance in CMC. In addition, two groups of five male and female SD rats received 0 or 450 mg/kg bw/d of test substance in CMC to be used as recovery groups.  The recovery period was 4 weeks.

Animals were observed twice daily for mortality and general clinical signs. More in-depth clinical observations were conducted weekly. Bodyweights were recorded weekly. Food and water consumptions were calculated on a weekly or daily basis, respectively.

During the last week of the treatment and recovery periods, blood and urine samples were collected to investigate haematology and clinical chemistry parameters, and to conduct urinalysis.

Ophthalmological examination was conducted on all groups prior to commencement, and during week 4 of treatment and recovery periods.

Animals were sacrificed at the end of the treatment or recovery period. Detailed post-mortem examinations were conducted. Absolute and relative weight of selected organs were determined. Histopathological examination of selected tissues was conducted.

The results of the study indicate that daily administration of the test substance was well-tolerated by animals exposed for 4 consecutive weeks. A slight increase in both absolute and relative adrenal weight was reported in all treated groups, but no relationship with dose levels was observed. Limited findings were concluded to be treatment-related, including brown staining of the coat in female animals receiving the highest-dose of test substance, as well as transient changes in the levels of creatinine, sodium and calcium in male animals at the same dose levels. While these changes in creatinine levels could potentially be indicative of a nephrotoxic effects, no supportive findings were identified during this study.

A NOAEL of 150 mg/kg bw/d can be derived from these results based on the brown staining observed in female animals, and changes in several clinical biochemistry parameters at 450 mg/kg bw/d.