Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2004-05-23 to 2004-06-23
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2004
Report Date:
2004

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
2001
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Version / remarks:
1996
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Version / remarks:
2002
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
impurity

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
Test System
Species
Rat, Wistar strain Crl:(WI) BR (outbred, SPF-Quality). Recognised by international guidelines as the recommended test system (e.g. OECD, EC). Source: Charles River Deutschland, Sulzfeld, Germany.
Number of animals
3 Females (nulliparous and non-pregnant) and 3 males.
Age and body weight
Young adult animals (approx. 8 weeks old) were selected. Body weight variation did not exceed +/- 20% of the sex mean.
Identification
Earmark

Animal husbandry
Conditions
Animals were housed in a controlled environment, in which optimal conditions were considered to be approximately 15 air changes per hour, a temperature of 21.0 ± 3.0°C (actual range: 18.5 - 22.5°C), a relative humidity of 30-70% (actual range: 35 - 68%) and 12 hours artificial fluorescent light and 12 hours darkness per day.
Accommodation
Group housing of 3 animals per sex per cage in labelled Macrolon cages (type IV; height 18 cm.) containing purified sawdust as bedding material (Woody Clean bedding (Woody-Clean type 3/4; Tecnilab-BMI BV, Someren, The Netherlands).
Certificates of analysis were examined and then retained in the NOTOX archives. Acclimatisation period was at least 5 days before start of treatment under laboratory conditions.
Diet
Free access to standard pelleted laboratory animal diet (from Altromin (code VRF 1), Lage, Germany). Certificates of analysis were examined and then retained in the NOTOX archives.

Water
Free access to tap-water. Certificates of quarterly analysis were examined and then retained in the NOTOX archives.

Results of analysis for ingredients and/or contaminants of diet, sawdust, and water wereassessed and did not reveal any findings that were considered to have affected study integrity.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
propylene glycol
Details on oral exposure:
Vehicle
Propylene glycol (specific gravity 1.036)

Rationale
The vehicle was selected based on trial formulations performed at NOTOX.

Preparation
The formulations (w/w) were prepared within 4 hours prior to dosing. Homogeneity was accomplished to a visually acceptable level. Adjustment was made for specific gravity of the vehicle.
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
3 animals per each sex per dose
Control animals:
no
Details on study design:
The toxicity of the test substance was assessed by stepwise treatment of groups of 3 females or 3 males. The first group was treated at a dose level of 2000 mg/kg. The absence or presence of mortality of animals dosed at one step determined the next step, based on the test procedure defined in the guidelines. The onset, duration and severity of the signs of toxicity were taken into account for determination of the time interval between the dose groups.

Treatment
A health inspection was performed prior to commencement of treatment. to ensure that the animals were in a good state of health.

Method
Oral gavage, using a stainless steel stomach tube.

Fasting
Food was withheld overnight (for a maximum of 20 hours) prior to dosing until 3-4 hours after administration of the test substance.

Frequency
Single dosage, on day 1 .
Dose level (volume)
2000 mglkg (10 ml/kg) body weight.

Observations
Mortality/Viability
Twice daily.
Body weights
Days 1 (pre-administration), 8 and 15.

Clinical signs
At periodic intervals on the day of dosing (day 1) and once daily thereafter, until day 15. The symptoms were graded according to fixed scales and the time of on set, degree and duration were recorded:
Maximum grade 4: grading slight (1) to very severe (4)
Maximum grade 3: grading slight (1) to severe (3)
Maximum grade 1: presence is scored (1).

Necropsy
At the end of the observation period. all animals were sacrificed by asphyxiation using an oxygen/carbon dioxide procedure and subjected to necropsy. Descriptions of all internal macroscopic abnormalities were recorded.

Interpretation
The oral LD50 value of the test substance was ranked within the following ranges: 0-5, 5-50, 50-300 or 300-2000 mg/kg b.w. or as exceeding 2000 mg/kg b.w.
No statistical analysis was performed (The method used is not intended to allow the calculation of a precise LD50 value).
The results were evaluated according to the OECD Harmonized Integrated Hazard Classification System for Human Health and Environmental Effects of Chemical Substances (OECD, 1998) and the EC criteria for classification and labelling of dangerous substances and preparations (Council Directive 67/548/EEC and all adaptations to technical progress and amendments of this Directive published in the Official Journal of the European Communities).

Results and discussion

Effect levelsopen allclose all
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Sex:
male
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred.
Clinical signs:
Hunched posture and piloerection were noted in all animals on day 1. Two males showed piloerection on day 2.
Body weight:
The body weight gain shown by the animals over the study period was considered to be similar to that expected of normal untreated animals of the same age and strain.
Gross pathology:
No abnormalities were found at macroscopic post mortem examination of the animals.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
The oral LD50 value of naphthalene-1,5-diol in Wistar rats was established to exceed 2000 mg/kg body weight.
According to the OECD 423 test guideline the LD50 cut-off value was considered to exceed 5000 mg/kg body weight.
Based on these results naphthalene-1,5-diol does not have to be classified and has no obligatory labelling requirement for oral toxicity according to the OECD Harmonized Integrated Hazard Classification System for Human Health and Environmental Effects of Chemical Substances (OECD. 1998) and EC criteria for classification and labelling requirements for dangerous substances and preparations (Council Directive 67/548/EEC).
Executive summary:

Assessment of acute oral toxicity with naphthalene-1,5-diol in the rat (Acute Toxic Class Method). The study was carried out based on the guidelines described in: "Acute Toxicity-Oral, Acute Toxic Class Method", OECD No.423 (2001); "Acute Oral Toxicity"; EC Commission Directive 96/54/EC, Part 8.1 tris (1996); Environmental Protection Agency (EPA): Health Effects Test Guidelines OPPTS 870.1100 (2002), "Acute Oral Toxicity - Acute Toxic Class Method" and JMAFF Japanese test guidelines (2000).

The substance was administered by oral gavage to three Wistar rats of each sex at 2000 mg/kg body weight. Animals were subjected to daily observations and weekly determination of body weight.

Macroscopic examination at macroscopic post mortem examination of the animals.

The oral LD50 value of naphthalene-1,5 -diol in Wistar rats was established to exceed 2000 mg/kg body weight.

According to the OECD 423 test guideline the LD50 cut-off value was considered to exceed 5000 mg/kg body weight.

Based on these results naphthalene-1,5 -diol does not have to be classified and has no obligatory labelling requirement for oral toxicity according to the OECD Harmonized Integrated Hazard Classification System for Human Health and Environmental Effects of Chemical Substances (OECD, 1998) and EC criteria for classification and labelling requirements for dangerous substances and preparations (Council Directive 67/548/EEC).