Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Start of experimental phase: 1 July 2015 and End of experimental phase: 30 July 2015
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2015
Report date:
2016

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
acute toxic class method
Limit test:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
2,2'-{octahydro-1H-4,7-methanoindene-2,5-diylbis[(2,1-phenylene)oxymethylene]}bis(oxirane)
EC Number:
943-519-6
Cas Number:
2149603-92-7
Molecular formula:
C28H32O4
IUPAC Name:
2,2'-{octahydro-1H-4,7-methanoindene-2,5-diylbis[(2,1-phenylene)oxymethylene]}bis(oxirane)
Test material form:
not specified

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals or test system and environmental conditions:
- Species and strain: Rat, Hsd: Sprague Dawley SD
- Sex: Females (nulliparous and non-pregnant)
- Age at order: 6-7 weeks old
- Weight at order: 150-174 grams
- Supplier: Harlan Italy s.r.l., San Pietro al Natisone (UD), ITALY.
- Date of arrival: 18 July 2015
- Acclimatisation period: At least 5 days
- Vetenary health check: During acclimatisation period

Animal husbandry:
-Animals per cage: 3 during the study; up to 5 during acclimatisation
- Housing: Polisulphone solid bottomed cages measuring 59.5x38x20 cm with nesting material provided into suitable bedding bags.
- Cage control: Daily inspected and changed as neccessary (at least 3 times/week)
- Water supply: Ad libitum
- Diest: 4 RF 18 (Mucedola S.r.l., Via G. Galilei, 4, 20019, Settimo Milanese (MI) Italy).
- Diest supplier: Ad libitum
- Room lighting: Artificial (fluorescent tubes ), daily light/dark cycle of 12/12 hours.
- Air changes: Approximately 15 to 20 air changes per gour
- Temperature range: 22°C +/-2°C
- Relative humidity range: 55% +/- 15%

Records of analyses of water and diet are kept on file at RTC. Components present in the drinking water or diet are not at a level likely to interfere with the purpose or conduct of the study. Actual housing conditions were monitored and recorded, and records retained. No relevant deviations occured.

Choice of the species and administration route: The Sprague Dawley SD rat was used, being a species and strain accepted ba many regulatory authorities and since there is ample experience and background data. The oral route of administration is a potential route of exposure during manufacturing handling or use of the substance.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Remarks:
PEG 400 . The maximum feasible concentration was 100 mg/ml.
Details on oral exposure:
The formulated test item was administred, by gavage, at a dose volume of 10 ml/kg using a plastic feeding tube aattached to a graded syringue.

Formulation procedure:
During the study, the test item was supsended as follows:
- Vehicle PEG 400.
Concentration: 100 mg/ml (maximum feasible concentration in the vehicle). The concentration was calculated and expressed in terms of test item as supplied.
The required amount of the test item was mixed with the vehicle and warmed up to 37-40°C, under magnetic stirring, in order to dissolve the test item. After dissolution, the fromulated test item was maintained under magnetic stirring at room temperature and administred to animals shortly after preparation.

Formulation analysis was not carried out, as not requested by the Sponsor.
Doses:
2000 mg/kg
No. of animals per sex per dose:
3 females rats
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight.

In vivo observations:
- Mortality and morbidity: Throughout the study all animals were checked twice daily.
- Clinical signs: Animals were observed for clinical signs as indicated below:
- Day of dosing:
Session 1: On first administation
Session 2: On second amdinistration
Session 3: Approximately 0.5 hour after the second administration
Session 4: Approximately 2 hours after the second administration
Session 5: Approximately 4 hours after the second administration
- Daily thereafter for a total of 14 days (Session 1)

Body weigt: All animals were weighed at allocation to the study (Day-1), on the day of dosing (Day 1) and on Days 2, 8 and 15 of the dosing phase was relevant to Day 1 of the phase.

- Necropsy: All animals were sacrfied on day 15 by carbon dioxide narcosis
Necropsy was carried out on all animals (gross necropsy examination for both external and internal abnormalities with particular attention to the gastro-intestinal tract).
Statistics:
No data

Results and discussion

Effect levels
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occured was observed in the first group of animals initially dosed at 2000 mg/kg (Step 1) and in the further group of 3 females dosed at the same dose level (Step 2).
Clinical signs:
No clinical signs were observed in the first group of animals initially dosed at 2000 mg/kg (Step 1) and in the further group of 3 females dosed at the same dose level (Step 2).
Body weight:
Changes in body weight observed during the study were within the expected range for this strain and age of animals.
Gross pathology:
No abnormalities were observed at necropsy examination performed on all animals dosed at 2000 mg/kg at the end of the observation period.

Applicant's summary and conclusion

Interpretation of results:
study cannot be used for classification
Remarks:
Migrated information
Conclusions:
The results indicate that the test item did not induce toxic effects in the rat following oral administrationat a level dose of 200 mg/kg. The lack of mortality demonstrates the acute toxicity expected to be greater than 2000 mg/kg body weight.
Classification: No category.
Signal word: No signal word required.
Hazard statement: No hazard statement required.
Executive summary:

The acute toxicity of the test item was investigated following oral administration to the Sprague Dawley rat followed by a 14 -day observation period.

A first group of 3 female animals was initially dosed at 2000 mg/kg (Step 1). No mortality occured and no clinical signs were observed. A second group of female animals was then dosed at the same dose level (Step 2). No death occured and no clinical signs were noted.

Body weight changes recorded during the study were within the expected range for this strain and age of animals.

No abnormalities were observed at necropsy examination performed at the end of the observation period in all animals.

These results indicate that the test item did not induce toxic effects in the rat following oral administration at a level of 2000 mg/kg. The lack of mortality demonstrates the acute toxicity expected (ATE) to be greater than 2000 mg/kg body weight.

European Directives concenring the classification, packaging and labelling of dangerous substances (Council Regulation (EC) N°. 1272/2008 and subsequent revisions ) would indicate the following:

- Classification: No category.

- Signal word: No signal word required.

- Hazard statement: No hazard statement required.