Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2017-12-06 to 2017-12-22
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2018
Report Date:
2018

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:
May 2008
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Version / remarks:
2002
Deviations:
no
Qualifier:
according to
Guideline:
other: Japanese Ministry of Agriculture, Foresty, and Fisheries
Version / remarks:
12 Nousan, Notification No 8147, November 2000; including most recent revisions
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid
Details on test material:
- Physical state: powder/solid
- Appearance: white powder
Specific details on test material used for the study:
Test Material SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 397451
- Expiration date of the lot/batch: 07 February 2018
- Purity correction factor: 1
- Purity: 99.86%
- Purity test date: 8 September 2017

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: In refrigerator (2-8°C)
- Solubility and stability of the test substance in the solvent/vehicle: Analysis of test item in vehicle for concentration, stability, homogeneity was not performed, however preparation was performed with approved procedure and documented in detail. Homogeneity was visually inspected prior to use.

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: Test preparation material was kept at room temperature, protected from light and were dosed within 4 hours after adding the vehicle to the test item. Adjustment was made for specific gravity of the vehicle. No correction was made for purity of the test item as the correction factor is 1.





Test animals

Species:
rat
Strain:
Wistar
Remarks:
Crl:WI (Han)(outbred, SPF-Qualtiy)
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: approximately 10 weeks
- Weight at study initiation: 163 - 184 grams
- Fasting period before study: animals were deprived of food overnight prior to dosing and until 3-4 hours after administration of the test item. Water was available ad libitum.
- Housing: group housing of 3 animals per cage in labeled Makrolon cages (MIV type; height 18 cm) containing sterilized sawdust as bedding material (Lignocel S 8-15, JRS - J.Rettenmaier & Söhne GmbH + CO. KG, Rosenberg, Germany) and paper as cage-enrichment (Enviro-dri, Wm. Lillico & Son (Wonham Mill Ltd), Surrey, United Kingdom).
- Diet (e.g. ad libitum): ad libitum, free access to pelleted rodent diet
- Water (e.g. ad libitum): ad libitum, free access to tap water.
- Acclimation period: at least 5 days before start of treatment under laboratory conditions.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-24 °C; actual daily mean temperature during study period was 20 to 21°C
- Humidity (%): 40-70%; actual daily mean relative humidity during study period was 43-51%
- Air changes (per hr): at least 10
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
propylene glycol
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 200 mg/mL
- Justification for choice of vehicle: The vehicle was selected based on trial preparations performed at Charles River Den Bosch and on test item data supplied by the Sponsor. The vehilce was chosen from: water (Elix) (not tested due to instability in water), 1% aq. carboxymethyl cellulose (not tested due to instability in water), propylene glycol (spec. gravity 1.036) (hazy solution), polyethylene glycol 400 (spec. gravity 1.125) (hazy solution) and corn oil (spec. gravity 0.92) (test item did not dissolve).

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

Doses:
2000 mg/kg body weight (single dosage)
No. of animals per sex per dose:
3 females per group (6 in total)
Control animals:
no
Details on study design:
Observations:
- Duration of observation period following administration: 14 days (until day 15)
- Frequency of observations and weighing:
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 signs were graded according to fixed scales and the time of onset, 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 of survivors performed: yes, at the end of the observation period, all animals were sacrificed by oxygen/carbon dioxide procedure and subjected to necropsy. Descriptions of all internal macroscopic abnormalities were recorded.


Statistics:
No statistical analysis was performed.

Results and discussion

Effect levels
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred
Clinical signs:
Hunched posture and/or piloerection were noted for the animals between Days 1 and 3.
Body weight:
The mean body weight gain shown by the surviving animals over the study period was considered to be similar to that expected for normal untreated animals of the same age and strain.
Gross pathology:
No abnormalities were found at macroscopic post mortem examination of all animals.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
The oral LD50 value of 1,4-dioxan-2-one (PDO monomer) in Wistar rats was established to exceed 2000 mg/kg body weight. According to OECD 423 test guideline, the LD50 cut-off value was considered to exceed 5000 mg/kg body weight.

Based on these results, 1,4-dioxan-2-one (PDO monomer) does not have to be classified and has no obligatory labelling requirement for acute oral toxicity according to the Globally Harmonized System of Classification and Labelling of Chemicals of the United Nations (2015) and Regulation (EC) No 1272/2008 on classification, labelling and packing of substances and mixtures (including all amendments).