Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
23 January 2019 - XX November 2019
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2019
Report date:
2019

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
Version / remarks:
2001
Deviations:
no
GLP compliance:
yes
Test type:
fixed dose procedure
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Reaction products of 2,3-epoxypropyl phenyl ether and 2,2'-iminodi(ethylamine)
EC Number:
948-518-4
Molecular formula:
(C13H23N3O2 . C31H43N3O6)x
IUPAC Name:
Reaction products of 2,3-epoxypropyl phenyl ether and 2,2'-iminodi(ethylamine)
Test material form:
liquid
Details on test material:
PGE-DETA adduct
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Olin Corporation Batch: 17-09-502-04 QM 14K17-54
- Expiration date of the lot/batch: 30 October 2019
- Purity test date: Approx. 97% (including the oligomeric isomers)

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room temperature
- Solubility and stability of the test substance in the solvent/vehicle: The test item formulations were prepared on the day of dosing and dosed within 1 hour of preparation.

Test Item Preparation
The test item was formulated as a clear solution at concentrations of 60 and 400 mg/mL in the vehicle and administered at a volume of 5 mL/kg body weight. Determination of the homogeneity, stability and purity of the test item or test item formulations were not undertaken.

Test animals

Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Envigo RMS (UK) Ltd
- Females (if applicable) nulliparous and non-pregnant: [yes]
- Age at study initiation: 8 - 12 weeks
- Weight at study initiation: 163 to 184 g
- Fasting period before study: overnight prior to and approximately four hours after dosing
- Housing: as groups of one or four rats per solid bottomed polycarbonate cages with a stainless steel mesh lid. Each cage contained a quantity of autoclaved softwood bark-free fiber bedding.
- Diet (ad libitum): Teklad 2014C Diet
- Water (ad libitum): Potable water taken from the public supply was freely available via polycarbonate bottles fitted with sipper tubes
- Acclimation period: at least five days before treatment.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 24
- Humidity (%): 40 to 70
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Remarks:
PEG400
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 60 and 400 mg/ml
- Justification for choice of vehicle: Test item could be dissolved into this vehicle to yield a clear solution.
- Lot/batch no. (if required): 17-09-502-04 QM 14K17-54
- Purity: 97%

MAXIMUM DOSE VOLUME APPLIED: 5ml/kg

DOSAGE PREPARATION (if unusual): The test item was formulated as a clear solution at concentrations of 60 and 400 mg/mL in
the vehicle and administered at a volume of 5 mL/kg body weight. The test item formulations were prepared on the day of dosing and dosed within 1 hour of
preparation.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose:
Doses:
300 and 2000 mg/kg bw
No. of animals per sex per dose:
5 females at 300 mg/kg bw and 5 females at 2000 mg/kg bw
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days

- Frequency of observations and weighing:

Clinical Signs: Animals were observed soon after dosing and at frequent intervals (at least 0.5, 1, 2 and 4 hours after dosing) on Day 1. On subsequent days, surviving animals were observed once in the morning and again at the end of the experimental day (with the exception of Day 15 - morning only).

Body Weight: The weight of each rat was recorded on Days -1, 1 (prior to dosing), 8 and 15 or at death.

- Necropsy of survivors performed: yes

Results and discussion

Effect levels
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 300 - < 2 000 mg/kg bw
Based on:
test mat.
Mortality:
Four females dosed at 2000 mg/kg were killed for welfare reasons on Day 1. No mortalities at 300 mg/kg bw.
Clinical signs:
No clinical signs were seen in any animal dosed at 300 mg/kg or the animal dosed at 2000 mg/kg in the sighting study.
Clinical signs observed prior to death for animals dosed at 2000 mg/kg comprised reduced body temperature, piloerection, underactive behavior, blue extremities and partially closed eyelids in all animals, hunched posture in three animals, elevated gait and irregular breathing in two animals, flat posture, gasping and
shallow breathing in two animals and a convulsion in one animal. These signs were seen from approximately two hours after dosing.
Body weight:
There was no toxicologically significant effects on body weight or body weight gain.
Gross pathology:
Macroscopic examination of the decedents revealed yellow liquid fluid contents in the stomach, duodenum and small and large intestines in all animals and in the caecum for 2 animals and congestion, characterized by darkened tissues/organs, in the subcutaneous tissue, brain and spleen in all animals and the stomach, duodenum and small and large intestines for three animals. The duodenum and small and large intestines were also enlarged, swollen or thickened in one animal.
No abnormalities were revealed in any animal surviving until Day 15.

Applicant's summary and conclusion

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The acute median lethal oral dose (LD50) to rats of 1,2-Ethanediamine, N-(2-
aminoethyl)-,reaction products with glycidyl Ph ether was demonstrated to be between 300
and 2000 mg/kg body weight.
Executive summary:

The study was performed to assess the acute oral toxicity of 1,2 -Ethanediamine, N-(2 -aminoethyl)-, reaction products with glycidyl Ph ether, to the rat in accordance with OECD Guideline 420 and

EEC Commission Regulation No. 440/2008, Part B, Method B.1 bis.

Fasted female rats received a single oral gavage dose of the test item, formulated in PEG400 to form a clear solution, at the following dose levels:

Sighting investigations: 300 and 2000 mg/kg body weight one female rat at each dose level

Main study: Based on the results of the sighting investigations a further four fasted females were similarly dosed at 2000 mg/kg body weight. Due to the number of deaths in the main study at 2000 mg/kg body weight, a further four fasted females were similarly dosed at 300 mg/kg body weight to complete the study.

During the study, clinical condition, body weight and macropathology investigations were undertaken.

Results:

Four females dosed at 2000 mg/kg were killed for welfare reasons on Day 1. Clinical signs prior to death comprised reduced body temperature, piloerection, underactive behavior, blue

extremities and partially closed eyelids in all animals, hunched posture in three animals, elevated gait and irregular breathing in two animals, flat posture, gasping and shallow

breathing in two animals and a convulsion in one animal. These signs were seen from approximately two hours after dosing. Macroscopic examination revealed yellow liquid fluid

contents in the stomach, duodenum and small and large intestines in all animals and in the caecum for two animals and congestion, characterized by darkened tissues/organs, in the

subcutaneous tissue, brain and spleen in all animals and the stomach, duodenum and small and large intestines for three animals. The duodenum and small and large intestines were

also enlarged, swollen or thickened in one animal.

No clinical signs were seen in any animal dosed at 300 mg/kg or the animal dosed at 2000 mg/kg in the sighting study.

All animals were considered to have achieved satisfactory body weight gains throughout the study.

No macroscopic abnormalities were revealed in any animal surviving until Day 15.

Conclusion

The acute median lethal oral dose (LD50) to rats of 1,2-Ethanediamine, N-(2 - aminoethyl)-,reaction products with glycidyl Ph ether was demonstrated to be between 300

and 2000 mg/kg body weight. 1,2-Ethanediamine, N-(2-aminoethyl)-,reaction products with glycidyl Ph ether is included in

Category 4, according to the Globally Harmonised System (GHS).