oligomeric reaction product of 2-hydroxybenzaldehyde with 1-chloro-2,3-epoxypropane and phenol

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

01 September 2015-16 September 2015

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2016

Report date:

2016

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

yes

Remarks:

These deviations have no presumed effect on the outcome or validity of the study.

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Test material

Test material information

Constituent 1

Reference substance name:

2-({2-[bis({2-[(oxiran-2-yl)methoxy]phenyl})methyl]phenoxy}methyl)oxirane; 2-({2-[bis({4-[(oxiran-2-yl)methoxy]phenyl})methyl]phenoxy}methyl)oxirane; 2-{[2-({2-[(oxiran-2-yl)methoxy]phenyl}({4-[(oxiran-2-yl)methoxy]phenyl})methyl)phenoxy]methyl}oxirane

EC Number:

942-639-6

IUPAC Name:

2-({2-[bis({2-[(oxiran-2-yl)methoxy]phenyl})methyl]phenoxy}methyl)oxirane; 2-({2-[bis({4-[(oxiran-2-yl)methoxy]phenyl})methyl]phenoxy}methyl)oxirane; 2-{[2-({2-[(oxiran-2-yl)methoxy]phenyl}({4-[(oxiran-2-yl)methoxy]phenyl})methyl)phenoxy]methyl}oxirane

Test material form:

solid

Details on test material:

Name: EPICLON EXA-7250
Batch/Lot number: B006
Appearance: Brown solid (in smaller amount colour is yellow)
Purity: >99%
Manufacture date: 02 October 2014
Expiry date: 02 March 2017
Storage condition: Room temperature 15-25°C, below 70 RH%
Safety precautions: Routine safety precautions (lab coat, gloves, safety glasses, face
mask) for unknown materials were applied to assure personnel
health and safety.

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material:B006
- Expiration date of the lot/batch:02 March 2017

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room temperature 15-25°C, below 70 RH%

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
The test item of a suitable chemical purity together with all precautions required in the
handling and disposal of the test item were supplied by the Sponsor. The identification
of the test item was made in the Pharmacy of CiToxLAB Hungary Ltd. on the basis of
the information provided by Sponsor.

The test item was freshly formulated at a concentration of 200 mg/mL in the vehicle,
in the Pharmacy of CiToxLAB Hungary Ltd. on the day of administration. The
formulation container was magnetic stirred continuously up to the end of dose
administration procedures.

Test animals

Species:

rat

Strain:

other: CRL:(WI) rats

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH, Sandhofer Weg 7, D- 97633 Sulzfeld.
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: Young healthy adult rats, 8 weeks old
- Weight at study initiation: 172 – 190 g
- Housing: 3 animals / cage
-Fasting: 1 day
- Diet (e.g. ad libitum): Animals received ssniff® SM R/M "Autoclavable complete diet for rats and mice – breeding and maintenance" produced by ssniff Spezialdiäten GmbH, D-59494 Soest Germany (Batch no.: 930 3907, expiry date: December 2015), ad libitum, except for the night before treatment. Tap water from the municipal supply, as for human consumption from a 500 ml bottle, ad libitum. The food is considered not to contain any contaminants that could reasonably be expected to affect the purpose or integrity of the study.
- Acclimation period: 5-6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.7 – 26.0°C
- Humidity (%): 28 – 70 %
- Air changes (per hr): 15 – 20 air exchanges/hour
- Photoperiod (hrs dark / hrs light): 12 hours daily, from 6.00 a.m. to 6.00 p.m.

IN-LIFE DATES: From:01 September 2015 To:16 September 2015

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

DMSO

Details on oral exposure:

VEHICLE
- Concentration in vehicle: The test item was freshly formulated at a concentration of 200 mg/mL in the vehicle.
- Amount of vehicle (if gavage):10 mL/kg bw
- Lot/batch no. (if required): SZBE0310V

MAXIMUM DOSE VOLUME APPLIED: 2000 mg/kg bw

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: The initial dose level was selected by the Study Director to be that which is most likely to produce mortality in some of the dosed animals. In the lack of any preliminary toxicological information, 2000 mg/kg bw was selected to be the starting dose. Initially, 3 female animals were treated with 2000 mg/kg bw of EPICLON EXA-7250. No mortality was observed, therefore further 3 animals were treated at the dose level of 2000 mg/kg bw. As no mortality was observed in this second dose group, further testing was not required according to the test guidelines (OECD 423, Commission Regulation (EC) NO 440/2008 of 30 May 2008, B.1.Tris).

Doses:

Initially, 3 female animals were treated with 2000 mg/kg bw of EPICLON EXA-7250. No mortality was observed, therefore further 3 animals were treated at the dose level of 2000 mg/kg bw. As no mortality was observed in this second dose group, further testing was not required according to the test guidelines (OECD 423, Commission Regulation (EC) NO 440/2008 of 30 May 2008, B.1.Tris).

No. of animals per sex per dose:

6 animals, 3 animals/group

Details on study design:

- Duration of observation period following administration: 14 days

- Frequency of observations and weighing: 30 minutes, 1, 2, 3, 4 and 6 hours after dosing and daily for 14 days thereafter.

- Necropsy of survivors performed: Macroscopic examination was performed on all animals. The animals were sacrificed by exsanguination under pentobarbital anaesthesia (Euthanimal® 40 % inj.; Lot No.: 1409236-06, Expiry Date: September 2017, Produced by: AlfasanNederland BV, Kuipersweg 9, Woerden). After examination of the external appearance, the cranial, thoracic and the abdominal cavities were opened and the organs and the tissues were
observed. Macroscopic abnormalities were recorded.

- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other: Individual observations were performed on the skin, fur, eyes, mucous membranes, respiratory, circulatory, autonomic and central nervous system, somatomotor activity and behaviour pattern. Particular attention was directed to observation of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma.

Results and discussion

Effect levels

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

EPICLON EXA-7250 did not cause mortality at a dose level of 2000 mg/kg bw.

Clinical signs:

other: Acute oral administration of EPICLON EXA-7250 did not cause any test item related effect.

Gross pathology:

There was no evidence of the macroscopic observations at a dose level of 2000 mg/kg bw.

Applicant's summary and conclusion

Interpretation of results:

Category 5 based on GHS criteria

Conclusions:

Under the conditions of this study, the acute oral LD50 value of the test item EPICLON EXA-7250 was found to be above 2000 mg/kg bw in female CRL:(WI) rats.
According the GHS criteria, EPICLON EXA-7250 can be ranked as "Category 5" or “Unclassified” for acute oral exposure.

Executive summary:

The single-dose oral toxicity of EPICLON EXA-7250 was performed according to the acute toxic class method (OECD 423 and Commission Regulation (EC) No 440/2008 of 30 May 2008, B.1.Tris) in CRL:(WI) rats.

Two groups of 3 female CRL:(WI) rats were treated with the test item at a dose level of 2000 mg/kg bw (Group 1 and Group 2).

A single oral treatment was carried out by gavage for each animal after an overnight food withdrawal. Food was made available again 3 hours after the treatment. The test item was administered formulated in DMSO at a concentration of 200 mg/mL at

a dose volume of 10 mL/kg bw.

Initially, three females (Group 1) were treated at a dose level of 2000 mg/kg bw. As no mortality was observed, a confirmatory group (Group 2) was treated at the same dose level. No mortality was observed in the confirmatory group, therefore no

further testing was required according to OECD 423 and Commission Regulation (EC) NO 440/2008 of 30 May 2008, B.1.Tris.

Clinical observations were performed at 30 minutes, 1, 2, 3, 4 and 6 hours after dosing and daily for 14 days thereafter. Body weight was measured on Days -1, 0 and 7 and before necropsy. All animals were subjected to a necropsy and a

macroscopic examination.

The results of the study were summarized as follows:

Mortality

EPICLON EXA-7250 did not cause mortality at a dose level of 2000 mg/kg bw.

Clinical Observations

Acute oral administration of EPICLON EXA-7250 did not cause any test item related effect.

Body Weight and Body Weight Gain

There were no effects on body weights or body weight gains that could be attributed to treatment with of EPICLON EXA-7250.

Macroscopic Findings

There was no evidence of the macroscopic observations at a dose level of 2000 mg/kg bw.

Conclusion:

Under the conditions of this study, the acute oral LD50 value of the test item EPICLON EXA-7250 was found to be above 2000 mg/kg bw in female CRL:(WI) rats. According to the GHS criteria, EPICLON EXA-7250 can be ranked as "Category 5" or “Unclassified” for acute oral exposure.