Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
31 August 2017 - 14 December 2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
The study has been performed according to OECD and/or EC guidelines and according to GLP principles.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2017
Report Date:
2017

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
December 2001
Deviations:
no
Qualifier:
according to
Guideline:
other: EC No 440/2008 Part B. 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:
December 2002
Qualifier:
according to
Guideline:
other: JMAFF Guidelines, Appendix to Director General Notification, No. 12-Nousan-8147, including the most recent revisions.
Version / remarks:
November 2000
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: crystalline
Details on test material:
- Identification: 1,4-Bis (4-hydroxy benzoyl) benzene
- Appearance: Off white crystalline powder
- Test item storage: At room temperature
- Stable under storage conditions until: 15 May 2018 (expiry date)
Specific details on test material used for the study:
- Appearance: Off white crystalline powder
- Test item storage: At room temperature
- Stable under storage conditions until: 15 May 2018 (expiry date)

Test animals

Species:
rat
Strain:
Wistar
Remarks:
(Han)
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source:
Charles River Deutschland, Sulzfeld, Germany
- Females nulliparous and non-pregnant: yes
- Age at study initiation:
approximately 8 weeks old
- Weight at study initiation:
146 to 166 g
- Fasting period before study: Animals were deprived of food overnight (for a maximum of 20 hours) prior to dosing and until 3-4 hours after administration of the test item. Water was available.
- Housing:
animals were group housed (up to 5 animals of the same sex and same dosing group together) in polycarbonate cages (Makrolon MIV type; height 18 cm.) containing sterilized sawdust as bedding material (Lignocel S 8-15, JRS - J.Rettenmaier & Söhne GmbH + CO. KG, Rosenberg, Germany) equipped with water bottles
- Diet (e.g. ad libitum):
Pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany), ad libitum except during designated procedures
- Water (e.g. ad libitum):
Municipal tap-water via water bottles, ad libitum
- Acclimation period:
at least 5 days before the commencement of dosing

ENVIRONMENTAL CONDITIONS
- Temperature (°C):
21 - 22°C
- Humidity (%): 46 - 67%
- Air changes (per hr):
Ten or greater air changes per hour with 100% fresh air (no air recirculation)
- Photoperiod (hrs dark / hrs light):
12-hour light/12-hour dark

IN-LIFE DATES: From: 02 September 2017 To: 27 September 2017

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
1% Aqueous carboxymethyl cellulose
Details on oral exposure:
VEHICLE
- Amount of vehicle (if gavage): 10 mL/kg bw
- Justification for choice of vehicle: The vehicle and formulation procedure were selected based on trial preparations performed at Charles River Den Bosch and on test item data supplied by the Sponsor. The vehicle was chosen from (in order of preference): water (Elix), 1% aq. carboxymethyl cellulose, propylene glycol, polyethylene glycol 400 and corn oil. Without heating of the formulations, no homogenous dosing formulations could be obtained using the vehicle as mentioned above. Water did not provide a homogenous formulation at all while the other vehicle provided clear to cloudy solutions. Based on the results, 1% aq. carboxymethyl cellulose was selected as suitable vehicle.

MAXIMUM DOSE VOLUME APPLIED: 2000 mg/kg bw

DOSAGE PREPARATION: Test item dosing formulations (w/w) were homogenized to visually acceptable levels at appropriate concentrations to meet dose level requirements. The dosing formulations were kept at room temperature until dosing. The dosing formulations were stirred until and during dosing.
No adjustment was made for specific gravity of the vehicle. No correction was made for the purity/composition of the test item.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: The starting dose level should be the one that is likely to produce mortality in at least some of the animals and was selected based on available toxicity data of the test item.
Doses:
A single dose of test item: 2000 mg/kg bw
No. of animals per sex per dose:
3 per step
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
- Mortality/Morbundity checks: twice daily, in the morning and at the end of the working day.
- Postdose observations: on the day of dosing (at least three times) and once daily thereafter.
- Body weights: weighed individually on Day 1 (predose), 8 and 15. A fasted weight was recorded on the day of dosing.
- Necropsy of survivors performed: yes, by oxygen/carbon dioxide procedure.
- Other examinations performed: clinical signs, body weight, other: internal macroscopic exmination
Statistics:
No statistical analysis was performed (The method used is not intended to allow the calculation of a precise LD50 value).

Results and discussion

Preliminary study:
None
Effect levelsopen allclose all
Key result
Sex:
female
Dose descriptor:
LD50
Remarks:
(oral)
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Sex:
female
Dose descriptor:
LD50
Remarks:
(cut-off)
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred.
Clinical signs:
Hunched posture was noted in all animals on Days 1 and/or 2. Piloerection was noted in five animals on Day 1.
Body weight:
The body weight gain shown by the 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 the animals.
Other findings:
None

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
Under the test conditions, the oral LD50 value of 1,4-Bis (4-hydroxy benzoyl) benzene in female 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.
Executive summary:

This Acute Toxicity study evaluated the potential toxicity of 1,4-Bis (4-hydroxy benzoyl) benzene, when given by oral gavage at a single dose of 2000 mg/kg bw to rats of a single sex to evaluate the potential reversibility of any findings. The study was carried out in compliance with the OECD No.423 guideline (Acute Oral Toxicity, Acute Toxic Class Method), EC Directive No 440/2008 (part B: "Acute Oral Toxicity, Acute Toxic Class Method"), OPPTS 870.1100 EPA guideline (Acute Oral Toxicity) and JMAFF Guidelines and in compliance with GLP.

The test substance was administered by oral gavage to two consecutive groups of three female Wistar rats at 2000 mg/kg body weight. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice (Day 15). No mortality occurred. Hunched posture was noted in all animals on Days 1 and/or 2. Piloerection was noted in five animals on Day 1. The body weight gain shown by the animals over the study period was considered to be similar to that expected for normal untreated animals of the same age and strain. No abnormalities were found at macroscopic post mortem examination of the animals.

Under the test conditions, the oral LD50 value of 1,4-Bis (4-hydroxy benzoyl) benzene in female Wistar rats was established to exceed 2000 mg/kg body weight and, 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, 1,4-Bis (4-hydroxy benzoyl) benzene 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 (GHS) of the United Nations (2017) (including all amendments) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of items and mixtures (including all amendments).