Registration Dossier

Administrative data

Description of key information

- Acute oral toxicity: LD50 (female) > 2000 mg/kg bw (OECD 423, GLP, K, Rel. 1)

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
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.
Reference:
Composition 0
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 information:
Composition 1
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)
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
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).
Preliminary study:
None
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
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).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw
Quality of whole database:
The key study performed on the registered substance in rats was GLP and was compliant with OECD Test guideline No 403 (Klimisch 1). This study was considered sufficiently robust to cover this endpoint.

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Acute toxicity (Oral):

A key study was identified (Acute Toxicity Oral, CRL 2017, rel. 1) to assess Acute Toxicity via oral route. In this acute oral toxicity study (limit test) performed 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, 1,4-Bis (4-hydroxy benzoyl) benzene, was 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. 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.

Acute toxicity (Dermal):

No study was available.

Acute toxicity (Inhalation):

No study was available.

Justification for classification or non-classification

Harmonized classification:

The substance has no harmonized classification according to the Regulation (EC) No. 1272/2008.

Self classification:

Acute toxicity (Oral):

Based on the available information, the substance is:

- not classified according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP) as the oral LD50 is higher than 2000 mg/kg bw

- not classified in Category 5 according to the UN-GHS since there is no reliable evidence indicating that the substance is toxic above 5000 mg/kg bw (according to the OECD 423 test guideline, LD50 cut-off value was considered to exceed 5000 mg/kg body weight).

Acute toxicity (Dermal):

No information was available.

Acute toxicity (Inhalation):

No information was available.

Specific target organ toxicity: single exposure (Oral):

The classification criteria according to the Annex VI of the Regulation (EC) No. 1272/2008 as specific target organ toxicant (STOT) – single exposure, oral are not met since no reversible or irreversible adverse health effects were observed immediately or delayed after exposure and no effects were observed at the guidance value (oral) for a Category 1 classification (C≤ 300 mg/kg bw) and for a Category 2 classification (2000 mg/kg bw ≥ C > 300 mg/kg bw). No classification is required.

The criteria for Transient Organ effects (STOT-SE Category 3) according to Annex VI of the Regulation (EC) No. 1272/2008 are not met since narcotic effects in the acute oral toxicity study and respiratory tract irritation were not expected.

Specific target organ toxicity: single exposure (Dermal):

No information was available.

Specific target organ toxicity: single exposure (Inhalation):

No information was available.