4,4'-bis(chloromethyl)-1,1'-biphenyl

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

22 November 2016 to 07 December 2016

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2017

Report date:

2017

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

yes

Test material

Test material information

1

Reference substance name:

4,4'-bis(chloromethyl)-1,1'-biphenyl

EC Number:

216-784-4

EC Name:

4,4'-bis(chloromethyl)-1,1'-biphenyl

Cas Number:

1667-10-3

Molecular formula:

C14H12Cl2

IUPAC Name:

4,4'-bis(chloromethyl)-1,1'-biphenyl

Test material form:

solid: particulate/powder

Details on test material:

- Storage conditions: Controlled room temperature (15-25 ºC, below 70 RH%), protected from humidity, under inert gas.

Test animals

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Females nulliparous and non-pregnant: Yes.
- Age at study initiation: Young healthy adult rats, 10 weeks old.
- Weight at study initiation: 200 – 229 g
- Fasting period before study: On the night before treatment, the animals were fasted. The food but not water was withheld during an overnight period. Animals were weighed just before treatment. The test item was administered by oral gavage in the morning. The food was returned 3 hours after the treatment.
- Housing: Three animals per cage were housed in type II polypropylene/polycarbonate cages and the bedding consisted of Lignocel 3/4-S Hygienic Animal Bedding and "Arbocel crinklets natural” nesting material.
- Diet: Ad libitum
- Water: Ad libitum
- Acclimation period: 19-20 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.2 – 23.6 °C
- Humidity (%): 28 - 59 %
- 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.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

methylcellulose

Details on oral exposure:

VEHICLE
- Concentration in vehicle: The test item was administered formulated in 1 % methyl cellulose at a concentration of 200 mg/mL.
- Amount of vehicle: 10 mL/kg bw
- Justification for choice of vehicle: Not specified

JUSTIFICATION OF THE 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.

MAXIMUM DOSE VOLUME APPLIED: Maximum dose volume of 10 mL/kg bw.

DOSAGE PREPARATION: The test item was freshly formulated at a concentration of 200 mg/mL in the vehicle on the day of administration. The formulation container was stirred continuously up to finishing the treatment.

CLASS METHOD
- Rationale for the selection of the starting dose: Initially, three female animals were treated with 2000 mg/kg bw of the test item. 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.

Doses:

2000 mg/kg

No. of animals per sex per dose:

A total of six animals per sex per dose.

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of clinical observations and weighing: Clinical observations were performed on all animals at 30 minutes, 1, 2, 3, 4 and 6 hours after dosing and daily for 14 days thereafter. 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.
The body weight was recorded on the day before treatment (Day -1), on the day of the treatment (Day 0) and weekly thereafter.
- Necropsy of survivors performed: Yes. Macroscopic examination was performed on all animals. The animals were sacrificed by exsanguination under pentobarbital anaesthesia. 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.

Results and discussion

Effect levels

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

The test material did not cause mortality at a dose level of 2000 mg/kg bw.

Clinical signs:

other: There were no systemic clinical signs noted in any animal throughout the study.

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:

GHS criteria not met

Conclusions:

Under the conditions of this study, the acute oral LD50 of the test item was found to be above 2000 mg/kg bw in female Crl:WI rats.

Executive summary:

The acute oral toxicity of the test material was assessed in the Wistar strain rat in accordance with the standardised guidelines OECD 423 and EU Method B.1 tris under GLP conditions.

Two groups of three 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 1 % methyl cellulose 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.

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 test material did not cause mortality at a dose level of 2000 mg/kg bw. There were no systemic clinical signs noted in any animal throughout the study. There were no treatment related body weight changes. Body weight gains of test material treated animals during the study showed no indication of a test item-related effect. There was no evidence of the macroscopic observations at a dose level of 2000 mg/kg bw.

Under the conditions of this study, the acute oral LD50 value of the test item was found to be above 2000 mg/kg bw in female Crl:WI rats.