4-bromo-2,2-diphenylbutanenitrile

Endpoint summary

Description of key information

Acute toxicity: Oral

In an acute oral toxicity study in female Wistar rats, following the acute toxic class method in accordance with the OECD Guideline 423, the LD50 was established to be greater than 2000 mg/kg (Latour, 2016).

Acute toxicity: Inhalation

No reliable acute toxicity study via the inhalation route was available. However, this endpoint is waived as specific data are available for the oral and dermal exposure routes.

Acute toxicity: Dermal

No reliable acute toxicity study via the dermal route was available. However, this can be waived based on the fact that the substance does not meet the criteria for classification for acute toxicity or STOT SE by the oral route, and no systemic toxicity is observed in in vivo studies with dermal exposure.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From 2016-06-09 to 2016-06-29

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

no

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: I16AB0081
- Expiration date of the lot/batch: 2018-01-11
- Purity test date: No data

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: At room temperature
- Stability under test conditions: No data
- Solubility and stability of the test substance in the solvent/vehicle: No data

OTHER SPECIFICS:
correction factor: 1

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: female rats (nulliparous and non-pregnant), Wistar strain Crl:WI (Han) (outbred, SPF-Quality); Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: approx. 8-11 weeks
- Weight at study initiation: mean 0.162 kg (1st group), 0.180 kg (2nd group)
- Fasting period before study: animals were deprived of food overnight prior to dosing and until 3-4 hours after administration of the test item. Water was available ad libitum.
- Housing: group housing of 3 animals per cage in labeled Makrolon cages (MIV type; height 18 cm.) containing sterilized sawdust as bedding material (Lignocel S 8-15, JRS - J.Rettenmaier & Söhne GmbH + CO. KG, Rosenberg, Germany) and paper as cage-enrichment (Enviro-dri, Wm. Lillico & Son (Wonham Mill Ltd), Surrey, United Kingdom).
- Diet (e.g. ad libitum): ad libitum, free access to pelleted rodent diet
- Water (e.g. ad libitum): ad libitum, free access to tap water.
- Acclimation period: at least 5 days before start of treatment under laboratory conditions.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-24 °C
- Humidity (%): 40-70%
- Air changes (per hr): at least 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: From 2016-06-09 to: 2016-06-29

Route of administration:

oral: gavage

Vehicle:

polyethylene glycol

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 200 mg/ml
- Amount of vehicle (if gavage): not indicated
- Justification for choice of vehicle:
The vehicle was selected based on trial preparations performed at Charles River Den Bosch and on test item data supplied. The vehicle was chosen from (in order of preference): water (Elix) (test item did not dissolve), 1% aq. carboxymethyl cellulose (test item did not dissolve), propylene glycol (spec.gravity 1.036) (cloudy solution), polyethylene glycol 400 (spec. gravity 1.125) and corn oil (spec. gravity 0.92).

MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg

DOSAGE PREPARATION (if unusual):
- The preparations (w/w) were kept at room temperature and were dosed within 4 hours after adding the vehicle to the test item. Homogeneity was obtained to visually acceptable levels and the formulations were stirred during dosing, which ensures homogeneity sufficient for these kinds of studies.
- Adjustment was made for specific gravity of the vehicle. No correction was made for purity of the test item.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose:
The toxicity of the test item was assessed by stepwise treatment of groups of 3 females. The first group was treated at a dose level of 2000 mg/kg. The absence or presence of mortality of animals dosed at one step determined the next step, based on the test procedure defined in the guidelines.

Doses:

2000 mg/kg (single dosage) (two groups were treated)

No. of animals per sex per dose:

3 females per dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days (until day 15)
- Frequency of observations and weighing:
mortality/viability: twice daily.
body weights: days 1 (pre-administration), 8 and 15
clinical signs: at periodic intervals on the day of dosing (day 1) and once daily thereafter, until day 15. The signs were graded according to fixed scales and the time of onset, degree and duration were recorded: maximum grade 4: grading slight (1) to very severe (4); maximum grade 3: grading slight (1) to severe (3); maximum grade 1: presence is scored (1).
- Necropsy of survivors performed: yes, all animals assigned to the study were subjected to necropsy and descriptions of all internal macroscopic abnormalities recorded.

Statistics:

No statistical analysis was performed.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred.

Clinical signs:

other: Hunched posture and/or piloerection were noted for four animals on Day 1.

Body weight:

other body weight observations

Remarks:

The mean body weight gain shown by the surviving 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 all animals.

Interpretation of results:

GHS criteria not met

Conclusions:

The oral LD50 value of JNJ-1597622-AAA (T000625) in 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. Based on these results, JNJ-1597622-AAA (T000625) does not have to be classified and has no obligatory labelling requirement for acute oral toxicity according to Regulation (EC) No 1272/2008.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

no data

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

documentation insufficient for assessment

Principles of method if other than guideline:

No data

GLP compliance:

not specified

Test type:

other: No data

Species:

rat

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

No data

Route of administration:

oral: unspecified

Vehicle:

not specified

Details on oral exposure:

No data

Doses:

640 mg/kg bw
No other concentrations mentioned

No. of animals per sex per dose:

No data

Control animals:

not specified

Details on study design:

No data

Statistics:

No data

Preliminary study:

No data

Dose descriptor:

LD50

Effect level:

> 640 mg/kg bw

Mortality:

640 mg/kg bw: no mortality

Clinical signs:

other: No data

Body weight:

other body weight observations

Remarks:

No data

Gross pathology:

No data

Other findings:

No data

Interpretation of results:

study cannot be used for classification

Conclusions:

The oral LD50-value of the T000625 is greater than 640 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Acute oral toxicity:

An acute oral toxicity study with T000625 according to the acute toxic class method in female Crl:WI (Han) (SPF) rats (OECD guideline 423) was performed (Latour, 2016). Single dosages of 2000 mg/kg bw (2 groups of 3 animals) were applied. The substance was formulated in propylene glycol at concentrations of 200 mg/ml  for both groups. The rats received a single oral dose of test item and were observed during 14 days following administration. Mortality and viability were observed twice daily, and bodyweight was monitored at day 1 (prior to administration), 8 and 15. Clinical signs were observed at periodic intervals on the day of dosing (day 1) and once daily thereafter. Necropsy of survivors and macroscopic examination were also performed. Internal macroscopic abnormalities were recorded. 

No mortality was observed and the clinical signs included hunched posture and/or piloerection. Bodyweight of all animals over the study period was considered similar to untreated animals. Macroscopic examination showed no abnormalities. 

The oral LD50 value of T000625 in Wistar rats was established to be greater than 2000 mg/kg body weight. Based on CLP Regulation, the test item is considered not to be classified for acute oral toxicity.

 

In a supporting acute toxicity study via oral administration, the LD50 was established to be > 640 mg/kg bw (K4; Schellekens, 1984). This study was evaluated to be insufficiently documented (Klimisch score 4).

 

Acute inhalation toxicity:

An acute inhalation toxicity study should not be performed.  In addition to the oral route of exposure, for substances other than gases, the information mentioned under REACH section 8.5.2 to 8.5.3 shall be provided for at least one other exposure route (REACH Regulation, column 2 adaptation of Annex VIII). However, for this substance, no key study is available for the dermal route of exposure. This can be waived based on the fact that the substance does not meet the criteria for classification for acute toxicity or STOT SE by the oral route, and no systemic toxicity is observed in vivo studies with dermal exposure.

 

Acute dermal toxicity:

No key study is available for the dermal route of exposure. This can be waived based on the fact that the substance does not meet the criteria for classification for acute toxicity or STOT SE by the oral route, and no systemic toxicity is observed in vivo studies with dermal exposure.

Justification for classification or non-classification

Based on the oral LD50 exceeding 2000 mg/kg bw and according to the criteria laid down in Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures, T000625 does not have to be classified and has no obligatory labelling requirement for acute oral toxicity. 

No data were available to decide on the classification for the inhalation route.

No data were available to decide on the classification for the dermal route.