Bromobenzene

Endpoint summary

Description of key information

acute toxicity, oral (no guideline followed, RL2), male rats: LD50 = 2383 mg/kg bw (fasted)

acute toxicity, inhalation (ODCD 403, RL2), male/female rats: LC50 = 29.7 mg/L (calculated); LT50 = 1.8 h

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:

13 Nov 1980 - 4 Feb 1981

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Remarks:

(no GLP, not according to guideline)

Qualifier:

no guideline followed

Principles of method if other than guideline:

- Principle of test: Single oral dose administration of three doses of bromobenzene administered to fasted and non-fasted rats
- Short description of test conditions: 10 males per dose were treated and observed for 14 - 16 days
- Parameters analysed / observed: mean time of death, clinical signs, mean body weight change from day 1 to 14, LD50

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source of test material: Fischer Chemicals, Fairlawn, NJ, USA

Species:

rat

Strain:

other: Crl-CD

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratory, North Wilmington, MA, USA
- Age at study initiation: Approx. 60 days
- Weight at study initiation: 220 - 280 g
- Fasting period before study: Yes, groups of fasted (24 h) and non-fasted animals were dosed
- Diet: Purina Rat Chow (Ralston Purina Co., St Louis, USA), ad libitum

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 10 - 25%

MAXIMUM DOSE VOLUME APPLIED: 4.5 mL

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: Dose levels were selected based on a range-finding study to deine a dose producing mortality.

Doses:

fasted animals: 2000, 2800 and 3500 mg/kg
non-fasted: 3000, 3500 and 4000 mg/kg

No. of animals per sex per dose:

10

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 - 16 days
- Frequency of weighing: Individual body weights were determined on Days 0, 1 and 14
- Necropsy of survivors performed: no
- Other examinations performed: mortality, clinical signs, body weight

Statistics:

LD50 values were determined by Probit analysis (Finney, 1971).

Preliminary study:

One rat was treated with 670 - 7500 mg/kg bw to roughly define the dose producing mortality. Mortality was observed starting at 3400 mg/kg bw.

Sex:

male

Dose descriptor:

LD50

Effect level:

3 591 mg/kg bw

Based on:

test mat.

Remarks on result:

other: non-fasted rats

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

2 383 mg/kg bw

Based on:

test mat.

Remarks on result:

other: fasted rats

Mortality:

Fasted animals
2000 mg/kg: 3/10 animals died
2800 mg/kg: 6/10 animals died
3500 mg/kg: 10/10 animals died

Non-fasted animals
3000 mg/kg: 1/10 animals died
3500 mg/kg: 4/10 animals died
4000 mg/kg: 8/10 animals died

Clinical signs:

other: Fasted animals All doses: stained and wet perineal area, stained face, lacrimation, chromodacryorrhea, diarrhea and congestion 2000 mg/kg: weakness 2800 mg/kg: weakness, lethargy, prostration 3500 mg/kg: salvation, tremors, prostration Non-fasted animals

Gross pathology:

Not performed

Table 1: Results of acute oral toxicity study

Dose [mg/kg]	Mortality (of 10 treated)	Day of death^a	Weight decrease day 0-1 [g]^a	Weight increase day 0-14 [g]^a
Fasted
2000	3	2 ± 1	7 ± 2	36 ± 4
2800	6	2 ± 1	8 ± 1	40 ± 2
3500	10	2 ± 1	5 ± 2	-
Non-fasted
3000	1	3 ± 0	11 ± 3	17 ± 4
3500	4	2 ± 1	9 ± 4	16 ± 4
4000	8	3 ± 2	12 ± 2	20 ± 3

a: mean ± SD

Interpretation of results:

other: CLP/EU GHS criteria not met, no classification required according to Regulation(EC) No. 1272/2008

Conclusions:

CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No 1272/2008

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 383 mg/kg bw

Quality of whole database:

The available information comprises an adequate and reliable study, and is thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, of Regulation (EC) No 1907/2006.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

Please refer to analogue justification provided in IUCLID section 13

Principles of method if other than guideline:

The acute toxic potential following inhalation was determined according to the Inhalation Hazard Test. Animals were exposed to a fixed concentration (66 mg/L) and the time after which no or 50% of test animals dies was determined.

GLP compliance:

no

Test type:

other: Inhalation Hazard Test

Limit test:

no

Species:

other: not specified

Strain:

not specified

Sex:

male/female

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: whole-body exposure system (only general information given)
- Exposure chamber volume: 1 - 2L
- System of generating particulates/aerosols: Glass flask generator. The part of the generator containing the glass fritt and filled with the test substance dips into a thermostated liquid bath kept at the 20 °C
- Temperature in air chamber: saturation temperature (e.g. 20 °C)

Analytical verification of test atmosphere concentrations:

yes

Remarks:

gravimetrically from the weight loss of the material and the volume of air passing through the generator

Concentrations:

66 mg/L (saturated vapour pressure at 20 °C)

No. of animals per sex per dose:

3

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days

Sex:

male/female

Dose descriptor:

other: LT50

Effect level:

66 mg/L air (nominal)

Based on:

test mat.

Exp. duration:

1.8 h

Remarks on result:

other: Exposure for 1.8 h to 66 mg/L test substance resulted in mortality of 50% of test animals within the 14 day observation period.

Sex:

male/female

Dose descriptor:

other: LT0

Effect level:

66 mg/L air (nominal)

Based on:

test mat.

Exp. duration:

0.17 h

Remarks on result:

other: Exposure for 0.17 h to 66 mg/L test substance did not result in any mortality within the 14 day observation period.

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

29.7 mg/L air (nominal)

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: Calculation according to Haber`s law (C∙t = k)

Mortality:

66 mg/L: 3/6 animals died after exposure for 1.8 h

Clinical signs:

other: not examined

Body weight:

not examined

Gross pathology:

not examined

The Inhalation Hazard Test was performed to determine the hazard of volatile substances including chlorobenzene. 3 male and 3 female animals were exposed to 66 mg/L (nominal concentration) in a glass system with tubes.

For the generation of a vapor saturated inhalation atmosphere, a glass flask generator was used. The LT0 (time T after which no animals died within 14 days of post-exposure observation period) and the LT50 (time of exposure after which 50% of the animals died within 14 days of the post-exposure observation period) were calculated.

In this inhalation hazard test, the value of LT0 was 0.17 h and the value of LT 50 was 1.8 h.

The LC50 was calculated according to the Haber´s law: LC50= 66 mg/L  (1.8 h /4 h) = 29.7 mg/L.

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

CLP: Acute Tox. 4, H332
Although available data on acute toxicity following inhalation do not meet the classification criteria according to Regulation (EC) 1272/2008, the registrant follows the harmonised classification.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

29 700 mg/m³ air

Quality of whole database:

The available information comprises an adequate and reliable study (Klimisch score 2 due to read-across) from a reference substance with similar structure. Read-across is justified based on common functional groups and structural similarities (please refer to analogue justification). The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.5, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Acute toxicity

Justification for read-across

There are data available regarding acute oral toxicity for bromobenzene (CAS 108-86-1). In addition, read-across from an appropriate substance (chlorobenzene (CAS 108-90-7)) is taking into account for the evaluation of inhalation toxicity in accordance with Regulation (EC) No 1907/2006, Annex XI, 1.5. Structural similarities and comparable toxicokinetic properties of the source and target substance are the basis of read-across. A detailed justification for the analogue read-across approach is provided in the technical dossier (see IUCLID Section 13).

 

Acute oral toxicity

An acute oral toxicity study performed with brombenzene is available (Dashiell et al., 1984). In this study, groups of 10 Crl-CD male rats were administered single doses of the test substance via oral gavage. Based on the outcome of a dose-range finding study to roughly estimate lethal doses, fasted males received doses of 2000, 2800 and 3500 mg bromobenzene/kg bw. In addition, ten non-fasted males received doses of 3000, 3500 and 4000 mg/kg bw. The animals were observed for 14 - 16 days after substance administration. Mortality, clinical signs and effects on body weights were noted in all groups. In fasted animals, 3/10, 6/10 and 10/10 animals died within 4 days after substance application at 2000, 2800 and 3500 mg/kg bw, respectively. In non-fasted animals, 1/10, 4/10 and 8/10 animals died within 4 days after test substance administration at 3000 , 3500 and 4000 mg/kg bw, respectively. The acute oral LD50 value was considered to be 2383 mg/kg for fasted and 3591 mg/kg for non-fasted animals (LD50 value of non-fasted animals is not taking into account for hazard evaluation). In conclusion, the derived LD50 value for fasted animals exceeds the currently applied limit dose of 2000 mg/kg bw. Thus, based on the conducted study, bromobenzene does not meet the classification criteria defined for acute oral toxicity according to Regulation (EC) No 1272/2008.

 

Acute dermal toxicity

No data on acute dermal toxicity are available for bromobenzene, which is in line with the standard information requirements defined in Annex VII of Regulation (EC) No 2006/1907.

 

Acute inhalation toxicity

The Inhalation Hazard Test was performed to determine the hazard of volatile substances including chlorobenzene. 3 male and 3 female animals were exposed to 66 mg/L (nominal concentration) in a glass system with tubes (Klimisch, 1988). For the generation of a vapor saturated inhalation atmosphere, a glass flask generator was used. The LT0 (time T after which no animals died within 14 days of post-exposure observation period) and the LT50 (time of exposure after which 50% of the animals died within 14 days of the post-exposure observation period) were calculated.

Based on the results of the conducted study, a LT0 of 0.17 h and a LT50 of 1.8 h was derived. Considering Haber’s Law (C.t = k) according to Regulation (EC) 1272/2008 and Guidance on information requirements and chemical safety assessment Chapter R.7a: Endpoint specific guidance (ECHA, 2008), a time-extrapolated LC50 value of 29.7 mg/L is achieved (66 [mg/L] x 1.8 h = c [mg/L] x 4h). In conclusion, based on the available data, the extrapolated LC50 value exceeds the defined cut off value of 20 mg/L. However, according to the harmonised classification, chlorobenzene is considered to meet the classification criteria for Acute toxicity, Cat. 4, H332 according to Regulation (EC) No 1272/2008.

Justification for classification or non-classification

Based on the available data on acute oral toxicity, bromobenzene does not meet the classification criteria according to Regulation (EC) 1272/2008. No data on the dermal route are available.

The analogue substance chlorobenzene (CAS 108-90-7) is classified as Acute Tox. 4, H332 according to Annex VI of Regulation (EC) No 1272/2008. Although the available data on acute toxicity following inhalation do not meet the classification criteria according to Regulation (EC) No 1272/2008, the registrant follows the harmonised classification of the source substance chlorobenzene and applies the classification for the target susbtance bromobenzene based on read across and self classification. Thus, based on the analogue approach, bromobenzene is considered to meet the classification criteria according to Regulation (EC) 1272/2008.