Benzene

Endpoint summary

Description of key information

Benzene does not pose an acute hazard following ingestion (oral LD50 > 2000 mg/kg), skin contact (dermal LD50 > 5000 mg/kg) or acute inhalation (4 hour LC50 > 20 mg/L) exposures.

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

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study from the literature, (pre-GLP), in which the test parameters documented do not totally comply with the specific testing guideline, but are sufficient to accept the data and well documented and scientifically acceptable

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

Pre-guideline. Used one sex for some age groups

GLP compliance:

not specified

Test type:

other:

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight: young adult rats (80-160 g); older adult rats (300-470 g).
- Not fasted prior to dosing
- Dosed by gavage

ENVIRONMENTAL CONDITIONS
- no data

IN-LIFE DATES: no data

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Doses:

No details of actual doses reported

No. of animals per sex per dose:

Groups of 6 males were used for studies in the young and older adult rats.

Control animals:

no

Details on study design:

- Duration of observation period following administration: 7days
- Frequency of observations and weighing: not reported
- Necropsy of survivors performed: no
- Other examinations performed: none reported

Statistics:

LD50 and associated confidence limits were calculated both by the method of Litchfield and Wilcoxon and by a probit analysis statistical program. Parallel probit analyses were carried out on the LD50 values to compare the potencies within the age groups.

Sex:

male

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Remarks on result:

other: young and older adults had LD50 of 3.8 (2.9-4.8) and 5.6 (4.0-7.8) mL/kg respectively

Acute oral LD50 in mL/kg (95% CL)

Young adults:  3.8 (2.9 -4.8)

Older adults : 5.6 (4.0 -7.8)

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Acute oral LD50 for adult rats >2000mg/kg

Executive summary:

Acute oral toxicity was determined in groups of at least 6 rats per age and dose level. Benzene was demonstrated to be of low acute oral toxicity (LD₅₀ >2000 mg/kg) and does not warrant classification under Dir 67/548/EEC or GHS

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

Studies in rats demonstrate that the oral LD50 for benzene exceeds 2000 mg/kg bw.

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:

other: Non-guideline, non-GLP, animal experimental study, published in peer-reviewed literature. Pre-dates implementation of GLP and guideline but otherwise acceptable for assessment.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

yes

Remarks:

only females, group size of 10 or 12

GLP compliance:

not specified

Test type:

other:

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 150-225 g
- Diet: NIH-D & G or Wayne Lab-Blox ad libitum except during exposure
- Water: ad libitum except during exposure

ENVIRONMENTAL CONDITIONS
- Photoperiod: 12 h dark / 12 h light
- No further details reported

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

other: air

Details on inhalation exposure:

Single 4 h inhalation exposures were performed in a chamber. Vapours generated by passing air through 2 fritted bubblers in series, each containing benzene. First bubbler maintained at approx. 35°C assuring that air emerging from second bubbler was saturated with benzene. The saturated air was diluted with filtered compressed air to desired concentration. Chamber concentrations of benzene were monitored at 30 minute intervals on a spectrophotometer.

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

6 exposure levels ranging from 11500-15500 ppm (exact levels not reported)

No. of animals per sex per dose:

10 or 12 female

Control animals:

no

Sex:

female

Dose descriptor:

LC50

Effect level:

13 700 ppm

95% CL:

13 050 - 14 380

Exp. duration:

4 h

Sex:

female

Dose descriptor:

LC50

Effect level:

43 767 mg/m³ air (nominal)

95% CL:

41 690 - 45 939

Exp. duration:

4 h

Mortality:

Animals which died as a result of exposure to benzene usually died during the exposure or in the first 24 h post-exposure. Death appeared to be caused by a depression of the central nervous system. These animals all had higher weights for both lung and liver.

Other findings:

Lung and liver congestion, defined as an increase in the number of red blood cells, and increases in the number of vacuolated hepatocytes seen in the livers of those animals which died from inhalation of benzene, were the principal observations noted histopathologically.

Interpretation of results:

not classified

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

The acute inhalation LC50 for benzene to female rats was 13700 ppm (43767 mg/m3; 43.7 mg/L) with a range of 13050-14380 ppm (41690-45939 mg/m3).

Executive summary:

The acute inhalation LC₅₀ of benzene was determined in groups of 10 or 12 female rats to be 13700 ppm (43767 mg/m³; 43.7mg/L) with a range of 13050-14380 ppm (41690-45939 mg/m³). Death appeared to be caused by a depression of the CNS. These animals had increased lung and liver weights, lung and liver congestion and an increased number of vacuolated hepatocytes in the liver.

Benzene is of low acute inhalation toxicity and does not warrant classification under Dir 67/548/EEC.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

43 767 mg/m³ air

Quality of whole database:

Studies in rats demonstrate that the inhalation LC50 of benzene exceeds 20 mg/L.

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Non-guideline, non-GLP, animal experimental study, published in peer-reviewed literature. Pre-dates implementation of GLP and guideline but otherwise acceptable for assessment

Qualifier:

according to guideline

Guideline:

other: 21 CFR 191.10

Deviations:

yes

Remarks:

rabbit skin abraded, animals not immobilised for 24 hours, 4 rabbits/group, no mortality or clinical observations/ bodyweight or gross necropsy results reported. Guinea pigs also tested.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

yes

Species:

other: guinea pig and rabbit

Strain:

other: Hartley-derived guinea pigs, white rabbits

Sex:

male/female

Details on test animals or test system and environmental conditions:

Guinea pigs: male Hartley-derived, 400-900 g
Rabbits: male or female (not specified) white, 1-4 kg

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Duration of exposure:

24 hours

Doses:

A minimum of 3 doses used - details not reported

No. of animals per sex per dose:

4 animals/dose (sex not specified)

Control animals:

not required

Details on study design:

No other data available

Statistics:

LD50 was calculated by the method of Finney

Sex:

not specified

Dose descriptor:

LD50

Effect level:

> 9.4 mL/kg bw

Remarks on result:

other: rabbit abraded skin

Sex:

male

Dose descriptor:

LD50

Effect level:

> 9.4 mL/kg bw

Remarks on result:

other: guinea pig intact skin

Sex:

male

Dose descriptor:

LD50

Effect level:

> 9.4 mL/kg bw

Remarks on result:

other: guinea pig abraded skin

Interpretation of results:

not classified

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

The acute dermal LD50 for benzene in the rabbit (applied to abraded skin) and the guinea pig (applied to intact abdominal or abraded back skin) was determined to be >9.4 mL/kg (8260 mg/kg) bodyweight.

Executive summary:

The acute dermal LD₅₀ for benzene was determined in groups of 4 rabbits (abraded skin) or guinea pigs (abraded back skin or non-abraded abdominal skin) using occlusive dressings. 

The acute dermal LD₅₀ was >9.4 mL/kg (8260 mg/kg) in each case.

In conclusion, benzene is of low acute dermal toxicity and does not warrant classification under Dir 67/548/EEC or GHS.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

8 260 mg/kg bw

Quality of whole database:

Studies in rats demonstrate that the dermal LD50 for benzene exceeds 5000 mg/kg bw.

Additional information

Non-human information

Acute toxicity oral

An oral LD50 value in rats of > 2000 mg/kg is derived from two studies (Kimura et al, 1971; Withey and Hall, 1975). Although little information on clinical signs is included in these publications the EU RAR (2008) stated "depending on the dose the main clinical signs are sedation and hind-limb paralysis".

Acute toxicity inhalation

Acute inhalation toxicity of benzene is low with a LC50 value of 44.5 mg/L after a 4-hour exposure for rats. Death was reported to be caused by depression of the central nervous system. The main pathological findings were congestion of the lungs and liver (Drew and Fouts 1974).

Acute toxicity dermal

A dermal LD50 value of >8260 mg/kg bw for rabbits and guinea pigs was reported by Roudabush et al. (1965). No information on clinical signs or necropsy information are provided.

Acute toxicity: other route

No information available

Human information

The EU RAR (2008) reports "existing data on human accidents demonstrate that ingestion of 15 mL (176 mg/kg bw) benzene can secondarily cause death after collapse, bronchitis and pneumonia due to lung aspiration." "Exposure for 5-10 minutes to benzene vapours of 65-61 mg/L is fatal and exposure to 25 mg/L for 30 minutes is dangerous to life, while a one-hour exposure to 1.6 mg/L causes only some symptoms of illness (Gerarde, 1960)".

Justification for selection of acute toxicity – oral endpoint
A consistent oral LD50 value in rats of > 2000 mg/kg is available from two studies. The EU RAR concluded "depending on the dose the main clinical signs are sedation and hind-limb paralysis".

Justification for selection of acute toxicity – inhalation endpoint
The acute inhalation toxicity of benzene is low with a LC50 of > 20 mg/L in rats following a 4-hour exposure. Death was reported to be caused by CNS depression.

Justification for selection of acute toxicity – dermal endpoint
The acute dermal LD50 of benzene in rats is >5000 mg/kg bw.

Justification for classification or non-classification

Benzene is of low acute toxicity by the oral, inhalation and dermal routes with LD50/LC50 values exceeding the doses which would warrant classification under Regulation (EC) No 1272/2008 of the European Parliament.

The viscosity of benzene is low (dynamic 0.604 mPa s at 25°C) and is expected to have a surface tension of 33mN/m at 25°C) which justifies classification as harmful and should be labelled under Regulation (EC) 1272/2008 "Aspiration toxicity Category 1, H304".