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Administrative data

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:
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 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
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:
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 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:
Migrated information 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
43 767 mg/m³
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:
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:
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 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:
Migrated information 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
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 mf/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 Dir 67/548/EEC or 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 Xn, R65, "May cause lung damage if swallowed" under Dir 67/548/EEC and under Regulation (EC) 1272/2008 "Aspiration toxicity Category 1, H304".