Benzene

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: GLP-status unknown, non-guideline, animal experimental study, published in peer-reviewed literature, notable limitations in design and reporting but contributing to a weight of evidence

Data source

Reference

Reference Type:

publication

Title:

Benzene hematotoxicity and leukemogenesis

Author:

Cronkite EP, Drew RT, Inoue T and Bullis JE

Year:

1985

Bibliographic source:

Am. J. Ind. Med. 7, 447-456

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Eight to twelve-week old male and female C57B1/6 BNL mice were exposed to air or benzene vapour in air. At various times during and after the exposure period, five to ten mice were removed from both the treated and control groups and the blood, bone marrow and spleens removed and examined for evidence of haematotoxicity.

GLP compliance:

not specified

Limit test:

no

Test material

Reference

Name:

Unnamed

Type:

Constituent

Test material form:

other: no data

Details on test material:

Common name: Benzene
No other data provided

Test animals

Species:

mouse

Strain:

C57BL

Sex:

male/female

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

other: air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: details on construction and design reported elsewhere
- Generation of vapour: No details reported

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

2-16 weeks

Frequency of treatment:

6 h/day, 5 days/week or 3 consecutive days/week

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0, 10, 25, 100, 300, 400 ppm (0, 32, 80, 320, 960, 1280 mg/m3)
Basis:
other: target concentration - (6h/d, 5d/wk for 2-16 wks)

Doses / concentrations 2

Remarks:

Doses / Concentrations:
0, 300 ppm (960 mg/m3)
Basis:
other: target concentration - (6h/day, 3 d/week for 8 weeks)

No. of animals per sex per dose:

No specific detail. At 300 ppm for 16 weeks 88 control and 89 exposed females

Control animals:

yes, concurrent no treatment

Details on study design:

Post-exposure period: 16 weeks

Results and discussion

Effect levels

1

Dose descriptor:

NOAEC

Effect level:

10 ppm

Sex:

male/female

Basis for effect level:

other: lymphocytopenia after 10 expousres at 25 ppm

2

Dose descriptor:

NOAEC

Effect level:

32 mg/m³ air (nominal)

Sex:

male/female

Basis for effect level:

other: lymphocytopenia after 10 expousres at 80 mg/m3

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Benzene (100 ppm or higher for 6 h/day, 5 days/week for 2 weeks) produced a reduction in bone marrow cellularity and the number of pluripotent stem cells in the bone marrow. There was also as increase in the fraction of stem cells in DNA synthesis. At 25 ppm lymphocyte concentration in peripheral blood was decreased. Exposure to 300 ppm 6 h/day, 5 days/ week for 2, 4, 8, and 16 weeks produced a diminution in the stem cell levels in bone marrow. Stem cells returned to control levels 2 weeks after the end of benzene exposure for 2 and 4 weeks, 16 weeks after exposure for 8 weeks, and to 92% of controls 25 weeks after 16 weeks of exposure. Blood lymphocytes showed a more rapid return to the control level.

Applicant's summary and conclusion

Conclusions:

Repeated inhalation exposure to benzene at 6h/day, 5 days/week produces haematotoxicity in mice. The NOAEC was 10 ppm (32 mg/m3).

Executive summary:

Haematotoxicity was examined in male and female C57Bl/6 BNL mice exposed to benzene vapour at concentrations of 0, 10, 25, 100, 300 or 400 ppm benzene for 2 -16 weeks. At various times during and after the exposure period, five to ten mice were removed from both the treated and control groups and the blood, bone marrow and spleens removed and examined.

At ≥100 ppm for 10 exposures benzene produced a reduction in bone marrow cellularity and the number of pluripotent stem cells in the bone marrow. The fraction of stem cells in DNA synthesis was also increased. At 25 ppm lymphocyte concentration was decreased. 16 weeks of exposure to 300 ppm benzene, 6 h/day, 5 days/week, produced a diminution in the haemopoietic stem cells with incomplete recovery 16 weeks after termination of exposure although full recovery was seen with shorter exposure durations (2, 4 or 8 weeks). There was a more rapid return of blood lymphocytes to control levels.

The NOAEC for haematotoxicity was 10 ppm (32 mg/m³).