Aromatic hydrocarbons, C6-10, C8-rich

Endpoint summary

Description of key information

After repeated dose exposure via oral or inhalation routes, benzene causes adverse effects on the haematopoietic system of animals and in humans.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

25 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

Adequate information is available to characterise the repeated oral toxicity of benzene in animals.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

11.2 mg/m³

Study duration:

chronic

Species:

other: human (epidemiological findings)

Quality of whole database:

Adequate information is available to characterise the repeated inhalation toxicity of benzene in animals and humans.

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Non-human data

Oral

Benzene toxicity following sub-chronic and chronic oral (gavage) exposure was investigated in studies using F344/N rats and B6C3F1 mice conducted as part of the National Toxicology Program (NTP, 1986). Animals were dosed 5 days per week for 17 or up to 103 weeks. The most significant findings in rats were a dose-related leukopenia and lymphocytopenia observed in males at ≥ 200 mg/kg and in females at ≥ 25 mg/kg in the 17 week study and in all groups dosed for one and two years. No NOAEL could be determined in the 2-year study. The LOAEL was 50 mg/kg/day for male rats and 25 mg/kg/day for female rats, i.e. the lowest doses administered.

In mice, tremors were observed intermittently at 400 and 600 mg/kg throughout the 17 week study. White blood cell and lymphocyte counts were decreased in males at 50 mg/kg bw or more and in females white blood cells were decreased at 600 mg/kg and lymphocytes were decreased at 400 mg/kg or more. In the chronic toxicity study weight gain reductions occurred in male and female mice at 100 mg/kg. Haematotoxic effects were limited to lymphocytopenia and associated leukocytopenia in all dose groups (males from 3 to 18 months, female mice from 12 to 18 months). Benzene increased the frequency of micronucleated normochromatic peripheral erythrocytes in male and female mice of all dose groups, males were more sensitive than females. Haematopoietic hyperplasia in the bone marrow and splenic haematopoiesis was observed in all dosed mice groups. The LOAEL was 25 mg/kg bw/day for male and female mice. A NOAEL was, therefore, not achieved.

Inhalation

In the rat, the key study is considered to be that of Ward et al, 1985. Animals were exposed to concentrations of 0, 1, 10, 30 or 300 ppm (0, 3.2, 9.6, 960 mg/m³) benzene vapour, 6 h/day, 5 days/week, for 13 weeks. Decreased blood lymphocyte counts, relative increase in neutrophil percentages and slightly decreased femoral marrow cellularity were the only significant treatment-related parameters noted in animals exposed to 300 ppm. The NOAEC for toxicity at 28 and 90 days was 30 ppm (96 mg/m³) for both male and female rats.

In mice haematotoxic effects following repeated inhalation exposure to benzene include: decreases in haematocrit, total haemoglobin, erythrocyte count, leukocyte count, platelet count, myeloid/erythroid ratios, and percentage of lymphocytes at 300 ppm (960 mg/m³) (Ward et al, 1985); depressed bone marrow and splenic Multipotential Haematopoietic Stem cells (CFU-S) and Granulocyte/Macrophage Progenitor cells (GM-CFU-C) at benzene concentrations ≥103 ppm (Green et al, 1981a, b); bone marrow erythroid progenitor cell numbers were depressed 1 day after exposure to concentrations ≥ 10 ppm (32 mg/m³) (Dempster and Snyder, 1990); significant depression in femoral lipopolysaccharide (LPS) -induced B-colony-forming ability and splenic phytohaemagglutinin (PHA) -induced blastogenesis at 31 ppm (Rozen et al, 1984); a reduction in bone marrow cellularity and the number of pluripotent stem cells in the bone marrow at ≥ 100 ppm for 10 exposures (Cronkite et al, 1985).

On the basis of these studies the LOAEC for haematotoxicity in mice is 10 ppm (32 mg/m³). A NOAEC could not be defined.

Dermal

No published data are available

 

Human data

For updated Human data (see section 7.10 Endpoint Summary). This section will be revised in the next the next dossier update.

References

Agency for Toxic Substances and Disease Registry (ATSDR) (2007). Toxicological profile for Benzene, Department of Health and Human Services, Public Health Service.

Collins JJ, Ireland BK, Easterday PA, Nair RS and Braun J (1997). Evaluation of lymphopenia among workers with low-level benzene exposure and the utility of routine data collection. J Occup Environ Med 39, 232-237.

Cronkite EP, Drew RT, Inoue T and Bullis JE (1985). Benzene hematotoxicity and leukemogenesis. Am. J. Ind. Med. 7, 447-456.

Dempster AM, Snyder CA. (1990). Short term benzene exposure provides a growth advantage for granulopoietic progenitor cells over erythroid progenitor cells. Arch Toxicol 64(7):539-544.

EU RAR (2008). European Union Risk Assessment Report for Benzene. http://ecb.jrc.ec.europa.eu/documents/Existing-chemicals/RISK_ASSESSMENT/REPORT/benzenereport063.pdf.

Green JD, Snyder CA, LoBue J, Goldstein BD, Albert RE (1981a). Acute and chronic dose/response effects of inhaled benzene on multipotential hematopoietic stem (CFU-S) and granulocyte/macrophage progenitor (GM-CFU-C) cells in CD-1 Mice. Toxicol. App. Pharmacol. 58, 492-503.

Green JD, Synder CA, LoBue J, Goldstein BD and Albert RE (1981b). Acute and chronic dose/response effect of benzene inhalation on the peripheral blood, bone marrow, and spleen cells of CD-1 male mice. Toxicol. Appl. Pharmacol. 59, 204-214.

Lan Q, Zhang L, Li G, Vermeulen R, Weinberg RS, Dosemeci M, Rappaport SM, Shen M, Alter BP, Wu Y, Kopp W, Waidyanatha S, Rabkin C, Guo W, Chanock S, Hayes RB, Linet M, Kim S, Yin S, Rothman N and Smith MT (2004). Haematotoxicity in workers exposed to low levels of benzene. Science 306, 1774-1776.

NTP (1986). Toxicology and carcinogenesis studies of benzene (CAS No. 71-43-2) in F344/N rats and B6C3F1 mice (gavage studies). NIH publication number 86-2545. Testing laboratory: Battelle Columbus Laboratories. Report no.: TR 289. Study number: NTP TR 289.

Pesatori AC, Garte S, Popov T, Georgieva T, Panev T, Bonzini M, Consonni D, Carugno M, Goldstein BD, Taioli E, Fontana V, Stagi E, Bertazzi PA and Merlo DF (2009). Early effects of low benzene exposure on blood cell counts in Bulgarian petrochemical workers. Med Lav, 100, 83-90.

Qu Q, Shore R, Li G, Jin X, Chen LC, Cohen B, Melikian AA, Eastmond D, Rappaport SM, Yin S, Li H, Waidyanatha S, Li Y, Mu R, Zhang X and Li K (2002). Hematological changes among Chinese workers with a broad range of benzene exposures. Am J Ind Med. 42, 275-285.

Qu Q, Shore R, Li G, Jin X, Chen LC, Cohen B, Melikian AA, Eastmond D, Rappaport S, Li H, Rupa D, Waidyantha S, Yin S, Yan H, Meng M, Winnik W, Kwok ESC, Li Y, Mu R, Xu B, Zhang X and Li K (2003). Validation and evaluation of biomarkers in workers exposed to benzene in China. Research Report 115, Health Effects Institute, Boston, MA.

Rothman N, Li GL. Dosemeci M, Bechtold WE, Mart GE, Wang YZ, Linet M, Xi L, Lu W, Smith MT, Titenko-Holland N, Zhang LP, Blot W, Yin SN and Hayes RB (1996). Hematotoxicity among Chinese workers heavily exposed to benzene. American Journal of Industrial Medicine, 29, 236-246.

Rozen MG, Snyder CA, Albert RE. (1984). Depression in B- and T-lymphocyte mitogen-induced blastogenesis in mice exposed to low concentrations of benzene. Toxicology Letters 20, 343-349.

Schnatter AR, Kerzic P, Zhou Y, Chen M, Nicolich M, Lavelle K, Armstrong T, Bird M, Lin l, Hua F and Irons R (2010). Peripheral blood effects in benzene-exposed workers. Chem Biol Interact (2009) doi:10.1016/j.cbi.2009.12.020

Swaen GMH, van Amelsvoort L, Twisk JJ, Versraeten E, Slootweg R, Collins JJ and Burns CJ (2010). Low level occupational benzene exposure and hematological parameters. Chem Biol Interact (2010).

Tsai SP, Fox EE, Ransdell JD, Wendt JK, Waddell LC and Donnelly RP (2004). A hematology surveillance study of petrochemical workers exposed to benzene. Reg Toxicol Pharmacol 40, 67-73.

US EPA IRIS (2002). Toxicological Review of Benzene (Noncancer Effects). US Environmental Protection Agency, Office of Research and Development, National Center for Environmental Assessment, Washington Office, Washington, DC, EPA/635/R-02/001F, 2002.

Vermeulen R, Li GL, Dosemeci M, Rappaport SM, Bohong X, Smith MT, Zhang L, Hayes RB, Liet M, Mu R, Wang L, Xu J, Yin S and Rothman N (2004). Detailed exposure assessment for a molecular epidemiology study of benzene in two shoe factories in China. Ann Occup Hyg, 48, 105-116.

Ward E, Hornung R, Morris J, Rinsky R, Wild D, Halperin W and Guthrie W (1996). Risk of low red or white blood cell count related to estimated benzene exposure in a rubberworker cohort (1940-1975). Am J Ind Med 29, 247 -257.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Sub-chronic and chronic studies indicate that benzene causes adverse effects on the haematopoietic system of rats and mice following repeated oral exposure.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
In the rat, decreased blood lymphocyte counts and slightly decreased femoral marrow cellularity were the only significant treatment-related parameters noted in animals exposed to 300 ppm with a sub-acute and sub-chronic NOAEC of 30 ppm (96 mg/m3). In mice, reductions in a range of haematological parameters were recorded with a LOAEC of 10 ppm (32 mg/m3). Human data show haematological changes in neutraphil counts with a NOAEC of 3.5 ppm (11.2 mg/m3).

Repeated dose toxicity: via oral route - systemic effects (target organ) cardiovascular / hematological: bone marrow

Repeated dose toxicity: inhalation - systemic effects (target organ) cardiovascular / hematological: hematopoiesis

Justification for classification or non-classification

After repeated dose exposure via oral or inhalation routes, benzene causes adverse effects on the haematopoietic system of animals and in humans. Consequently, benzene is classified as T, Cat 1 (H372) according to Regulation (EC) No 1272/2008 of the European Parliament.