Registration Dossier

Toxicological information

Carcinogenicity

Currently viewing:

Administrative data

Description of key information

Long term experimental carcinogenicity bioassays have shown that benzene is a carcinogen producing a variety of tumours in animals (including lymphomas and

leukaemia). Human epidemiological studies indicate a causal relationship between benzene exposure and acute non-lymphatic leukaemia.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
25 mg/kg bw/day
Study duration:
chronic
Species:
mouse
Quality of whole database:
Adequate information is available to characterise the oral carcinogenicity of benzene in animals.

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEC
960 mg/m³
Study duration:
subchronic
Species:
mouse
Quality of whole database:
Adequate information is available to characterise the oral carcinogenicity of benzene in animals and humans.

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Non-human data

Oral

Oral cancer studies showed increased tumour rates in multiple organs, some of which were also tumour sites in the inhalation studies. The majority of tumour types at sites other than the haematopoietic system are of epithelial origin. In mice benzene produced increased tumour incidences in Zymbal gland, (Cronkite et al,1985; Farris et al, 1993; NTP, 1986; Maltoni et al, 1989), lung (Farris et al, 1993; NTP, 1986; Maltoni et al, 1989), Harderian gland (NTP, 1986), preputial gland (Farris et al,1993; NTP, 1986), forestomach (Farris et al, 1993; NTP, 1996), mammary gland (NTP, 1986; Maltoni et al, 1989), liver (Maltoni et al, 1989) and ovaries (Cronkite et al, 1985; NTP, 1986). In rats, benzene treatment was associated to increased tumour incidences in the Zymbal gland (NTP, 1986; Maltoni et al, 1989), oral cavity (NTP, 1986; Maltoni et al, 1989), forestomach (Maltoni et al, 1989), nasal cavity (Maltoni et al, 1989), and skin (NTP, 1986; Maltoni et al, 1989).

Dermal

No published data are available.

Inhalation

From several animal studies with inhalation and oral exposure there is evidence that benzene is carcinogenic. Target organs were similar in several studies irrespective of the application route and include the haematopoietic system and tissues of epithelial origin. The predominant tumours induced in the inhalation studies were located in the haematopoietic system, particularly lymphomas in mice (Farris et al, 1993; NTP 1986; Cronkite, 1985). In rats, increased frequencies of leukaemia in comparison to controls were found in benzene-exposed Sprague-Dawley rats and Wistar rats (Maltoni et al, 1989) and one case (out of 40 animals) of chronic myelogenous leukaemia was reported in Sprague-Dawley rats exposed to benzene (Goldstein et al, 1982).

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

Baan R, Grosse Y, Straif K, Secretan B, El Ghissassi F, Bouvard V, Benbrahim-Tallaa L, Guha N, Freeman C, Galichet L and Cogliano V (2009). A review of human carcinogens—Part F: Chemical agents and related occupations. The Lancet Oncology 10, 1143-1144.

Bloeman LJ, Youk A, Bradley TD, Bodner KM & Marsh G (2004). Lymphohaematopoietic cancer risk among chemical workers exposed to benzene. Occup. Environ. Med. 61, 270-274.

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

Crump KS (1994). Risk of benzene-induced leukemia: a sensitivity analysis of the Pliofilm cohort with additional follow-up and new exposure estimates. J Toxicol Environ Health 42, 219-242.

Crump KS and Allen BC (1984). Quantitative estimates of risk of leukemia from occupational exposure to benzene. Prepared for the Occupational Safety and Health Administration by Science Research Systems, Inc., Ruston, LA. Unpublished

EC (1993). Occupational exposure limits: Criteria document for benzene. Report EUR 14491 en, ISSN 1018-5593, Commission of the European Communities, pp126.

EC (1999). Council Directive 1999/38/EC of 29 April 1999 amending for the second time Directive 90/394/EEC on the protection of workers from the risks related to exposure to carcinogens at work and extending it to mutagens. Official Journal of the European Communities, L138, 66-69, 1 June 1999.

ECHA (2008). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health, pp150.

Farris GM, Everitt JI, Irons RD, Popp JA (1993). Carcinogenicity of inhaled benzene in CBA mice. Fund Appl Toxicol 20, 503-507.

Glass DC, Gray CN, Jolley DJ, Gibbons C, Sim MR (2005). Health Watch exposure estimates: do they underestimate benzene exposure? Chem Biol Interact 153 -154, 23-32.

Glass DC, Gray CN, Jolley DJ, Gibbons C, Sim MR (2006). The health watch case-control study of leukemia and benzene: the story so far. Ann N Y Acad Sci 1076, 80-9.

Glass DC, Gray CN, Jolley DJ, Gibbons C, Sim MR, Fritschi L, Adams GG, Bisby JA, and Manuell R (2003). Leukemia risk associated with low-level benzene exposure. Epidemiology 14, 569–577. Epidemiology. 2004;15, 509; author reply 510-1.

Goldstein BD, Snyder CA, Laskin S, Bromberg I, Albert RE and Nelson N. (1982). Myelogenous leukaemia in rodents inhaling benzene. Toxicology Letters 13, 169 -173.

Gun RT, Pratt N, Ryan P, Roder D (2006). Update of mortality and cancer incidence in the Australian petroleum industry cohort. Occup Environ Med 63, 476-81.

Hayes RB, Yin SN, Dosemeci M, Li GL, Wacholder S, Travis LB, Li CY, Rothman N, Hoover RN and Linet MS (1997). Benzene and the dose-related incidence of haematologic neoplasms in China. Natl Cancer Inst 89, 1065-1071

IARC (International Agency for Research on Cancer) (1982). IARC monographs on the evaluation of carcinogenic risks of chemicals to humans: some industrial chemicals and dyestuffs. Vol. 29, IARC, pp. 93-148.

Irons RD, Gross SA, Le A, Wang XQ, Chen Y, Ryder J, Schnatter AR. Integrating WHO 2001-2008 criteria for the diagnosis of Myelodysplastic Syndrome (MDS): a case-case analysis of benzene exposure. Chem Biol Interact. 2010;184:30-8.

Maltoni C, Ciliberti A, Cotti G, Conti B and Belpoggi F (1989). Benzene, an experimental multipotential carcinogen: results of the long-term bioassays performed at the Bologna Institute of Oncology. Environmental Health Perspective 82, 109-124.

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.

Paustenbach DJ, Price PS, Ollison W, Blank C, Jernigan JD, Bass RD, Peterson HD (1992). Reevalution of benzene exposure for the Pliofilm (rubberworker) cohort (1936-1976). J Toxicol Environ Health 36, 177-231.

Paxton MB, Chinchilli VM, Brett SM and Rodricks JV (1994a): Leukaemia risk associated with benzene exposure in the Pliofilm cohort: I. Mortality update and exposure distribution. Risk analysis 14: 147-54

Paxton MB, Chinchilli VM, Brett SM and Rodricks JV (1994b): Leukaemia risk associated with benzene exposure in the Pliofilm cohort: II. Risk estimates. Risk analysis 14: 155-61

Richardson DB (2008). Temporal variation in the association between benzene and leukemia mortality. Environ Health Perspect. 116(3):370-4.

Rinsky RA, Young RJ, and Smith AB (1981). Leukaemia in benzene workers. American Journal of Industrial Medicine 2, 217-45.

Rinsky RA, Smith AB, Hornung RW, Filloon TG, Young RJ, Okun AH, and Landrigan PJ (1987). Benzene and leukemia. An epidemiological risk assessment. New England Journal of Medicine 316: 1044-50

Rinsky RA, Hornung RW, Silver SR and Tseng CY (2002). Benzene exposure and haematopoietic mortality: a long-term epidemiologic risk assessment. Am J Ind Med, Vol 42, pp 474-480.

Rushton L and Romaniuk H (1997). A case-control study to investigate the risk of leukaemia associated with exposure to benzene in petroleum marketing and distribution workers in the United Kingdom. Occup Environ Med 54, 152-166.

Schnatter AR, Armstrong TW, Nicolich MJ, et al. Lymphohaematopoietic malignancies and quantitative estimates of exposure to benzene in Canadian petroleum distribution workers. Occup Environ Med. 1996;53:773–781.

Schnatter, AR, Glass DC, Tang G, Irons RD and Rushton L (2012).Myelodysplastic syndrome and benzene exposure among petroleum workers: an international pooled analysis. J Natl Cancer Inst, 104, 1724-37

Schnatter AR, Rosamilia K, Wojcik NC (2005). Review of the literature on benzene exposure and leukemia subtypes. Chem Biol Interact.153-154, 9-21.

Swaen GM, Scheffers T, de Cock J, Slangen J and Drooge H (2005). Leukemia risk in caprolactam workers exposed to benzene. Ann Epidemiol 15, 21-8.

Swaen GM, van Amelsvoort L, Twisk JJ, Verstraeten E, Slootweg R, Collins JJ, Burns CJ (2010). Low level occupational benzene exposure and hematological parameters. Chem Biol Interact 2010 Jan 14. [Epub ahead of print]

Texas Commission on Environmental Quality (TCEQ) (2007). Development Support Document. Benzene. Chief Engineer’s Office. Available: http://tceq.com/assets/public/implementation/tox/dsd/final/benzene_71-43-2_final_10-15-07.pdf

Utterback DF and Rinsky RA (1995). Benzene exposure assessment in rubber hydrochloride workers: a critical evaluation of previous estimates. Am J Indust Med 27, 661-76.

Vlaanderen J, Portengen L, Rothman N, Lan Q, Kromhout H, Vermeulen R. (2010) Flexible meta-regression to assess the shape of the benzene-leukemia exposure-response curve. Environ Health Perspect. 118:526-32.

WHO (2000). Air quality guidelines for Europe, 2nd ed., World Health Organization Regional Office for 2000 (WHO Regional Publications, European Series No. 91).

Wong O, Harris F, Yiying W, Hua F. A hospital-based case-control study of acute myeloid leukemia in Shanghai: analysis of personal characteristics, lifestyle and environmental risk factors by subtypes of the WHO classification. Regul Toxicol Pharmacol 2009;55:340-52.


Justification for selection of carcinogenicity via oral route endpoint:
Rodent oral cancer studies showed increased tumour rates in multiple organs, some of which were also tumour sites after inhalation. The majority of tumour types at sites other than the haematopoietic system are of epithelial origin.

Justification for selection of carcinogenicity via inhalation route endpoint:
The predominant tumours induced in animal inhalation studies were located in the haematopoietic system, particularly lymphomas in mice. In rats, increased frequencies of leukaemia in comparison to controls were found in benzene-exposed Sprague-Dawley rats and Wistar rats, with one report of chronic myelogenous leukaemia. In humans, benzene causes acute myelogenous (non-lymphocytic) leukaemia (AML or ANLL), however IARC has concluded that evidence of an association between benzene exposure and acute lymphocytic leukaemia (ALL), chronic lymphocytic leukaemia (CLL), multiple myeloma and non-Hodgkin’s lymphoma (NHL) is limited, while evidence for chronic myeloid leukaemia (CML) is inadequate.

Carcinogenicity: via oral route (target organ): other: all gross lesions and masses

Carcinogenicity: via inhalation route (target organ): cardiovascular / hematological: bone marrow

Justification for classification or non-classification

It is concluded that benzene is carcinogenic in animals and humans and therefore is classified as follows: Carcinogenic Cat 1A, H350 under Regulation (EC) No 1272/2008 of the European Parliament.