Registration Dossier

Toxicological information

Carcinogenicity

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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

Link to relevant study records
Reference
Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP compliant, near guideline study, published as NIH report, minor limitations in design but fully adequate for assessment
Qualifier:
equivalent or similar to
Guideline:
EPA OPP 83-5 (Combined Chronic Toxicity / Carcinogenicity)
Deviations:
no
GLP compliance:
yes
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories (Portage, MI)
- Age at study initiation: 7-8 weeks
- Weight at study initiation: mean weights per group males 151-155 g ; females 112-115 g
- Housing: 5 per sex per cage in polycarbonate cages
- Diet: NIH 07 Rat and Mouse Ration (Ziegler Bros, Gardners, PA) ad libitum
- Water: ad libitum
- Acclimation period: 19 days

ENVIRONMENTAL CONDITIONS
- Temperature: 23±3°C
- Humidity: 40-60%
- Air changes: 15 per h
- Photoperiod: 12 h dark / 12 h light

IN-LIFE DATES: From: 10 December 1979 To: 11 December 1981
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: A weighed amount of benzene was mixed with the appropriate amount of corn oil and mixed by inversion (21 times). Rats were dosed at a rate of 5 mL/kg bw. Benzene in corn oil was found to be stable at 25ºC for at least 7 days. Dose mixtures were used within 2 weeks of preparation.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Benzene/corn oil mixtures were analyzed by gas chromatography. All analyzed samples were within ±10% of the target concentrations.
Duration of treatment / exposure:
103 weeks
Frequency of treatment:
once per day, 5 days/week
Post exposure period:
Up to 15 days
Remarks:
Doses / Concentrations:
Males: 0, 50, 100, 200 mg/kg bw; Females: 0, 25, 50, 100 mg/kg bw
Basis:
other: nominal in corn oil
No. of animals per sex per dose:
50/sex/group
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on the results of a 17 week study: No compound-related deaths occurred; Final mean body weights (relative to those of the vehicle controls) were depressed 14%-22% for male and female rats that received 200, 400, or 600 mg/kg benzene. A dose-related leukopenia was observed for both male and female rats. Lymphoid depletion in the B-cell of the spleen was observed in 3/5 male and 4/5 female rats that received 200 mg/kg benzene and 5/5 male and 5/5 female rats that received 600 mg/kg benzene for 60 days and in 10/10 male and 10/10 female rats that received 600 mg/kg for 120 days. Increased extramedullary haematopoeisis was observed in the spleen of 4/5 male and 315 female rats that received 600 mg/kg for 120 days. Based on these composite observations, the doses were selected for rats for the 2-year study.

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly for initial 13 weeks, monthly thereafter

HAEMATOLOGY: Yes
- Time schedule and number of animals for collection of blood: Main study - 10/sex/group bled orbitally at 12, 15, 18, 21 and 24 (termination) months. 40/sex/group bled by cardiac puncture at 24 months.
- Anaesthetic used for blood collection: No anaesthesia for interim samples, pentobarbital used prior to cardiac puncture terminal samples.
- Animals fasted: No data
- Parameters examined: packed cell volume, red blood cell count, total and differential white blood cell count, haemoglobin, and mean corpuscular volume, reticulocyte count and prothrombin time.

CLINICAL CHEMISTRY: No

URINALYSIS: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes. Examinations for grossly visible lesions were performed on major tissues or organs.

HISTOPATHOLOGY: Yes. The following tissues were examined histologically: gross lesions and tissue masses, mandibular or mesenteric lymph
node, salivary glands, sternebrae, femur, or vertebrae including marrow, thyroid gland, thymus, parathyroids, liver, small intestine, colon, brain, prostate/testes or ovaries/uterus, skin, heart, oesophagus, stomach, trachea, pancreas, spleen, kidneys, adrenal glands, urinary bladder, pituitary gland, spinal cord, eyes, mammary gland, lung/mainstem bronchi.
Statistics:
The probability of survival was estimated by the product-limit procedure of Kaplan and Meier. Statistical analyses for a possible dose-related effect on survival used the method of Cox for testing two groups for equality and Tarone's life table test for a dose-related trend.
The incidence of neoplastic or non-neoplastic lesions is given as the ratio of the number of animals bearing such lesions at a specific anatomic site to the number of animals in which that site was examined.
Three statistical methods were used to analyze tumour incidence data - Life table analysis, incidental tumour analyses and unadjusted analyses. The two that adjust for intercurrent mortality employ the classical method for combining contingency tables developed by Mantel and Haenszel. Tests of significance included pairwise comparisons of high dose and low dose groups with vehicle controls and tests for overall dose-response trends. Haematology data was initially screened for outliers the same animals were examined across time, a repeated measures analysis of variance was considered to be an appropriate method to investigate temporal and dose-related variation.
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
effects observed, treatment-related
Details on results:
CLINICAL SIGNS AND MORTALITY: Survival decreased with increasing dose for both male and female rats. Survival of the high dose male rats and of the mid and high dose female rats was significantly lower than that of the vehicle controls. Most rats that died early had neoplasia (Table 1).

BODY WEIGHT AND WEIGHT GAIN: Dose related weight gain reductions occurred in mid and high dose males, and in high dose females. Differences in bodyweight at 103 weeks were 12% and 23% in 100 and 200 mg/kg males, respectively and 10% in 100 mg/kg females. The low dose group was comparable to vehicle controls throughout the study.

HISTOPATHOLOGY: For male rats, benzene caused increased incidences of Zymbal gland carcinomas, squamous cell papillomas and squamous cell carcinomas of the oral cavity, and squamous cell papillomas and squamous cell carcinomas of the skin. For female rats, benzene caused increased incidences of Zymbal gland carcinomas and squamous cell papillomas and squamous cell carcinomas of the oral cavity (Tables 2 and 3).
Dose descriptor:
LOAEL
Effect level:
50 mg/kg bw/day (nominal)
Sex:
male
Basis for effect level:
other: increased incidences of Zymbal gland carcinomas, squamous cell papillomas and squamous cell carcinomas of the oral cavity, and squamous cell papillomas and squamous cell carcinomas of the skin ≥50 mg/kg
Remarks on result:
other: Effect type: carcinogenicity (migrated information)
Dose descriptor:
LOAEL
Effect level:
25 mg/kg bw/day (nominal)
Sex:
female
Basis for effect level:
other: increased incidences of Zymbal gland carcinomas and squamous cell papillomas and squamous cell carcinomas of the oral cavity ≥25 mg/kg
Remarks on result:
other: Effect type: carcinogenicity (migrated information)

The high-dosed male and mid- and high-dosed female groups had significantly decreased survival rates when compared to the control groups.  The female control group, however, apparently had exceptionally good survival when compared with historic control data for the same strain and sex of animal.

 

Table 1: Survival

Week

Vehicle Control

Low Dose

Mid Dose

High Dose

Male

92

35/50 (70%)

38/50 (76%)

31/50 (62%)

30/50 (60%)

104

32/50 (64%)

29/50 (58%)

25/50 (50%)

16/50* (32%)

Female

92

49/50 (98%)

42/50 (84%)

40/50 (80%)

38/50 (76%)

104

46/50 (92%)

38/50 (76%)

34/50* (68%)

25/50* (50%)

* Decreased (P0.05) survival compared with vehicle controls

 

Zymbal gland carcinomas occurred in both the male and female treated rats with a significant positive trend, the incidences in the mid- and high-dosed males and all the dosed females being significantly greater than in the vehicle control group (incidences = 6, 13, 24 and 40% in males and 0, 13, 11 and 30% in females for the control and three dose groups respectively). A significant positive trend was seen for the number of benzene-treated rats with squamous cell papillomas or carcinomas of the palate, lip and tongue when considered either separately (in the case of the males) or combined (in both the males and females) (combined incidence = 2, 18, 32 and 46% in males and 2, 10, 24 and 20% in females for the four groups respectively). The individual or combined incidences of skin squamous cell papillomas and carcinomas were increased in the male rats with a significant positive trend, the incidences in the high-dosed animals being significantly greater than in the controls (incidence = 0, 4, 2 and 10% for squamous cell papillomas and 0, 10, 6 and 16% for squamous cell carcinomas in the four groups respectively). A significant positive trend was found for endometrial stromal polyps of the uterus, the high-dose incidence being significantly greater than in the controls (incidence = 14, 14, 14 and 28% for the four groups respectively).

 

Table 2: Incidence of selected neoplastic lesions

Male

Female

Tissue and lesion

control

Low dose

Mid dose

High dose

control

Low dose

Mid dose

High dose

Zymbal gland

Carcinoma

2/32

6/46

10/42

17/42

0/45

5/40

5/44

14/46

Oral cavity

Squamous cell papilloma or carcinoma

1/50

9/50

16/50

19/50

1/50

5/50

12/50

9/50

Skin

Squamous cell papilloma or carcinoma

0/50

7/50

4/50

11/50

Liver

Adenoma

Adenoma or carcinoma

2/50

2/50

2/48

2/48

4/49

5/49

1/49

1/49

0/50

3/49

1/50

0/50

 

Table 3: Primary neoplasms (percentage of neoplasm-bearing animals)

Control

Low Dose

Mid Dose

High Dose

Male

Oral cavity

2a

18b

32b

38b

Zymbal gland

6a

15

24b

43b

Skin

2a

14c

10c

24b

Female

Oral cavity

2a

10c

24b

18b

Zymbal gland

0a

13b

14b

33b

Uterus

14a

14

14

28b

a = dose-related trend (P0.05)

b = increased (P0.05) relative to vehicle controls

c = marginal increase (P0.10) relative to vehicle controls

Conclusions:
Benzene is carcinogenic in rats following oral exposure. Increased tumour incidences were seen in the Zymbal gland, oral cavity and skin.
Executive summary:

The carcinogenic potential of benzene was investigated in rats using oral exposures of 0, 50, 100 or 200 mg/kg in males and 0, 25, 50 or 100 mg/kg in females 5 days/week for 103 weeks. Increased incidences of neoplasms were observed at multiple sites for male and female rats. There was clear evidence of carcinogenicity of benzene for male and female F344/N rats. For male rats, benzene caused increased incidences of Zymbal gland carcinomas, squamous cell papillomas and squamous cell carcinomas of the oral cavity, and squamous cell papillomas and squamous cell carcinomas of the skin. For female rats, benzene caused increased incidences of Zymbal gland carcinomas and squamous cell papillomas and squamous cell carcinomas of the oral cavity.

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

Link to relevant study records
Reference
Endpoint:
carcinogenicity: 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.
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 300 ppm benzene vapour in air for up to 16 weeks. After 2, 4, 8 or 16 weeks of exposure 4, 8 or 16 weeks 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 the incidence of leukaemia and development of solid tumours.
GLP compliance:
not specified
Species:
mouse
Strain:
other: C57B1/6
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 8-12 weeks
- Diet: ad libitum except during exposure
- Water: ad libitum except during exposure
Route of administration:
inhalation
Type of inhalation exposure (if applicable):
whole body
Vehicle:
other: air
Details on 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 for 2-16 weeks or
Post exposure period:
Post exposure period: up to 20 months (to approximately 750 days of age)
Remarks:
Doses / Concentrations:
0, 300 ppm ( 960 mg/m3)
Basis:
other: target concentration - (6h/d, 5d/wk for 2-16 wks)
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, sham-exposed
Dose descriptor:
NOAEC
Effect level:
300 ppm (nominal)
Sex:
female
Basis for effect level:
other: increased rate of lymphoma/leukaemia and increased incidence of Zymbal gland and ovary tumours compared to control at 300 ppm (only dose examined)
Remarks on result:
not determinable
Remarks:
no NOAEC identified. Effect type:carcinogenicity (migrated information)
Dose descriptor:
NOAEC
Effect level:
960 mg/m³ air (nominal)
Sex:
female
Basis for effect level:
other: Increased rate of lymphoma/leukaemia and increased incidence of Zymbal gland and ovary tumours compared to control at 960 mg/m3 (only dose examined)
Remarks on result:
not determinable
Remarks:
no NOAEC identified. Effect type:carcinogenicity (migrated information)

Benzene at ≥100 ppm (10 exposures, 6 h/day, 5 days/week) produced a reduction in bone marrow cellularity and the number of pluripotent stem cells in the bone marrow and the fraction of stem cells in DNA synthesis was increased. At 25 ppm lymphocyte concentration in peripheral blood was decreased.

Exposure to 300 ppm (6 h/day, 5 days/week) for 2, 4, 8 or 16 weeks produced a temporary decrease in the stem cell levels in bone marrow. Cell numbers returned to control values 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 returned to control levels more rapidly.

Early mortality and an increase in mortality rate were noted in the benzene-treated group. Mice exposed to 300 ppm (6 h/day, 5 days/week) for 16 weeks began dying at 330 days of age, whilst no sham-exposed mice died until 440 days of age. The benzene-exposed mice died in two waves: the first was from 330-390 days of age, with a second wave commencing at 570 days of age. Mortality in the first wave was due primarily to thymic lymphomata and in the second wave was caused by a mixture of nonthymic lymphomata and solid tumours.

All leukaemias and, in particular, thymic and nonthymic lymphocytic neoplasms, benign and malignant Zymbal gland tumours and ovarian tumours were increased in the treated animals when compared with the control animals:

Tumour incidence in female mice (Based on Cronkite et al, 1985, Table 1)

 

Sham–exposed

n/88, (%)

Benzene-exposed

n/89 (%)

Leukaemia (all types):

8 (9.1)

20 (22.5)

Lymphocytic neoplasm (thymic)

1 (1.1)

10 (11.2)

Lymphocytic neoplasm (nonthymic)

2 (2.3)

6 (6.7)

Myelogenous leukaemia

3 (3.4)

0 (0.0)

Leukaemia (type not specified)

2 (2.3)

4 (4.5)

Zymbal gland

1 (1.1)

16 (18)

Ovarian tumour

0 (0)

8 (9)

 

Conclusions:
Benzene inhalation at 300 ppm (960 mg/m3) for 6h/d, 5d/week for 16 weeks was carcinogenic in C57Bl/6 female mice. There was an increased incidence of lymphoma/leukaemia and Zymbal gland and ovarian tumours.
Executive summary:

Haematotoxicity and leukaemogenisis was examined in male and female mice exposed to air or benzene vapour in air at a concentration of 300 ppm 6h/day, 5 days/week for 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 for the incidence of leukaemia and development of solid tumours.

A diminution in the haemopoeitic stem cells was seen with incomplete recovery 16 weeks after termination of exposure. There was increased mortality and increased rate of lymphoma/leukaemia (20/89 v. 8/88) and incidence of Zymbal gland tumours (16/89 v. 1/88) and ovarian tumours (8/89 v. 0/88). Benzene is carcinogenic in mice following inhalation exposure.

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

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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.