Hydrocarbons, C4

Carcinogenicity

Administrative data

Endpoint:

carcinogenicity: inhalation

Type of information:

other: EU Risk Assessment

Adequacy of study:

other information

Reliability:

other:

Data source

Reference

Reference 1

Reference Type:

other: EU Risk Assessment

Title:

European Union Risk Assessment Report 1,3-BUTADIENE, CAS No: 106-99-0, EINECS No:203-450-8

Author:

[ECB] European Chemicals Bureau

Year:

2002

Reference 2

Reference Type:

publication

Title:

Carcinogenicity of 1,3-butadiene in C57BL/6 x C3H F1 mice at low exposure concentrations.

Author:

Melnick, R.L. et al.

Year:

1990

Bibliographic source:

Canc Res. 50; 6592-6599.

Reference 3

Reference Type:

publication

Title:

Inhalation toxicology and carcinogenicity of 1,3-butadiene in B6C3F1 mice following 65 weeks of exposure.

Author:

Melnick, R.L. et al.

Year:

1990

Bibliographic source:

Environ Health Persp. 86; 27-36.

Reference 4

Reference Type:

publication

Title:

Toxicology and carcinogenesis studies of 1,3-butadiene in B6C3F1 mice (inhalation studies).

Author:

National Toxicology Program

Year:

1993

Bibliographic source:

NTP Technical Report Series no 434, NIH Publication 93-3165, Research Triangle Park, NC, USA.

Materials and methods

Principles of method if other than guideline:

EU Risk Assessment on the major component of C4 Hydrocarbons: 1,3-Butadiene

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Buta-1,3-diene

EC Number:

203-450-8

EC Name:

Buta-1,3-diene

Cas Number:

106-99-0

Molecular formula:

C4H6

IUPAC Name:

buta-1,3-diene

Details on test material:

- Name of test material (as cited in study report): 1,3-butadiene
- CAS number: 106-99-0
- EINECS number: 203-450-8

Test animals

Species:

mouse

Strain:

B6C3F1

Sex:

male/female

Details on test animals or test system and environmental conditions:

EU Risk Assessment on the major component of C4 Hydrocarbons: 1,3-Butadiene

Administration / exposure

Route of administration:

inhalation: gas

Duration of treatment / exposure:

up to 2 years

Frequency of treatment:

6 hours/day, 5 days/week

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 6.25, 20, 62.5, 200 or 625 ppm
Basis:
nominal conc.

No. of animals per sex per dose:

70

Control animals:

yes

Results and discussion

Results of examinations

Details on results:

Butadiene is a genotoxic carcinogen in the mouse and the risk of carcinogenicity in mice is high even at low exposure concentrations.
From stop-exposure studies it appears that butadiene can elicit a carcinogenic response in the mouse even after a short exposure of 13 weeks to 625 ppm.

Effect levels

1

Dose descriptor:

LOAEC

Effect level:

6.25 ppm (nominal)

Sex:

female

Basis for effect level:

other: Lung neoplasms, including malignant neoplasms, were increased in females at 6.25 ppm and above.

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

2

Dose descriptor:

NOAEC

Sex:

male/female

Remarks on result:

not determinable

Remarks:

no NOAEC identified. Effect type:carcinogenicity (migrated information)

Any other information on results incl. tables

An NTP study was conducted in which B6C3F1 mice were exposed to 0, 6.25, 20, 62.5, 200 or 625 ppm butadiene, 6 hours/day, 5 days/week for up to 2 years. There were 70 mice per sex per group except at 625 ppm, which had 90 mice per sex. Up to 10 animals per group were sacrificed for examination at 40 and 65 weeks. A full gross necropsy and histopathological examination was carried out on each animal sacrificed during or at the end of the study. In addition, the study included a series of stop-exposure studies, in which male mice were exposed to butadiene for a limited period and the animals were then kept in control chambers for the remainder of a 2-year period. In these stop-exposure experiments, groups of 50 male mice were exposed to one of the following exposure regimens: 625 ppm for 13 weeks; 200 ppm for 40 weeks; 625 ppm for 26 weeks; or 312 ppm for 52 weeks. All tumour incidences quoted are adjusted for mortality. In the main 2-year exposure study, survival in animals exposed to 20 ppm butadiene or greater was statistically significantly reduced and at the highest concentration, 625 ppm, there was 100% mortality by week 65 of the study. Survival was reduced due mainly to the development of treatment-related malignant tumours. The major cause of death in the 625 ppm exposure group was lymphocytic lymphoma of thymic origin which developed in 91% of animals (mortality adjusted tumour incidence) compared with 4% incidence in controls. These tumours appeared from week 23 onwards. The incidence of lymphocytic lymphoma was also statistically significantly increased in females at 200 ppm (41% incidence). Haemangiosarcoma of the heart occurred with statistically significantly increased incidence in males exposed to 62.5 ppm and higher and in females at 200 and 625 ppm. At 625 ppm this tumour was seen in 6 males (53%) and 26 females (84%) compared with zero incidence in controls. The appearance of this tumour is considered to be important since it is a very rare tumour in the mouse. The historical control incidence is 1 in 2,500 animals. Other tumours which occurred with a statistically increased incidence in treated animals compared with controls and which included malignant neoplasms, were alveolar-bronchiolar neoplasms of the lung, squamous cell neoplasm of the forestomach, Harderian gland adenoma or carcinoma and hepatocellular neoplasm. In males there was also a significantly increased incidence of preputial gland adenoma or carcinoma, while in females, there was increased incidence of adenocarcinoma of the mammary gland and ovarian neoplasms. In general, at each of these sites, there was evidence of increases in the incidence of related nonneoplastic proliferative lesions. In females, only benign neoplasms of the lung, forestomach, Harderian gland and ovary were seen in control animals but malignant neoplasms were seen in these organs in exposed animals. In males, progression from alveolar-bronchiolar adenoma to carcinoma was seen at 200 ppm. In most cases there was evidence of a dose-relationship in the tumour incidence, with increased incidence beginning at 62.5 or 200 ppm. However, it was observed that for some tumours, the incidence was higher in the lower exposure groups compared with the highest exposure group and statistical significance was lost at 625 ppm. This pattern of the tumour incidence is attributed to the high mortality in the 625 ppm group and the high incidence of the early developing lethal tumour, lymphocytic lymphoma, in these animals. At lower butadiene concentrations, the lymphomas do not occur, which allows the development of tumours in other tissues in the low exposure groups. In females, the incidence of hepatocellular neoplasm was increased from 20 ppm and above and appeared to be mainly due to an increase in hepatocellular carcinomas. Lung neoplasms, including malignant neoplasms, were increased in females at 6.25 ppm and above. The results and tumour profile in the stop-exposure groups were similar to those in the main study. Survival in all groups was markedly reduced, again due to the development of malignant tumours. For example, even after only 13 weeks exposure to 625 ppm butadiene, there was a statistically significant increase in the incidence of lymphocytic lymphoma, haemangiosarcoma of the heart, alveolar-bronchiolar adenoma and carcinoma, squamous cell benign and malignant neoplasm of the forestomach, Harderian gland adenoma or adenocarcinoma and preputial gland carcinoma. The development of tumours other than the lymphomas (which require high butadiene concentrations) appeared to show a concentration x time dependency. Overall, this study demonstrates butadiene to cause malignant tumours at multiple sites in mice. A statistically significantly increased incidence of malignant lung tumours was seen at the lowest concentration tested, 6.25 ppm. The evidence indicates that butadiene is a genotoxic carcinogen in the mouse and that the risk of carcinogenicity in mice is high even at low exposure concentrations. From stop-exposure studies it appears that butadiene can elicit a carcinogenic response in the mouse even after a short exposure of 13 weeks to 625 ppm.