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Carcinogenicity

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Description of key information

Members of the butenes category have a low potential for carcinogenicity. Carcinogenicity studies carried out on 2-methylpropene were reported to produce an increase in thyroid follicular cell tumours.  The thyroid tumours occurred only in male rats at the highest exposure concentration (8000 ppm: 18,359 mg/m3) at an incidence slightly above the laboratory historical incidence in control animals and no tumours were observed in female rats or male and female mice.  As all members of the butenes category are not genotoxic, if 2-methylpropene did cause an increase in thyroid tumors in male rats, a threshold mechanism is likely to be involved and the relevance of tumours of this type to human health is low.

Key value for chemical safety assessment

Carcinogenicity: via inhalation route

Endpoint conclusion
Dose descriptor:
NOAEC
4 589 mg/m³

Additional information

Members of the butenes category are flammable gases at room temperature and therefore significant exposure via the dermal or oral routes is unlikely. Inhalation exposure is the most appropriate route for carcinogenicity testing.

 

Carcinogenicity studies via inhalation exposure are available for 2-methylpropene (also called isobutylene). F344 Rats and B6C3F1 mice were exposed by inhalation at 0, 500, 2,000 or 8,000 ppm (1147, 4589, 18,359 mg/m3), for 105 weeks (NTP 1998). In rats, treatment-related non-neoplastic findings were limited to increased kidney weights, hyaline degeneration of the olfactory epithelium and hypertrophy of goblet cells lining the nasopharyngeal duct in rats. In mice, treatment-related non-neoplastic findings were limited to increased hyaline degeneration of the olfactory and respiratory epithelium. These findings were generally considered to be of low toxicological significance and are discussed in detail in Section 7.5 (Repeated dose toxicity). The major urinary metabolite of 2-methylpropene (2-hydroxyisobutyric acid: HIBA) was measured in the urine of both species as an indicator of isobutene exposure, these results are discussed in Section 7.1 Toxicokinetics.

 

There were no treatment-related neoplasms in female rats or male and female mice. The NTP concluded that there was no evidence of carcinogenic activity of isobutene in female rats or male and female mice exposed to 500, 2,000, or 8,000 ppm. A NOAEC of 8000 ppm (18,359 mg/m3) for carcinogenicity in female rats, male mice and female mice was established based on these results. 

 

The incidence of thyroid gland follicular cell carcinoma in male rats exposed to 8000 ppm was increased compared to the chamber control group (1/48, 0/48, 0/48, 5/50 at 0, 500, 2000 and 8000 ppm respectively) and exceeded the historical control range. The NTP therefore concluded that there was some evidence of carcinogenic activity of 2-methylpropene in male rats and established a NOAEC of 2000 ppm (4589 mg/m3) for carcinogenicity in male rats based on the thyroid follicular cell carcinomas. The relevance of the thyroid follicular tumours for human cancer risk is questionable as the tumours occurred in male rats only and not in either sex in mice. There were no precursor lesions, no dose-response relationship, the tumours were singular and unilateral, did not form metastases and there was no increase in liver weight indicating a secondary mechanism. In addition, the thyroid was not a target organ in repeat dose studies in rats. Although the 10% incidence of tumours was outside the historical control at the time, reported to be 0-4% (NTP 1998, Haseman et al 1998), a carcinogenicity study on propylene (NTP 1985) had a 7% incidence of thyroid follicular carcinomas in the control group, further diminishing the significance of the incidence with 2-methylpropene and suggesting that the tumor findings may have been spurious. IARC (1999) published guidance noting that no non-radioactive chemical exposure is known to cause thyroid follicular carcinomas in humans. It concluded that agents causing thyroid neoplasms in rodents by hormonal imbalance must be non-genotoxic. Although studies investigating hormonal imbalance have not been conducted, 2-methylpropene is not genotoxic, indicating if 2-methylpropene did cause an increase in thyroid tumors in male rats, that a non-genotoxic mechanism, likely to have a threshold, is involved and the relevance of tumours of this type to human health is low.

  

There is no data on the carcinogenicity of the butenes in humans. Toxicokinetic data on members of the butenes category (see Toxicokinetics Section), indicate that humans have the lowest capacity for oxidative metabolism and the highest for detoxification pathways.

In conclusion, as no tumours were observed in female rats or male and female mice and the thyroid tumours observed only in male rats were either spurious or of questionable relevance to humans. As all members of the butenes category are not genotoxic, members of the butenes category have a low potential for human carcinogenicity.

 

 

Additional References:

Haseman JK, Hailey JR, Morris and RW (1998). Spontaneous neoplasm incidences in Fischer 344 rats and B6C3F1 mice in two-year carcinogenicity studies: a National Toxicology Program update. Toxicol Pathol, 26, 428-441

 

NTP (1985). NTP Toxicology and Carcinogenesis Studies of Propylene (CAS No. 115-07-1) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). Natl Toxicol Program Tech Rep Ser, 272, :1-146

 

IARC Sci Publ. (1999). Agents that induce epithelial neoplasms of the urinary bladder, renal cortex and thyroid follicular lining in experimental animals and humans: summary of data from IARC monographs volumes 1-69. ;Ed Wilbourn JD, Partensky C, Rice JM. 147,191-209.



Carcinogenicity: via inhalation route (target organ): glandular: thyroids

Justification for classification or non-classification

Members of the butenes category have a low potential for human carcinogenicity and therefore do not warrant classification under Dir 67/548/EEC or GHS/CLP.