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Carcinogenicity

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Description of key information

There are no specific studies on the streams in the C4 low 1,3-butadiene category (CAS Numbers; 91052-98-1, 92045-23-3, 95465-89-7, 95465-90-0 and 95465-91-1) but data on one of the component substances (2-methylpropene) indicate that members of this category have low potential for human carcinogenicity. Carcinogenicity studies carried out on 2-methylpropene in rats and mice 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 component substances in this 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

There are no carcinogenicity data on the streams in the C4 low 1,3-butadiene category (CAS Numbers; 91052-98-1, 92045-23-3, 95465-89-7, 95465-90-0 and 95465-91-1) but data are available on one of the component substances; 2-methylpropene (butene isomer). There are no data available on the other component substances (butane or isobutane). The members of this category are not mutagenic (see Section on Mutagenicity) and the carcinogenic potential of the component substances is low. Based on the data available, the members of this category have low potential for human carcinogenicity and therefore do notwarrant classificationunder Dir 1999/45/EC or GHS/CLP.

 

Specific data are as follows:

 

Butene isomers (butenes): Carcinogenicity studies via inhalation exposure are available for 2-methylpropene. 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).

 

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 component substances 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.

 

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

There are sufficient data available on component substances to conclude that streams within the C4 low 1,3-butadiene category have a low potential for human carcinogenicity and therefore do not warrant classification under Dir 1999/45/EC or GHS/CLP. The mammalian toxicity effects of this category will be not driven by the content of 1,3-butadiene as this is less than 0.1% w/w for all category members and therefore exempt from classification/hazard assessment based on this substance.