Propyloxirane

Carcinogenicity

Justification for classification or non-classification

According to Annex I of the Directive 67/548/EEC, 1,2 -butennoxide is classified as carcinogen category 3 and labeled with R40. According to Annex VI of the Regulation (EC) 1272/2008 (CLP) it is classified as carciongen category 2 and labeled with H341.

Since 1,2 -Butenoxide was used as read-across for n-Pentenoxide-1,2, n-Pentenoxide-1,2 will also be classified as carcinogen category 3 and labeled with R40 (according to the Directive 67/548/EEC), or carciongen category 2 and labeled with H341 (according to Regulation (EC) 1272/2008 (CLP)).

Additional information

Justification for read-across to 1,2 -Butenoxide:

No data evaluating the carcinogenic potential of n-Pentenoxide-1,2 are available. However, a read-across to 1,2-Butenoxide, another member of the epoxide family can be made. The only structural difference between n-Pentenoxid-1,2 and 1,2-Butenoxide is the presence of an additional CH2-group in n-Pentenoxide-1,2. The chemical characteristics between these two substances are quite similar, with 1,2 -Butenoxide being more soluble in water (86.6 g/L vs 23 g/L water solubility), less lipophilic (log Pow=0.68 vs 1.29) and exhibiting a higher vapor pressure (227 hPa vs 70 hPa) as compared with n-Pentenoxide-1,2. It has been shown that the toxicities of epoxides decrease from ethylenoxide to propylenoxide to 1,2 -Butanoxide, suggesting that the toxicity of this reactive group of epoxide chemicals decreases with increasing length of the carbon backbone (Fox et al, 1983; NTP report No 267, 1985). In line with this assumption, the oral LD50 of 1,2-Butenoxide is smaller (900 mg/kg) as compared with n-Pentenoxide-1,2 (1460 mg/kg), further supporting the validity of a read-across from n-Pentenoxide-1,2 to 1,2-Butenoxide, taking into account that this will represent a worst case scenario.

NTP (1988) reported a toxicity and carcinogenity study in male and female rats applying vapor concentrations (whole body exposure) of 200 and 400 ppm 1,2-Butenoxide. The study duration was 103 weeks; the frequency of treatment was 6 hours per day and 5 days per week. With respect to the benign nasal tumours observed in this study, these showed no sign of progression to malignancy and must be seen against the background of extensive non-neoplastic lesions at this dose level (400 ppm). These tumours are likely to be a direct consequence of the irritant properties of 1,2 -Butenoxide leading to stimulation of cell proliferation. It is therefore highly unlikely that these tumours occur at dose levels which do not produce chronic tissue irritation. A small but statistically significant incidence of lung tumours (carcinomas and adenomas combined) was confined to the male rat and to the top dose level of 400 ppm. These tumours occurred late in the study and showed no evidence of metastasis. The increase in malignant lung tumours alone was not statistically significant. It required the combination of benign and malignant tumours to obtain the statistical significance to enable NTP to classify 1,2 -Butenoxide as "clear evidence of carcinogenic activity". Furthermore, one could question whether a practical maximum Tolerated Dose was exceeded in the NTP study in view of the significant upper respiratory tract irritation. NTP categorized the results obtained with female rats as "equivocal evidence of carcinogenic activity", demonstrated by studies that are interpreted as showing a marginal increase of neoplasms that may be chemically related. Two high dose (400 ppm) females developed benign nasal cavity tumours and 1 female developed a benign alveolar/bronchiolar tumour. On the other hand, one female control developed a malignant alveolar/bronciolar tumour. On this basis it is highly questionable as to whether or not the treated females could be considered to "show a marginal increase of neoplasms that may be chemically related".

Male and female mice did not show tumours in any organ at either dose level (50 and 100 ppm) in a 102-week inhalation vapor study (whole body), in which animals were treated for 6 hours per day, 5 days per week (NTP, 1988).

These results show that 1,2 -Butenoxide only possesses a species-specific potential to induce cancer at local sites of contact. The toxicities for epoxydes were described to decrease with increasing carbon backbone chain length (Fox et al, 1983, NTP 1985); hence, classification of n-Pentenoxide-1,2 as cancer category 2 according to Regulation (EC) 1272/2008 (CLP) describes a worst case scenario.