Propyloxirane

Endpoint summary

Additional information

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

For the determination of the repeated dose toxicity of n-Pentenoxide-1,2, a read-across was performed to 1,2-Butenoxide, another member of the epoxide family. 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) and 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 -Butenoxide, 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, 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.

In a NTP study (1988; internal NTP guidelines), male and female rats were given 0 - 800 ppm 1,2-Butenoxide via inhalation (vapor) for 6 h/d, 5 d/w (65 exposures) over a study period of 13 weeks. The NOEC was found to be 200 ppm (males and females = 0.6 mg/L) and the LOAEC was established to be 400 ppm (both genders). No compound-related deaths occurred. The final mean body weight of rats exposed at 800 ppm was 23% lower than that of the controls for males and 16% lower for females. No compound-related clinical signs were observed. Liver weight to body weight ratios were similar in dosed and control rats. Inflammation of the nasal cavity was seen in all rats that received 1,2 -Butenoxide at 800 ppm but not at lower concentrations. The inflammation was present primarily in the dorsal and lateral portions of the nasal cavity and affected the respiratory and olfactory epithelium. The lesion was characterized by lymphocytic and neutrophilic infiltration of the mucosa and accumulation of purulent exudate in the lumen of the nasal cavity, with focal loss of epithelial cells from the mucosa.

In another NTP study (1988; internal NTP guidelines) male and female mice were given 0 - 800 ppm 1,2 -Butenoxide via inhalation (vapor) for 6 h/d, 5 d/w (65 exposures) over a study period of 13 weeks. The NOEC was found to be 50 ppm (males and females= 0.15 mg/L) and the LOAEC was established to be 100 ppm (both genders). All mice exposed at 800 ppm died before the end of the studies. Final mean body weights were not affected by exposure to 1,2 -Butenoxide. Mice exposed at 800 pprn were listless during and after the first day of exposure; clinical signs were not seen at lower doses. The liver weight to body weight ratio of female mice that received 400 ppm was significantly lower than that of the controls. Renal tubular necrosis was seen in 6/10 males and 8/10 females exposed at 800 ppm but not at lower exposure concentrations. Inflammation of the nasal turbinates was observed in all mice exposed at 200 ppm or higher, in 0/10 males and 7/10 females exposed at 100 ppm, and in none of the controls. Renal and upper respiratory tract changes were considered to be compound related.

Miller et al. (1981) reported an OECD guideline study (413) with a NOEC of 150 ppm for male and female rats (=0.45 mg/L) and a LOEC of 600 ppm for male and female rats. Application route was inhalative (vapor), the concentrations ranged from 75 - 600 ppm, study duration was 90 days. The following findings were reported: The mean body weight gain for female rats in the 600 ppm group was significantly lower than for controls during the last few weeks of study. In addition, the body weight gains of male rats in the 600 ppm group tended to be lower than for controls, although not statistically significantly so. Growth of rats in the 75 and 150 ppm groups was not altered by the exposures. There were several statistically significant changes in absolute or relative organ weights of rats (particularly those in the 600 ppm group) after 30 days or 90 days of exposure which were considered to be reflections of reduced body weight gain or generalized stress, rather than direct toxic effects of the test material. Hematologic analyses for rats sacrificed after 4 weeks revealed no changes of toxicological significance. After 13 weeks, there were no statistically significant differences and no apparent effects on the hematologic parameters of male rats. The mean hemoglobin values of female rats in the 150 ppm group, and the mean red blood cell count of female rats in the 150 ppm group were statistically significantly higher than for controls; these values were within the range of normal for female rats of the same strain and age, and were considered to be sporadic occurrences with no toxicological significance. Clinical chemistry analyses for rats were unremarkable. Urinary parameters of rats were unaltered in rats sacrificed after 4 weeks. The mean urinary specific gravity values of male and female rats in the 600 ppm group were statistically significantly lower than for controls after 13 weeks. However, there were no apparent effects on any other urinary parameters measured, nor any other indications of nephrotoxicity in rats. Gross pathologic observations in rats in the 600 ppm group included decreased amounts of abdominal adipose tissue, and decreased size of the thymus and mediastinal fat. AII other gross pathologic observations in rats were considered spontaneous in nature and unrelated to exposure. There were no treatment-related gross pathologic observations in rats in the 75 or 150 ppm groups. Histopathological examinations of tissues from rats after 13 weeks of exposure to 600 ppm revealed changes in the nasal mucosa which were attributed to primary upper respiratory irritation. The microscopic changes in the nasal turbinates were minimal and were characterized by flattening of the oIfactory and respiratory epithelium with some focal thickening f the respiratory epithelium. In addition, increased numbers of inflammatory cells were present in the nasal mucosa and within the lumen of the nasal cavity. Lower portions of the respiratory tract (e.g., trachea and lungs) were apparently unaffected by exposure to 1,2 -Butenoxide vapors, although there were some observations in the lungs and trachea of a few treated female rats which were considered spontaneous in nature and unrelated to exposure. There were several microscopic changes in rats exposed to 600 ppm which were considered to be indirect effects of exposure to the test material, including decreased hepatocellular size, decreased cell content in the cortex of the thymus gland, and myeloid hyperplasia in vertebral bone marrow (3 of 10 male rats only). All other microscopic observations in rats were considered to be spontaneous in nature and unrelated to exposure. Notably, there were no microscopic changes suggesting nephrotoxicity which would be correlated with the specific gravity changes of urine in rats exposed to 600 ppm. There were no microscopic observations in either male or female rats in the 75 and 150 ppm groups which were considered to be related to exposure to 1,2 -Butenoxide. Since only minor pathologic treatment-related effects were detected microscopically after 13 weeks of exposure, microscopic examinations were not performed on tissues from rats sacrificed after 4-weeks of exposure.

The same author (1981) reported an OECD guideline study (413) with a NOEC of 150 ppm for male and female mice (=0.45 mg/L) and a LOEC of 600 ppm for male and female mice. Application route was inhalative (vapor), the concentrations ranged from 75 - 600 ppm, study duration was 90 days. The following findings were reported: One male mouse in the 150 ppm group died spontaneously during the course of the study. Gross pathologic examination of this animal indicated that it probably died as a result of a urethral obstruction unrelated to exposure. All other mice survived and appeared normal and healthy throughout the study. The mean body weight gain for female mice in the 600 ppm group was significantly lower than for controls during the last few weeks of study. In addition, the body weight gains of male mice in the 600 ppm group tended to be lower than for controls, although not statistically significantly so. Growth of mice in the 75 and 150 ppm groups was not altered by the exposures. The mean body weight gain values of male mice in the 75 ppm group were statistically lower than controls on several occasions, but this was not considered to be an adverse treatment-related effect due to the absence of similar changes for male mice in the 150 ppm group. There were several statistically significant changes in absolute or relative organ weights of mice (particularly those in the 600 ppm group) after 30 days or 90 days of exposure which were considered to be reflections of reduced body weight gain or generalized stress, rather than direct toxic effects of the test material.

Hematologic analyses for mice sacrificed after 4 weeks revealed no changes of toxicological significance. There were a variety of statistically significant differences for hematologic parameters of mice after 13 weeks. For males, the mean white blood cell counts of animals in the 150 and 600 ppm groups were statistically higher than for controls. However, the mean white blood cell counts of treatment groups of male mice were within the range of normal values for animals of the same strain and age, and there was no dose-response relationship. Therefore, the statistical differences for white blood cell counts in male mice were thought to be reflections of normal biological variability. The white blood cell counts for treatment groups of female mice, on the other hand, were statistically lower than for controls. However, in this case, the mean white blood cell count for the female mice in the concurrent control group was higher than for historical control groups while the mean white cell counts for treatment groups were well within the range of historical control values. Therefore the statistical differences for white blood cell counts of female mice were considered to be unrelated to exposure, and of no toxicological significance. The mean packed cell volume, mean red blood cell count, and mean hemoglobin concentration of female mice in the 150 and 600 ppm groups were also statistically lower than for controls. However, none of the hematologic parameters were analytically altered, with only the mean packed cell volume and mean hemoglobin values of 600 ppm female mice being slightly lower than the range of historical control values. In addition, there was no clear dose-response relationship, since the mean values in the two treatment groups were very similar. Moreover, there was no microscopic evidence of bone marrow toxicity in mice. Hence, the statistical differences for hematologic parameters of male mice are probably of minimal, if any, toxicogic significance. Clinical chemistry analyses for mice were unremarkable. However, there were no apparent effects on any other urinary parameters measured, nor any other indications of nephrotoxicity in mice. Gross pathologic observations in mice in the 600 ppm group included decreased amounts of abdominal adipose tissue, and decreased size of the thymus and mediastinal fat. All other gross pathologic observations in mice were considered spontaneous in nature and unrelated to exposure. There were no treatment-related gross pathologic observations in mice in the 75 or 150 ppm groups. Histopathological examinations of tissues from mice after 13-weeks of exposure also revealed changes only in the nasal mucosa of animals exposed to 600 ppm which were considered to be direct effects of exposure to the test material. The microscopic changes in the nasal turbinates were characterized by a minimal degree of focal thickening and flattening of the respiratory epithelium. There were increased numbers of inflammatory cells present in the nasal mucosa and within the lumen of the nasal cavity; no treatment-related changes were noted in the lungs or trachea of mice. Also, there were several other microscopic changes in mice exposed to 600 ppm which were considered to be indirect effects of exposure to the test material including decreased hepatocellular size and decreased cell content in the cortex of the thymus gland. All other microscopic observations in mice were considered to be spontaneous in nature and unrelated to exposure. There were no microscopic observations in either male or female mice in the 75 and 150 ppm exposure groups which were considered to be related to exposure to the test material. Since only minor treatment-related effects were detected microscopically after 1 3-weeks of exposure, microscopic examinations were not performed on tissues from mice sacrificed after 4 weeks of exposure.

Justification for classification or non-classification

Based on the results obtained from the repeated dose study with 1,2 -Butenoxide, no classifcation and labelling is required for n-Pentenoxide-1,2 for which a read-across to 1,2 -Butenoxid can be made due to structural similarities (according to Directive 67/548/EEC (DSD) and to Regulation /EC) No 1272/2008 (CLP))