Propene

Endpoint summary

Description of key information

The weight of evidence indicates that the effects in rodents, which unlike man are obligate nasal breathers, superimposed on a high background of spontaneous nasal pathology and with equivocal dose responses, are likely to be of little relevance in extrapolation of risk to humans and considered an inappropriate finding from which to derive a DNEL.  In addition, the concentrations at which the mild rhinitis was reported in lifetime animal experiments are very high compared to the concentrations that humans may be exposed to in practice.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Key information for the assessment of the repeat-dose toxicity of propene has been reported in near-guideline sub-chronic and chronic studies by NTP (NTP, 1985), with additional expert review of kidney (Hard, 2001) and nasal (Harkema, 2002) histopathology findings, and a well-conducted investigative study (Pottenger et al, 2007). A second long-term propene study (Sprague-Dawley rat & Swiss mouse by Ciliberti et al., 1988) has been less fully reported.

In the NTP sub-chronic studies groups of Fischer-344 (F344/N) rats (9-11/sex/group) and B6C3F1 mice (10/sex/group) were exposed by inhalation for 6 hours/day, 5 days/week for 14 weeks to 0, 625, 1,250, 2,500, 5,000, or 10,000 ppm propene in air (NTP, 1985). In both rats and mice no compound-related deaths or clinical signs and no gross or microscopic pathologic effects (including reproductive organs or nasal cavity changes) were observed. The NOAEC for both these studies was 10,000 ppm (17,200 mg/m³).

In the NTP chronic studies groups of F344/N rats (50 of each sex/group) and B6C3F1 mice (50 males and 49-50 females/group) were exposed to propene in air by inhalation at concentrations of 0, 5,000 or 10,000 ppm, 6 hours per day, 5 days per week, for 103 weeks. In rats histopathological examinations revealed an increased incidence of squamous metaplasia at 5,000 and 10,000 ppm and inflammation of the nasal cavities at 10,000 ppm. Expert histopathology review (Harkema, 2002) of archived rat and mouse nasal slides revealed that the morphologic nature of the exposure-induced inflammatory and epithelial lesions is characteristic of the nasal mucosa’s response to low-grade, chronic irritation. The site-specific location of these lesions corresponds to intranasal airflow. Therefore, these mild lesions appear to be air-flow driven and may be due to exposure to a mild inhaled irritant. However it is unusual not to find a dose-response relationship with these types of nasal epithelial alterations (Harkema, 2002). In mice similar effects, but with less epithelial alterations, were reported and consistent with the rat study there was no clear dose-response relationship. In short, the nasal effects were due to mild rhinitis (mild irritation) and were present in rats and mice, with no obvious dose-response relationship in either species (nasal pathology was not assessed in the carcinogenicity study of Ciliberti et al, 1988). The LOAEC (based on effects in the respiratory tract) was 5,000 ppm (8,600 mg/m³) for both rats and mice. The NOAEC for systemic effects was 10,000 ppm (17,200 mg/m³) in rats. [Note: the report of Harkema (2002) was overlooked in the response letter to ECHA of 6 December 2013, but it does not change the overall conclusion on the significance of the findings].

An extensive mode of action study of propene in rats investigated nasal effects and other endpoints (Pottenger et al., 2007). They assessed nasal pathology after exposure of male rats to propene (10,000 ppm, for 4 weeks) and used intranuclear incorporation of bromodeoxyuridine (BrdU) to assess induction of cell proliferation as a potential precursor event.  They reported no exposure-related inflammation (rhinitis) or alterations (e. g., degeneration, necrosis, hyperplasia, metaplasia) in the squamous, transitional, respiratory or olfactory epithelium lining the nasal airways in any of the sections examined from these propene-exposed rats. In addition, there were no apparent exposure-related changes, compared to that of controls, in the density of BrdU-labelling in the four specific nasal epithelial populations studied. They concluded that if the NTP results were indeed due to irritant properties of propene, then those properties must be extremely weak. Indeed these authors suggest other contributory factors, such as dryness of mucous membranes due to chronic inhalation exposure, may be important.

In mice (NTP, 1985) chronic focal inflammation of kidneys was reported at both dose levels and based on this finding the LOAEC for systemic effects was reported to be 5,000 ppm (8,600 mg/m³). Subsequent expert histopathology reviews of relevant archive slides revealed that the kidney effects were not compound-related. The presence of perivascular and cortical infiltrates of lymphoid cells in propene-exposed mice of both sexes was confirmed by this histopathology re-evaluation, but the background of similar change in the control mice was almost as high as for the exposed groups. Propene did not cause exacerbation of spontaneous chronic progressive nephropathy, nor was there any evidence of renal tubule toxicity. In the opinion of this reviewer, the inflammatory change observed in the mouse kidney represents a spontaneous lesion without toxicological significance (Hard, 2001). This report was generally supported by NTP (letter from NTP to Dr Moran, ACC, January, 10, 2002). In consequence, the NOAEC for systemic effects for the mouse study was revised to 10,000 ppm (17,200 mg/m³), the same value determined for rats.

Conclusion

Propene has been thoroughly tested for repeated exposure toxicity up to very high exposure concentrations (10,000 ppm (17,200mg/m³), half of its lower explosive limit value). Overall, only minimal local effects to the nasal cavity (mild rhinitis) were observed and only following chronic lifetime exposure to high doses (in rats and mice). Nasal effects have not been reported in any shorter-term studies, including 28 day and 90 day NTP studies, which could reasonably be expected to identify the same lesions. Indeed, a 4 week investigative study on propene, using sensitive methodology, was unable to even detect any precursor proliferative events (Pottenger et al, 2007). The effects in rats were reported in only one study, while three other studies that would be capable of identifying the same lesion showed no effects. Consequently, the effect of rhinitis as a result of exposure to propene is not a consistent finding (based upon dose response data), and cannot lead to classification.

Similar findings, characteristic of mild rhinitis, were also prevalent in the control animals in the 2-year NTP study and these propene-induced effects have no obvious dose-response relationships, and are superimposed on a high background of spontaneous nasal pathology (Harkema, 2002). It has been suggested that other factors may have contributed to the mild irritation observed, such as dryness of mucous membranes due to chronic inhalation exposure (Pottenger, 2007). Drying of mucous membranes by (very high concentrations of) a gas is not an adverse effect, and the finding of mild rhinitis does not lead to any classification pursuant to the CLP Regulation or DSD.

Justification for classification or non-classification

There is sufficient repeat-dose exposure information for propene to conclude that classification under the DSD or CLP is not warranted.