Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.4 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
170 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

According to the REACH “Guidance on information requirements and chemical safety assessment”, a leading DN(M)EL needs to be derived for every relevant human population and every relevant route, duration and frequency of exposure, if feasible.

 

1.Acute toxicity

Propylene oxide is labelled for acute toxicity as toxic by inhalation and in contact with skin and harmful if swallowed.A DNELacuteshould be established for substances if an acute hazard toxicity (leading to Classification and Labelling) has been identifiedanda potential for high peak exposures exists.

An assessment of acute toxicity and derivation of safe exposure levels is available for propylene oxide. Under the authority of the United States Federal Advisory Committee Act (FACA) P. L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances (NAC/AEGL Committee) has developed interim Acute Exposure Guideline Levels (AEGLs) for propylene oxide. AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes to 8 hours. Three levels, AEGL-1, AEGL-2 and AEGL-3, are developed for each of five exposure periods (10 and 30 minutes, 1 hour, 4 hours, and 8 hours) and are distinguished by varying degrees of severity of toxic effects. The three AEGLs are defined as follows. AEGL-1 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic, non-sensory effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure. AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including susceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects or an impaired ability to escape. AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including susceptible individuals, could experience life-threatening health effects or death.

For propylene oxide,Interim AEGLs have been established following review and consideration by the NAC/AEGL of public comments. Interim AEGLs are available for use by organizations while awaiting NRC/NAS peer review and publication of Final AEGLs. 

 The derived AEGL values for Propylene Oxide are listed in the following table.

Summary of Proposed AEGL Values for Propylene Oxide [ppm (mg/m3)]

 

Classification

10-min

 30-min

      1-hr

     4-hr

     8-hr

      Endpoint (Reference)

AEGL-1

(Nondisabling)

73 [170]

73 [170]

73 [170]

73 [170]

73 [170]

Humans: Strong odor and

irritation noted in

monitoring study; average of

4 exposure concentrations

and durations:

380 ppm for 177 minutes,

525 ppm for 121 minutes,

392 ppm for 135 minutes,

460 ppm for 116 minutes

(CMA, 1998)

AEGL-2

(Disabling)

440 [1000]

440 [1000]

290 [690]

130 [310]

86 [200]

Dyspnea in mice at 387 ppm

for 4 hours (NTP, 1985)

AEGL-3

(Lethality)

1300

[3100]

1300

[3100]

870 [2100]

390 [930]

260 [620]

Calculated 4-hour BMCL05

of 1161 ppm in rats (NTP,

1985)

For AEGL-1, values are based on a workplace survey which measured propylene oxide exposure concentrations of 380 ppm for 177 minutes, 525 ppm for 121 minutes, 392 ppm for 135 minutes, and 460 ppm for 116 minutes in the breathing zone of three workers during drumming operations (CMA, 1998). Strong odor and irritation were noted in the survey. The exact nature of the irritation was not provided, but occasional eye irritation was noted as the reason for the monitoring program. Because the effects were considered mild irritation, the AEGL values were set equal across time. Therefore, the four exposure concentrations were averaged together, resulting in a point of departure of 440 ppm. A total uncertainty factor and modifying factor of 6 was applied. An interspecies uncertainty factor was not needed, since the data were from human exposures. An intraspecies uncertainty factor of 3 was applied because irritation is a point of contact effect and is not expected to vary greatly among individuals. A modifying factor of 2 was applied because the defined effects are above an AEGL-1 (undefined irritation) but below an AEGL-2 endpoint. 

The AEGL-2 values are based on animal data, specifically dyspnea in mice was the most sensitive endpoint consistent with the AEGL-2 definition, and mice were the most sensitive to the toxic effects of propylene oxide vapor. The AEGL-2 values are based on data from the NTP (1985) study in which mice exposed to 387 ppm for 4 hours exhibited dyspnea. Although a no-effect-level was not established for dyspnea at this concentration, no other adverse effects were noted. In addition, when compared to other studies investigatingpropylene oxidetoxicity in mice, the NTP study reported toxic effects occurring at much lower concentrations than those observed in other studies. An interspecies uncertainty factor of 1 was applied because mice are the most sensitive laboratory species in terms of the lethal effects ofpropylene oxideclinical signs of toxicity, and available data indicate that mice are equally or slightly more sensitive than humans in the manifestation of clinical signs. An intraspecies uncertainty factor of 3 was applied because the mechanism of irritation is a point of contact effect and is not expected to vary greatly among individuals. Therefore, a total uncertainty factor of 3 was applied. Although the mechanism of action appears to be a direct irritant effect, it was deemed not appropriate to set the values equal across time because the irritation was no longer considered mild, but part of the continuum of respiratory tract irritation leading to lethality. The experimentally derived exposure value was therefore scaled to AEGL time frames using the concentration-time relationship given by the equationCnx t = k, whereC= concentration,t= time,kis a constant, andnwas 1.7 as calculated using the rat lethality data reported by Rowe et al. (1956) (ten Berge et al., 1986). The 10-minute value was set equal to the 30-minute value because of the uncertainty in extrapolating from the exposure duration of 4 hours to 10 minutes.

The AEGL-3 derivation was based on the calculated 4-hour BMCL05 of 1161 ppm, the lowest BMCL05 value in rats (NTP, 1985). Lethality data in the dog, a non-obligate nose breather, support the use of the BMCL05 value in the rat, but the dog values should not be used as the basis for the AEGL-3 derivation because 2 of 3 animals in the high-dose group were dead before removal from the exposure chamber. Mouse data were not used because the mouse is overly sensitive topropylene oxidecompared to the other species tested. The BMCL05 values in mice are 282 and 673 ppm (Jacobson et al., 1956; NTP, 1985), compared to 1161-3328 ppm in rats (NTP, 1985; Jacobson et al., 1956; and Shell Research Ltd., 1977) and 1117 ppm in dogs (Jacobson et al., 1956). Other data demonstrating that the mouse BMCL05 values are unreasonably low include the studies in which only minimal effects were noted in monkeys exposed to 300 ppm for 6 hours/day, 5 days/week for 2 years (Sprinz et al., 1982; Setzer et al., 1997; Lynch et al., 1984b) or to 457 ppm for 7 hours/day for 154 days (Rowe et al., 1956); and the highest documented human exposure of 1520 ppm for 171 minutes which caused irritation that was not severe enough to cause the worker to cease working (CMA, 1998). These data all support the 4-hour BMCL05 of 1161 ppm in rats as a reasonable point of departure. An intraspecies uncertainty factor of 3 was applied because the mechanism of toxicity, irritation, is a point of contact effect and is not expected to vary greatly among individuals. An interspecies uncertainty factor of 1 was applied because of the supporting data in dogs (similar 4-hour BMCL05) and monkeys (2-year studies which produced minimal effects). The 4-hour AEGL-3 value using a total uncertainty factor of 3 is 387 ppm, which is conservative when compared to the 300 ppm or 457 ppm chronic exposure in monkeys producing minimal effects. Therefore, a total uncertainty factor of 3 was considered reasonable. As for the AEGL-2 derivation, the point of departure for the AEGL-3 derivation was scaled to AEGL time frames using the concentration-time relationship given by the equationCnx t = k, whereC= concentration,t= time,kis a constant, andnwas 1.7 as calculated using the rat lethality data reported by Rowe et al. (1956) (ten Berge et al., 1986). The value was extrapolated across time because the irritation is no longer considered mild, but rather the concentration represents the threshold for lethality. The 10-minute value was set equal to the 30-minute value because of the uncertainty in extrapolating from the exposure duration of 4 hours to 10 minutes.

For the purposes of the propylene oxide acute DNELs, it is proposed that for both workers and the general population that the AEGL-1 value be used for Acute-inhalation, local effects. The value was based on worker data and hence is relevant to workers but was derived to be protective of acute exposures to the general population and hence this value can be applied to both workers and the general population. An acute-inhalation, systemic effects DNEL could be similarly derived from the propylene oxide AEGLs and the AEGL-2 values would be an appropriate basis but as these values are higher than the local effects based acute DNEL, separate acute DNELs for systemic effects were not derived.

 

Worker DNEL Acute-inhalation, local effects (15 minutes to 8 hours) – 170 mg/m3

General Population DNEL Acute-inhalation, local effects (15 minutes to 8 hours) – 170 mg/m3

 

2.Irritation

Propylene oxide is classified as irritating to eyes and the respiratory system( Eye Irrit 2, STOT SE3 – respiratory tract).The available data do not allow a quantitative approach. According to the REACH guidance on information requirements and chemical safety assessment, Part E: Risk Characterisation, a qualitative risk characterisation should be performed for this endpoint. In order to guarantee ‘adequate control of risks’, it is necessary to stipulate risk management measures that prevent eye and respiratory system irritation.

 

3.Mutagenicity and carcinogenicity

Propylene oxide is classified as Carc. Cat. 2 (May cause cancer) and Muta. Cat. 2 (May cause heritable genetic damage).

Investigations into the mode of action of rodent nasal carcinogenesis due to propylene oxide inhalation point to decisive contributions of several factors besides genotoxicity. Upon propylene oxide inhalation, glutathione depletion is most marked in nasal respiratory mucosa, where a level of only 43% of control was observed following a single exposure of rats to 50 ppm for 6 h. At inhalation of 5 ppm the glutathione level at this site was maintained at 90% (Lee et al., 2005). This is important, because glutathione has an important scavenging function in the detoxification of propylene oxide. For cytotoxic and proliferative changes in the nasal epithelium Eldridge et al. (1995) determined a NOAEL of 50 ppm in a 4-week study in rats. Similarly, Kuper et al. (1988) found focal hyperplasia of the nasal turbinates and degenerative changes and proliferative hyperplasia of the nasal epithelium, particularly at the highest concentration tested (300 ppm propylene oxide). At 30 ppm these responses were rated “slight” and of low incidence, and were only identified in the 28-month treatment group, compared to the greater incidence of moderate effects at 100 ppm (TNO, 1984, Kuper et al., 1988). This study therefore points to a NOAEL of 30 ppm for 24 months of inhalation exposure (LOAEL of 30 ppm for 28 months).

Propylene oxide, when administered by oral gavage to rats, produced tumors of the forestomach, which were mainly squamous-cell carcinomas. In mice exposed by inhalation, propylene oxide produced haemangiomas and haemangiosarcomas of the nasal cavity and a few malignant nasal epithelial tumors, although it is probable the maximum tolerated dose was exceeded in this study. In a study in rats of each sex exposed by inhalation, papillary adenomas of the nasal cavity were observed in males and females and thyroid adenomas and carcinomas were found in females but were considered not treatment-related; in the second study, males only, papillary adenomas of the nasal cavity and an increased incidence of adrenal phaeochromocytomas were observed, but were not dose-related; in the third study, in females, increased incidences of mammary fibroadenomas and adenocarcinomas were observed, but incidences were within historical control values. Subcutaneous administration of propylene oxide to mice produced local sarcomas; the study in rats was inadequate for evaluation. Thus, propylene oxide induces tumors in rodents, although only at high concentrations and mainly confined to the portals of entry; all systemic tumors were considered by the authors to be not treatment-related.

The primary aspect to be considered in deriving safe exposure levels for propylene oxide is its local carcinogenicity with the nasal epithelium as primary target, which is well established experimentally in rats and mice. There are no reports of carcinogenicity of propylene oxide from studies in humans.

Althoughpropylene oxidewas not shown to be a hereditary mutagen in standard assays for such effects (e.g., dominant lethal test in mice) at oral doses as high as 250 mg/kg/d for 14 days and inhalation doses as high as 300 ppm for 5 days, it is classified as a germ cell mutagen based on evidence of mutagenicity to somatic cells and that the wide tissue distribution ofpropylene oxideexposure results in DNA adducts in the testis. However, mutagenicity to somatic cells was only demonstrated under extreme exposure conditions that are not relevant to human exposure patterns (i.e., intraperitoneal injection).Propylene oxideis not mutagenic to somatic cells under conditions that are relevant to human use and exposure (up to 400 ppm over 4 weeks inhalation in rats; up to 300 ppm over 2 years inhalation in primates) or by the oral route. DNA adducts (N7-hydroxypropylguanine), which were identified in whole testis homogenate only and not specifically in the germs cells, represent a marker of exposure, not of effect, and are not suitable for the identification of the point of departure. Accordingly, a NOAEC cannot be reliably defined, and thus it is proposed not to derive a DMEL for this endpoint.

 

4.Long term toxicity

Worker DNELs

 

Long-term DNEL – inhalation local 

The European Parliament and the Council of the European Union has established for propylene oxide an 8-h limit value for occupational exposure of 1 ppm (2.4 mg/m3)(Directive (EU) 2017/2398 OF THE European Parliament and of the Council of 12 December 2017, Official Journal of the European Union 12.27.2017). This value is used in place of developing a DNEL.

 

.

Worker DNEL Long term-inhalation, local effects – 2.4 mg/m3

 

Long-term DNEL – dermal local 

As the long term DNEL for inhalation exposure is based on local effects, this value cannot be used to arrive at a long-term value for the dermal route (by route to route extrapolation).

No dermal exposure studies were available, only studies in which propylene oxide was injected intradermally. Subcutaneous administration of propylene oxide to mice produced local sarcomas; the study in rats was inadequate for evaluation. When administered by oral gavage to rats propylene oxide produced tumors of the forestomach, which were mainly squamous-cell carcinomas. And as described above, the primary local target in rats and mice for propylene oxide is the nasal epithelium in which tumors were found.

Propylene oxide induces tumors in rodents, although only at high concentrations and mainly confined to the portals of entry. Therefore, it cannot be excluded that the local effectsviathe dermal route would be the most critical effect, which could represent a cause for concern for human health and must be properly controlled. However, given its volatility, exposureviadermal route is a less likely worker exposure scenario.

Therefore, a qualitative risk characterisation should be performed for this endpoint. In order to guarantee ‘adequate control of risks’, it is necessary to stipulate risk management measures that indicate that exposure to propylene oxide is stringently controlled.

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.6 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
170 mg/m³
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
Explanation for the modification of the dose descriptor starting point:

Use by the general population restricted by Directive 76/769/EEC

Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

General population DNELs

Long-term inhalation DNEL

 

Regarding long-term exposure, the European Parliament and the Council of the European Union has established an 8-h limit value for occupational exposure of 1 ppm (2.4 mg/m3)(Directive (EU) 2017/2398 OF THE European Parliament and of the Council of 12 December 2017, Official Journal of the European Union 12.27.2017). The limit value is derived for workers. To arrive at a long-term value for the general population, a factor for exposure modification and intraspecies differences (ECHA Guidance, Chapter R.8, 2012) will be applied to the 8-h limit value:

1 ppm (2.4 mg/m3) * 10/20 (a) * 5/10 (b) = 0.25 ppm (0.6 mg/m3)

(a) modification based on differences in exposure duration and activity (10 m3 in 8 h for workers, 20 m3 in 24 h for the general population)

(b) correction for intraspecies differences: workers default factor: 5, general population default factor: 10

Note: Using the overall repeated exposure inhalation NOAEC of 30 ppm (70 mg/m3) as starting point for the DNEL derivation and applying a factor of 6/24 (exposure duration adjustment) and the ECHA assessment factors for interspecies (2.5), intraspecies (10) results in DNEL of 0.3 ppm (0.7 mg/m3). The DNEL derived from the EU 8-h limit value for occupational exposure is more conservative and hence selected for the risk characterisation.

 

General Population DNEL Long term-inhalation, local effects – 0.6 mg/m3

Long-term DNEL – dermal local 

As the long term DNEL for inhalation exposure is based on local effects, this value cannot be used to arrive at a long-term value for the dermal route (by route to route extrapolation).

No dermal exposure studies were available, only studies in which propylene oxide was injected intradermally. Subcutaneous administration of propylene oxide to mice produced local sarcomas; the study in rats was inadequate for evaluation. When administered by oral gavage to rats propylene oxide produced tumors of the forestomach, which were mainly squamous-cell carcinomas. And as described above, the primary local target in rats and mice for propylene oxide is the nasal epithelium in which tumors were found.

Propylene oxide induces tumors in rodents, although only at high concentrations and mainly confined to the portals of entry. Therefore, it cannot be excluded that the local effectsviathe dermal route would be the most critical effect, which could represent a cause for concern for human health and must be properly controlled. However, given its volatility, exposureviadermal route is a less likely general population exposure scenario.