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Several long-term studies have been conducted for this substance and the only consistent, toxicologically significant, non-neoplastic findings are localized to the site of application.   In rodent chronic inhalation bioassays, propylene oxide vapor produced upper respiratory tract clinical signs (e.g. dyspnea, gasping, rhinitis) and lesions (e.g. nasal cavity edema and inflammation, degeneration and necrosis of nasal cavity mucosal epithelium, squamous metaplasia and hyperplasia of the respiratory epithelium of the nasal mucosa and epithelium of the mucosal glands). In a chronic oral study conducted in the rat, the principal non-neoplastic findings associated with gavage dosages were reactive changes (epithelial hyperplasia) in the squamous epithelium of the forestomach.

Key value for chemical safety assessment

Additional information

Only limited repeated exposure experience is reported for propylene oxide exposure in human. A study of a group of German workers exposed to a mixture of alkene oxides, including propylene oxide, with an average of nearly 11 years of exposure to low concentrations of propylene oxide, reportedly did not exhibit clinical abnormalities (Stocker and Thiess, 1979).

Several long term animal studies have been conducted for propylene oxide and the only consistent toxicologically significant non-neoplastic findings are localized to the site of contact.

One repeated exposure chronic study is reported for rats by the oral route of exposure. Dunkelberg (1982) administered 0, 15 or 60 mg/kg bwt propylene oxide by gavage, twice weekly, to groups of 50 female Sprague-Dawley rats for 150 weeks and found a dose-related increased incidence of non-neoplastic effects in the forestomach but no evidence of toxicity in other distal sites.

As part of a large comprehensive and well-conducted investigation of propylene oxide, carried out for the U.S.National Toxicology Program (National Toxicology Program, 1985), results were reported from three repeated exposure studies, all conducted in F344/N rats and B6C3F1 mice. These data are supported and supplemented by several 4-wk and 90-d inhalation exposure studies investigating specific aspects of the mode of action of propylene oxide toxicity. Key observations for repeat dose toxicity include the following:

Ø      nasal effects of inflammatory response in respiratory epithelium of upper airway of rodents

o       hyperplasia and goblet cell hypertrophy with NOAEC values of 30 ppm for chronic (24-month) inhalation exposures, and 50-150 ppm for 4-wk exposures;

o       target nasal cell proliferation induction triggered by severe, sustained glutathione (GSH) depletion, with NOAEC values of 200 and 400 ppm propylene oxide for 4-wk exposures to rats and mice, respectively;

Ø      statistically significant decreased survival in mice exposed to high levels of propylene oxide: chronic NOAEC value of 200 ppm; survival in rats unaffected

Ø      body weight loss and body weight gain depression, for repeated high dose exposures: chronic 2-yr and 90-d NOAEC values of 200 and 250 ppm propylene oxide, respectively;

In a 90-days study (National Toxicology Program, 1985), conducted to determine the concentrations to be used in a subsequent 2-year study, groups of rats and mice (10 per sex per group) were exposed to air containing propylene oxide at concentrations of 0, 31, 63, 125, 250, or 500 ppm (0, 73, 149, 296, 593 or 1,185 mg/m3) for 6 hours/day, 5 days/week, for 13 weeks. No treatment-related deaths occurred. The final mean body weight was depressed in animals receiving 1,185 mg/m3(500 ppm) compared to controls (rats by approx. 6%, mice by approx. 14%). No gross or microscopic pathological effects, including nasal turbinates or treatment-related mortality were noted. Based on the effect on body weight, exposure concentrations of 200 ppm and 400 ppm were selected for the 2-year study, 400 ppm being considered by the NTP to be the maximum tolerated dose.

In the 2-year study (National Toxicology Program, 1985) groups of 50 of each species and sex were exposed whole-body to 0, 200 or 400 ppm (0, 474 or 948 mg/m3) for 6 hours/day, 5 days/week, for 24 months. Routine observations included clinical signs of toxicity, bodyweight, macroscopic and microscopic pathology. In mice and rats exposed to 400 ppm, mean body weight gain was reduced, compared to controls, and other treatment-related effects were noted as well, as discussed below. Therefore, a LOAEC was derived only and set at 200 ppm for rats and mice.

In rats, the mean terminal body weight was slightly affected (8-9% depressed) at 400 ppm, and there was no effect on survival. The primary target tissue was the respiratory epithelium of the nasal turbinates in which the following effects were noted: increase in suppurative inflammation of the nasal cavity (males: 7/50, 19/50 and 33/50: females 3/50, 5/50 and 20/50), increase in epithelial hyperplasia (males: 0/50, 1/50, and 11/50; females 0/50, 0/48 and 5/48) and squamous metaplasia (males:1/50, 3/50, 21/50; females 1/50, 2/48 and 11/48).

Survival of exposed male and female mice decreased relative to that of the controls (male: control, 42/50; low dose, 34/50; high dose, 29/50; female: 38/50; 29/50; 10/50), but the difference was significant only for animals in the high dose groups. High dose female mice had a mean terminal body weight 10% below that of the controls; high dose male mice had a terminal body weight 22% below that of the controls.

The respiratory epithelium of the nasal turbinates was also one of the primary tissues affected in male and female mice; exposure-related increases occurred in the incidences of inflammation, and squamous metaplasia was observed in one low dose male and two high dose female mice. Hyperplasia and metaplasia sporadically observed at 400 ppm was more pronounced in the anterior part of the nasal cavity. Chronic inflammation of the nasal cavity was reported (males: 1/50, 13/50, and 38/50; females 0/50, 13/50 and 17/50).

In another range finding study for a subsequent carcinogenicity study, rats of both sexes were exposed whole-body to concentrations of 0, 75, 150, 300 or 600 ppm (0, 178, 356, 711 or 1,422 mg/m3) propylene oxide vapour for 6 hours/day, 5 days/week, for 13 weeks (TNO, 1981). Routine observations included clinical signs of toxicity, food intake, body weight, and macroscopic- and microscopic pathology. Body weight gain was reduced at 300 and 600 ppm. Degenerative and hyperplastic epithelial changes in the nasal passages were observed in both sexes at the highest dose (600 ppm). No effects were observed at 150 ppm (356 mg/m3) in this range-finding study.

In the subsequent carcinogenicity study, groups of 100 male and 100 female rats were exposed, whole-body, to propylene oxide vapour at 0, 30, 100 or 300 ppm (0, 71, 237 or 711 mg/m3) for 6 hours/day, 5 days/week, for 123-124 weeks (TNO, 1984; Kuper et al., 1988). No adverse effect of treatment was observed on behaviour, food consumption, serum biochemistry, urinalysis or haematology, compared to controls.

Mortality was increased in both sexes at 300 ppm (55/100 males and 55/100 females) compared to controls (32/100 males and 30/100 females) and a similar tendency appeared for females at 100 ppm (43/100) associated with the occurrence of mostly benign mammary gland tumors.

The following nasal effects were reported ( TNO, 1984; Kuper et al., 1988):

·   300 ppm: moderate atrophy of the olphactory epithelium accompanied by a thickened sub-mucosa (and moderate to marked basal-cell hyperplasia at 28 months only).

·   100 ppm: slight basal cell hyperplasia of the olfactory epithelium at 28 months (females) and slight nest-like infolds of the respiratory epithelium

·   30 ppm: chronic, 24-month NOAEC for nasal effects of slight nest-like infolds of the respiratory epithelium only, reported at 28 months only

·   Hyperplasia was noted at 300 ppm, increased incidence of degenerative changes (slight to moderate “nest”- like infolds) of the nasal mucosa was observed in all exposed groups.

Lynch et al.(1984a) conducted a long-term inhalation study in which groups of 80 male rats were exposed, whole-body, to 0, 100 or 300 ppm propylene oxide vapour for 7 hours/day, 5 days/week, for 24 months. Body weight gain in both exposure groups was significantly reduced compared to controls. However, from about 16 months, all rats in this study were affected byMycoplasma pulmonisinfection. This condition, alone or in combination with exposure to propylene oxide, affected survival of exposed rats and influenced the development of proliferative lesions in the nasal mucosa. No treatment-related changes in clinical chemistry or urinalysis were seen.

In rats and mice, repeated inhalation exposure to propylene oxide for two years produces chronic irritation and inflammatory response of the nasal epithelium, with such effects being only marginal in nature at 30 ppm and only at 28 months. However, concentrations of 100 ppm and above produce pronounced epithelial damage.

The derived LOAECs were not used in the derivation of the DNEL, as documents on occupational exposure limits (OELs) together with the recently clarified mode of action (Sweeney et al. 2009) were available. The primary aspect considered in deriving an OEL for propylene oxide is its local carcinogenicity with the nasal epithelium as primary target, which is well established experimentally in rats and mice. There is no evidence for carcinogenicity of propylene oxide from studies in humans. Because there is a well-established mode of action for the local carcinogenicity that demonstrates a practical threshold (Sweeney et al.,2009), a DNEL rather than a DMEL is supportable for propylene oxide. Based on the threshold mode of action, exposures to propylene oxide at levels that do not induce severe, sustained GSH depletion in target nasal respiratory epithelium will not lead to initiation of the required key event, induction of cell proliferation in nasal target tissue.

Justification for classification or non-classification

According Annex VI of EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 - 9th ATP 19 July 2016, classification and labelling is not needed for repeated dose toxicity