Registration Dossier

Administrative data

Description of key information

Monopropylene glycol was found to be non-irritating to rabbit skin in an OECD Guideline 404 compliant study. Only minor signs of skin irritation were reported in studies with human volunteers, involving 24- and 48-hr patch testing at both occlusive and semi-occlusive conditions and 14-day cumulative exposure test. The eye irritation study with rabbits, performed according to OECD Guideline 405, gave negative results. Overall, monopropylene glycol is considered to be non-irritating to skin and eyes.

Monopropylene glycol has been evaluated for respiratory irritation in a number of animal and human studies. Although some minor respiratory findings were reported in some of the studies, these changes do not support that monopropylene glycol is a respiratory irritant.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study, available as unpublished report, minor restrictions in design and reporting, but otherwise adequate for assessment.
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
occlusive application
GLP compliance:
not specified
Species:
rabbit
Strain:
other: Kleine weiße Russen
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Fa. Dr. Karl Thomae GmbH, Biberach
- Weight at study initiation: 2.3-2.7 kg
- Diet (e.g. ad libitum): K4 Alleindiät für Kaninchen, Ssniff Spezialfutter GmbH, ad libitum
- Water: e.g. ad libitum
- Acclimation period: 14 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 +/- 1
- Humidity (%): 60 +/- 5
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 / 12

Type of coverage:
occlusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Amount / concentration applied:
0.5 ml
Duration of treatment / exposure:
4 hours
Observation period:
72 hours
Number of animals:
6
Details on study design:
TEST SITE
- Area of exposure: ca. 6 cm2


REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes, with distilled water
- Time after start of exposure: 4 hours


SCORING SYSTEM: according to OECD Guideline 404
Irritation parameter:
edema score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Reversibility:
other: No irritation effects seen during the study
Remarks on result:
no indication of irritation
Irritation parameter:
erythema score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Reversibility:
other: No irritation effects seen during the study
Remarks on result:
no indication of irritation
Irritation parameter:
primary dermal irritation index (PDII)
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
8
Irritant / corrosive response data:
No skin reactions were present in any of the six animals at 1hr, 24hr, 48hr and 72hr following removal of the patch.
Interpretation of results:
not irritating
Remarks:
Migrated information
Conclusions:
CL-Freetext:
Not irritating to rabbit skin
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study, published in peer-reviewed literature, very limited reporting, but acceptable for assessment.
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
GLP compliance:
not specified
Species:
rabbit
Strain:
New Zealand White
Vehicle:
unchanged (no vehicle)
Controls:
not specified
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 100 µl
Duration of treatment / exposure:
Single instillation
Observation period (in vivo):
96 hours
Number of animals or in vitro replicates:
6
Details on study design:
SCORING SYSTEM: Draize


TOOL USED TO ASSESS SCORE: fluorescein
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Score:
0.1
Max. score:
2
Reversibility:
fully reversible within: 48 hr
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
24/48/72 h
Score:
0.4
Max. score:
3
Reversibility:
fully reversible within: 96 hr
Irritation parameter:
chemosis score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Additional information

One skin irritation study with rabbits, performed according to OECD Guideline 404 (Hüls, 1984), but using occlusive conditions, was available for assessment. 0.6 ml of the test material was applied to shaved backs of six rabbits under occlusive dressing for 4 hours. No skin reactions were present in any of the six animals at 1hr, 24hr, 48hr and 72 hr following the removal of the patch. 

In addition, three studies with human volunteers, in which patients with suspected allergic contact eczema were patch tested with aqueous solution of monopropylene glycol, were available for assessment. In the study with 33 human volunteers (30 females and 3 males) of Hill Top Research, Inc., 1995, a 24-h semi-occluded patch test was conducted to compare the skin irritancy potential of several test articles, including monopropylene glycol. Negative controls of distilled water and mineral oil USP and a positive control of 0.5% sodium lauryl sulfate were also tested. Under the conditions of the study, monopropylene glycol exhibited mild irritation compared to that of the positive control, with thirteen subjects exhibiting mild to moderate erythema at the 30 min evaluation. Three of these subjects responses were resolved by the 24-hour evaluation. The ten remaining subjects exhibited mild erythema (which is similar to a Draize score of 1) and four subjects exhibited mild erythema and peeling at the 24-hour evaluation evaluation (which is approximately similar of a Draize score of 2). As at 24 h, the average Draize score would be lower than 2, these results indicate that monopropylene glycol should not be considered a skin irritant. Also only very minor signs of irritation were reported in a 48-hour patch test with two female volunteers, administered doses of ca. 0.2 ml of the test material under an occlusive and semi-occlusive dressing for 48 hours (Consumer Product Testing Co., 1999c).

A cumulative 14-day skin irritation test with monopropylene glycol (100% and 50% solution in water) in human volunteers was performed by Consumer Product Testing Co., 1997. Approximately 0.2 ml of monopropylene glycol was applied neat and as 50% solution under occlusive dressing to the upper back of 26 human volunteers. The test material was applied to the appropriate treatment side Monday through Friday. Patches applied on Friday remained in place until the following Monday for a total of 14 days of skin contact. 26 male and female volunteers (18 to 70 years) with self-assessed sensitive skin were used; 25 subjects completed the study. Upon application of neat monopropylene glycol, one out of 26 subjects exhibited a marked (3+) response and the applications were discontinued by the second observation day. This type of immediate reaction is indicative of a dose dependant pre-sensitization to the test material. Five more subjects exhibited mild erythema (grade 1, similar to Draize score 1) one day after the application, which was resolved on the second observation day in 4 subjects and on the third day in the last subject. No further signs of irritation were observed in the study. As the average Draize score for all subjects over the 24, 48 and 72 h evaluations would be less than 2, these results indicate monopropylene glycol should not be considered a skin irritant.

Furthermore, Lessmann et al., 2005, reported the analysis of patch test data of 45138 patients with suspected allergic contact eczema, who have been tested with 20% aqueous solution of monopropylene glycol between 1992 and 2002 (see Section 5.5.1.2 for the study details). Out of these, 1044 patients (2.3%) tested positive, 1083 showed a doubtful, follicular or erythematous reaction (2.4%) and 271 explicit irritant reactions (0.6%). The authors stated that this profile of patch test reactions is indicative of a slightly irritant preparation.

Overall, monopropylene glycol tested negative for skin irritation in a guideline animal dermal irritation study and in three human volunteer studies, even after a prolonged exposure of 14 days. Therefore, monopropylene glycol does not need to be classified for skin irritation.

One eye irritation study with rabbits, performed in accordance with OECD guideline 405, was available for assessment (Jacobs, 1988). 0.1 ml of the test substance was instilled in the eye of each of six New Zealand White rabbits and the reactions were scored 4, 24, 48, 72 and 96 hours later. Mean scores at 24 + 48 + 72 hr examination points for cornea and chemosis were 0; mean score for conjunctivae was 0.4 and for iris 0.1 according to Draize scoring system. All reactions were fully reversible within 96 hours, indicating that monopropylene glycol does not exhibit eye irritating potential.

A number of data sources are available that contribute to the conclusion that monopropylene glycol is not to be considered a respiratory irritant. This data along with critiques of the methodology where appropriate are presented in the section below ‘justification for classification or non-classification.’

Justification for classification or non-classification

SKIN AND EYE IRRITATION

Based on the available evidence from animal and human studies on skin irritation and the evidence from the eye irritation study with rabbits, performed according to OECD guideline 405, monopropylene glycol does not need to be classified as skin and eye irritant in accordance with Directive 67/548/EEC and EU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.

RESPIRATORY IRRITATION.

Summary:

The available information on possible respiratory effects of monopropylene glycol do not support a H335 CLH classification as a respiratory irritant. Overall, the currently available evidence is not convincing for monopropylene glycol as causative for respiratory tract irritation. The existing data for humans and animals is very limited, the reported findings weak and do not rise to the level of classifiable effects. Most of the human data is based on exposures to mixtures of substances and hence cannot inform on any associations between monopropylene glycol and respiratory irritation. Only one study evaluated exposures to monopropylene glycol alone (Wieslander, 2001), however, the study’s findings do not demonstrate respiratory irritation effects. Importantly, the study’s objective measurements showed a small change well within the normal variation expected for this type of repeated spirometric measurements thatdoes not indicate adverse respiratory effects. The reported subjective symptoms of throat and ocular dryness also do not support the classification of respiratory irritation as, according to ECHA’s CLP guidelines, these are not considered relevant sensations.The animal data likewise only indicate mild clinical and mucosal changes that are not hallmarks of irritation responses.There are no credible histopathology reports in the animal studies that document monopropylene glycol-induced cytotoxicity or inflammation in the respiratory tract of inhalation-exposed laboratory animals. The findings that are reported were limited to exposure-related increases in the amounts of nasal epithelial mucus, but without evidence of any associated inflammatory cell response in the nasal mucosa. Without evidence of concurrent or preceding inflammation or epithelial cytotoxicity (cell death or degeneration), this single mucus morphologic finding does not warrant a label of irritancy for monopropylene glycol at these levels of exposure. The effects reported for monopropylene glycol in humans and animals do not indicate irritation responses and more likely are indirect effects of the local drying of the airway mucosa due to the hygroscopic nature of this substance. Theseeffects are not harmful or adverse and rather are adaptive to the minor physiological change.Given these reports and questionable findings, the major European producers of monopropylene glycol have committed to improve the information on human respiratory irritation with a new study. Due to the absence of data supporting safe use of propylene glycol for artificial smoke and electronic cigarettes,the major European producers of monopropylene glycol do not support and advise against these uses.

Human data:

The H335 classification of monopropylene glycol as a respiratory irritant is not justified based on the findings of four studies conducted in humans, three of which involve exposures to multiple other compounds, including monopropylene glycol. Analysis of these studies indicates that there is insufficient human scientific evidence presented to classify monopropylene glycol as a respiratory irritant. 

 

The specific guidance document that is used to classify substances as respiratory tract irritants requires that the evaluation of human data is based on, (1) experience from occupational exposure, (2) published data on volunteers (including objective measurements, psychophysical methods and subjective reports and (3) other data such as from nasal lavage. The effects required to substantiate respiratory irritation are stated as: localized redness, oedema, pruritis and/or pain and functional impairments such as cough, pain, choking and breathing difficulties (European Chemicals Agency, 2015).

 

Four studies are available as potentially providing evidence for respiratory irritation:

 

Burr, G.A., Van Gilder, T.J., Trout, D.B., Wilcox, T.G. and Driscoll, R. (1994). Health Hazard Evaluation. HETA 90-0355-2449.http://www.cdc.gov/niosh/hhe/reports/pdfs/1990-0355-2449.pdf

 

Moline, J.M., Golden, A.L., Highland, J.H., Wilmarth, K.R. and Kao, A.S. (2000). Health effects of evaluation of theatrical smoke, haze and pyrotechnics. Equity-League Pension and Health Trust Funds.

 

Wieslander, G. and Norbäck, D. (2010). Ocular symptoms, tear film stability, nasal patency and biomarkers in nasal lavage in indoor painters in relation to emissions from water-based paints. International Archives of Occupational and Environmental Health. 83: 733-741.

 

Wieslander, G., Norbäck, D. and Lindgren, T. (2001). Experimental exposure to propylene glycol mist in aviation emergency training; acute ocular and respiratory effects. Occupational and Environmental Medicine. 58:649-655.

 

Of the four studies cited, only one (Wieslander et al., 2001) is capable of associating any observed effects with monopropylene glycol exposure.  

 

The NIOSH study (Burr et al.,1994) evaluated symptom reports among actors in Broadway productions who were exposed to a variety of glycol compounds in addition to monopropylene glycol, including ethylene glycol, 1,3-butylene glycol, diethylene glycol and triethylene glycol. Ethylene glycol, in particular, has been shown to be a respiratory irritant (Wills et al., 1974), although at higher concentrations than those measured in this study. 

 

The Moline et al. (2000) study also evaluated exposure to mixed glycols, including butylene, diethylene, triethylene and monopropylene glycol. No significant acute change in voice quality, pulmonary function, or vocal cord appearance was found. Although actors with exposures to elevated or peak levels of glycols reported more symptoms than actors with less exposure, the mixed nature of the exposures makes it impossible to identify any symptoms as being due to monopropylene glycol exposure. 

 

The Wieslander and Norbäck (2010) study evaluated exposure of painters to a water-based paint that included monopropylene glycol among other glycol compounds and other volatile organic compounds. The authors concluded that the increase in eosinophilic cationic protein (ECP) obtained from nasal lavage was indicative of airway irritation. However, it is impossible to attribute the association between monopropylene glycol and ECP as due to the mixed exposures to different components emitted from the water-based paints, the findings cannot be associated with monopropylene glycol as the only origin of irritative effects on the eyes and nasal mucosa. 

 

The key study that could possibly be used as an indication that classification of monopropylene glycol as a respiratory irritant is relevant is the Wieslander et al. (2001) study. This study evaluated subjective symptom reports, and two measures of putative respiratory irritant response: pulmonary function and nasal resistance. There was a 1% change in FEV1, post-exposure, which is neither statistically or clinically significant, especially since post-exposure values were 102% of predicted for this healthy cohort. The small, albeit significant, decrease in the FEV1/FVC ratio is also not indicative of impairment of lower airways as the ratio was greater than 80% both pre- and post-exposure, indicating an absence of any obstructive defect (American Thoracic Society, 2005). 

 

A 5% decrease in FEV1, shown by only 4 out of 27 volunteers, cannot be considered significant or indicative of lung impairment due to exposure to a respiratory irritant, as this decrease is well within the normal variation expected with repeated spirometric measurements.The testing and, most importantly, the interpretation given to any measured change in lung function, must be consistent with the standards established by the American Thoracic Society and European RespiratorySociety (American Thoracic Society, 1994; American Thoracic Society, 2005). It is necessary to determine whether a measured change reflects a true change in pulmonary status or is only a result of technical or normal biological variation. Such variability is inherent in the spirometry test procedure, which relies completely on the willingness of the subject to expend maximal effort in test trials. The Society guidelines for interpretation are clear that even a ‘statistically significant change may be of no clinical relevance’ and that the ‘largest errors occur when attempting to interpret serial changes in subjects without disease because test variability will usually far exceed any true decline’ (American Thoracic Society, 2005).

 

As to the subjective reports of ‘throat and ocular dryness’, the criteria clearly state that ‘the sensation of smell, unpleasant taste, tickling sensation and dryness…. are outside the scope of classification for respiratory irritation’ (European Chemicals Agency, 2015). Thus, on the basis of the EU criteria reports of ‘dryness’ cannot be considered as indicative of respiratory irritation. 

 

Three out of the four studies reviewed cannot inform on any association between exposure to monopropylene glycol and respiratory irritation, due to the mixed glycol exposures all cohorts experienced. As ECHA’s CLP (2015) guidelines state, real-life human observational experience can be considered as long as ‘exposure details are well documented and due consideration given to possible confounding factors’, which is the case with the mixed exposures to multiple glycol compounds that are potentially greater irritants than monopropylene glycol. The key study conducted by Wieslander et al. (2001) did expose individuals to propylene glycol alone. However, the subjective symptom reports of throat and ocular dryness do not support the classification of respiratory irritation as these are not considered relevant sensations, according to the guidelines. The objective measurements, showing a small 5% pulmonary function decrease in only 4 out of 27 volunteers following exposure to propylene glycol, also do not indicate or constitute an adverse respiratory effect. 

 

Therefore, the available scientific human data do not support the classification of monopropylene glycol as a respiratory irritant in humans.

 

Animal data:

Four studies are cited as possibly providing evidence for respiratory irritation:

 

Konrádová, V., Vávrová, V. and Janota J. (1978). Effects of the inhalation of a surface tension-reducing substance (propylene glycol) on the ultrastructure of the epithelium of the respiratory passages in rabbits. Folia Morphologica. 26:28-34

 

Robertson, O.H., Loosli, G.C., Puck, T.T., Wise, H., Lemon, H.M. and Lester W. (1947). Test for the chronic toxicity of propylene glycol on monkeys and rats by vapor inhalation and oral administration. J Pharmacol Exp Therap. 91:52-76.

 

Suber, R.L., Deskin, R., Nikiforov, I., Fouillet, X. and Coggins, C.R. (1989). Subchronic nose-only inhalation study of propylene glycol in Sprague-Dawley rats. Fd. Chem. Toxic. 27: 573-583

 

Werley, M.S., McDonald, P., Lilly, P., Kirpatrick, D., Wallery, J., Byron, P. and Venitz, J. (2011). Non-clinical safety and pharmacokinetic evaluations of propylene glycol aerosol in Sprague-Dawley rats and Beagle dogs. Toxicology. 287:76-90

 

The published papers by Robertson et al. (1947) and Konrádová et al. (1978) are not of sufficient quality, due to their limited experimental designs and methodologies; these limitations include: small numbers of animals/group, lack of adequate control animals, no rigorous statistical analysis, poor or no standardized and unbiased histopathological examination approaches that are mandated in current animal toxicology and safety assessments. Overall, the findings in these publications are incredulous and of no use for risk assessment and especially not for setting safety standards for monopropylene glycol. 

 

The study design and methodologies of the published paper by Suber et al. (1989) also lacked the scientific rigor for assessing exposure-related toxicologic histopathology. For example, the authors provided no histopathological confirmation of the source or reason behind the “nasal bleeding” or “ocular discharge.” Red-tinged fluid around the nose and eyes due to excess porphyrin secretion sometimes is misdiagnosed as bleeding and is a common finding in rodents undergoing environmental stress (e.g., inhalation exposures). It is not clear if this was ruled out of the differential diagnosis. With a lack of histopathology in targeted tissues demonstrating hemorrhage it cannot be accurately concluded that propylene glycol exposure caused adverse effects (vascular rupture) responsible for the implied pathologies in hemostasis.

 

Interestingly, the authors of this subchronic nose-only inhalation study of monopropylene glycol, provided no details on the tissue sampling for light microscopic analysis of targeted organs in the respiratory tract (e.g., nose and lung) or descriptions of the histopathological sections (number and location) selected for examination. No unbiased quantitative pathology assessment (a common procedure in pathology today) of the only significant, but subjective, histopathology finding (increase in epithelial mucus) was conducted in this study. An unbiased quantitative assessment would have delineated and substantiated the severity and dose/response relationship for the increase of AB/PAS (Alcian blue and periodic acid-Schiff’s)-stained mucosubstances in the nasal epithelium. In addition, the study design lacked a post-exposure period (“recovery”) in filtered air which would have determined the persistent or transitory nature of this epithelial change.

 

Most importantly, there is no description of any associated inflammatory cell response in the nasal mucosa.Exposure-related increases in the amounts of nasal epithelial mucus alone is not enough for an experienced respiratory pathologist to conclude that the monopropylene glycol exposure induced an adverse, rather than adaptive, effect on the nasal airway epithelium.Without evidence of concurrent or preceding inflammation or epithelial cytotoxicity (cell death or degeneration) this single morphologic finding does not warrant a label of irritancy for monopropylene glycol at these levels of exposure. The increase in stored mucus in the nasal airway epithelium can be a normal physiologic adaptive response that occurs with changes in humidity, temperature or other factors not related to chemical toxicity. This epithelial change is not uncommon in the nasal cavity of filtered air control animals and without a definitive etiology. Generally, chemical exposure-related inflammatory and/or other epithelial change (e.g., rhinitis, epithelial hyperplasia, hyalinosis) in association with mucous cell metaplasia/hyperplasia would warrant a definitive morphologic diagnosis of a pathologic response (adverse outcome) to the compound. However, no such finding was reported in this study after monopropylene glycol exposure.

 

It should also be noted that there is inconsistency in the light microscopic examination and histopathologic assessment in the more recently conducted inhalation studies of propylene glycol in rats and beagle dogs (Werley et al., 2011). No single, statistically-supported, histopathologic finding (adverse effect) caused by inhaled monopropylene glycol was found in all of these reported studies. None of the acute, short-term inhalation exposure studies to propylene glycol included a full microscopic examination of the target tissues in the respiratory tract. Therefore, based on reported animal acute or repeated studies to date, there is no microscopic findings in the respiratory target organs of laboratory animals exposed by inhalation to monopropylene glycol aerosol that could be labeled as a histopathologic finding or morphologic adverse outcome in the targeted tissues.

 

There are no credible histopathology reports in the published literature that document -induced cytotoxicity or inflammation in the respiratory tract of propylene glycol inhalation exposed laboratory animals.

 

Therefore, the available scientific animal data do not support the classification of monopropylene glycol as a respiratory irritant in humans.

 

Possible explanations for observed effects of monopropylene glycol on the respiratory tract:

As discussed above, the available information does not demonstrate that monopropylene glycol meets the criteria for a respiratory irritant. Monopropylene glycol does not produce evidence of respiratory tract damage or irritant changes and rather the reported mild tissue changes and reported symptoms may be explained by simple drying effects on mucus membranes. 

 

Monopropylene glycol is strongly hygroscopic and miscible with water under normal physiologic conditions (ATSDR, 1997). Many of monopropylene glycols uses take advantage of its physico-chemical hydroscopic properties so this property would similarly be anticipated to potentially dehydrate moist mucus membranes that may impart sensory symptoms and tissue adaptation responses. These same symptoms occur in low humidity climates to which adaptation occurs. Thus the effects are not harmful or adverse and rather adaptive to the minor physiological change.

 

When deposited as a vapor or aerosol on the apical surface of the airway mucosa, monopropylene glycol will rapidly absorb water from the protective epithelial lining layer. The likely result of this is a rapid local increase in osmolarity. The drying effect of monopropylene glycol is analogous to breathing dry air which can result in decreased cell volume (Van Oostdam et al., 1986) and may result in epithelial changes (Chalon et al., 1972; Freed et al,, 1994; reviewed by Anderson and Holzer, 2002). Sensory nerve endings lining the conducting airways are sensitive to changes in osmolarity (Pisarri et al., 1992) and cell volume as evidenced by the cough that occurs in healthy human subjects inhaling nonisotonic aerosols (Eschenbacher et al., 1984; Higenbottam 1984). The drying effect of inhaled monopropylene glycol may be the underlying basis for the reported cough and feeling of airway irritation and a feeling of dyspnea reported in volunteers exposed to high concentrations (220 and 520 mg/m3) of monopropylene glycol and/or other hydroscopic substance aerosol (Wieslander et al., 2001) and stage actors and show personnel exposed to glycols in theatrical fogs (Moline et al., 2000; NIOSH, 1992). In the NIOSH study, the fogs were generally composed of a mixture of glycols, with less than 2.1 mg/m3of monopropylene glycol and the reported concentrations were reported as TWA from personal and area monitors. While these exposures were associated with self-reporting of nasal symptoms (sneezing, runny or stuffy nose), respiratory symptoms (cough, wheeze, breathlessness, chest tightness), and mucous membrane symptoms (sore throat, hoarseness, dry throat, itchy, burning eyes) during their performances, no objective analytical measures were linked to these reports and the possibility of transient high exposure concentrations could not be ascertained from the reported TWA values. 

 

An increase in osmolarity can also result in hypersecretion by mucous goblet cells of the surface epithelium and submucosal seromucous glands (Dwyer and Farley, 1997). The physical drying effect of inhaled monopropylene glycol aerosol is the likely mechanism leading to the observation of rapid hypersecretion of mucins from mucous goblet cells in the trachea of rabbits exposed for 20 or 120 minutes to 10% monopropylene glycol aerosols (Konradova et al, 1978). In this ultrastructural study monopropylene glycol exposure resulted in an increase in partially or fully discharged goblet cells. No recovery group was included in this study so the persistence of the morphologic alterations cannot be determined. The data from repeat exposure studies, however, suggest that exposure to high aerosol concentrations of monopropylene glycol do not induce epithelial injury or inflammation. Suber et al. (1989) exposed male and female Sprague Dawley rats to 0, 160, 1000, or 2200 mg/m3of monopropylene glycol aerosol 6 h/day, 5 days/week for 90 days. Rats exposed to the two highest concentrations of monopropylene glycol developed mucous cell hypertrophy/hyperplasia in the nasal respiratory epithelium as evidenced by an increase in the amount of stored AB/PAS stain sequence positive glycoproteins in mucous goblet cells. This is suggestive of an adaptive response to protect the epithelium from the repeated drying effects of high concentration monopropylene glycol aerosol exposure. There were reports of nasal hemorrhage and ocular discharge in a high proportion of the animals, however, there was no histopathologic evidence of nasal epithelial injury and there was no evidence of hemorrhage or ocular discharge on weekends when the animals were not exposed. This suggests that the observations, if not just porphyrin staining, were likely due to increased nasolacrimal discharge resulting from the drying effects of the monopropylene glycol aerosol.

 

Therefore, the available evidence suggests that the reported findings in human and animal studies associated with exposure to high levels of monopropylene glycol aerosol are the result of the physicochemical properties of monopropylene glycol (e.g. hygroscopic and highly water soluble) and not the result of chemical toxicity. Furthermore, there is no evidence that monopropylene glycol is a sensory irritant. Suber et al. (1989) reported that male and female rats exposed to 160, 1000 or 2200 mg/m3of monopropylene glycol had no change in breathing frequency, minute volume or tidal volume. A decrease in breathing frequency in rodents is typical of a sensory irritant and serves to limit exposure to noxious xenobiotics by reducing the total inhaled dose.

 

Overall, the data demonstrate a lack of direct epithelial toxicity and rather suggest an adaptive response often associated with non toxic irritant vapors and aerosols. The lack of reported airway epithelial injury or inflammation suggest that any perceived irritating effects of high concentration monopropylene glyco laerosols are indirect effects of the local drying of the airway mucosa due to the hygroscopic nature of monopropylene glycol. The ECHA CLP (2015) criteria clearly state that ‘the sensation of smell, unpleasant taste, tickling sensation and dryness…. are outside the scope of classification for respiratory irritation’ (European Chemicals Agency, 2015).

 

References

 

ATSDR (Agency for Toxic Substances and Disease Registry). (1997). Toxicological Profile for Propylene Glycol. U.S. Department of Health and Human Services. Public Health Service.

 

American Thoracic Society. (1995). Standardization of Spirometry: 1994 Update, American Journal of Respiratory and Critical Care Medicine. 152:1107-1136.

 

American Thoracic Society. (2005). Interpretative Strategies for Lung Function Testing in ATS/ERS Task Force: Standardization of Lung Function Testing (V. Brusasco, R. Crapo & G. Viegi (Eds.) European Respiratory Journal. 26:948-968.

 

Anderson, S.D. and Holzer, K. (2002). Pathophysiology of Exercise-Induced Asthma. ( In Exercise-Induced Asthma: Pathophysiology and Treatment. K. W. Rundel, R. L. Wilber, and R. F. Lemanske Jr. Eds. Human Kinetics Publishers, Inc. ISBN: 0-7360-3389-0.

 

Burr, G.A., Van Gilder, T.J., Trout, D.B., Wilcox, T.G. and Driscoll, R. (1994). Health Hazard Evaluation HETA 90-0355-2449.http://www.cdc.gov/niosh/hhe/reports/pdfs/1990-0355-2449.pdf

 

Chalon, J., Loe, D. A., and Malebranche, J. (1972). Effects of dry anesthetic gases on tracheobronchial ciliated epithelium. Anaesthesiology. 37:338-342.

 

Dwyer, T. M. and Farley, J. M. (1997). Mucus glycoconjugate secretion in cool and hypertonic solutions. American Journal of Physiology. 272 (Lung Cell Mol. Physiol. 16):L1121-L1125.

 

European Chemicals Agency. (2015). Guidance on the Application of the CLP Criteria. Guidance to Regulation (EC) No 1272/2008 on Classification, Labelling and Packaging (CLP) of Substances and Mixtures. Version 4.1. June 2015.

 

Eschenbacher, W.I., Boushey, H.A. and Sheppard, D. (1984). Alteration in osmolarity of inhaled aerosols cause bronchoconstriction and cough, but absence of a permeant anion causes cough alone. American Review of Respiratory Disease. 129:211-215.

 

Freed, A.N., Omori, C., Schofield, B.H. and Mitzner, W. (1994). Dry air-induced mucosal cell injury and bronchovascular leakage in canine peripheral airways. American Journal of Respiratory and Cellular Molecular Biology. 11:724-732.

 

Higenbottam, T. (1984). Cough induced by changes of ionic composition of airway surface liquid. Bulletin of European Physiopathology and Respiration. 20:553-562.

 

Pisarri, T.E., Jonson, A., Coleridge, H.M. and Coleridge, J.C.G. (1992). Vagal afferent and reflex responses to changes in surface osmolarity in lower airways in dogs. Journal of Applied Physiology. 73:2305-2313.

 

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