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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. 

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other: Guideline study, available as unpublished report, minor restrictions in design and reporting, but otherwise adequate for assessment.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:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
occlusive application
GLP compliance:
not specified
Species:
rabbit
Strain:
other: Kleine weiβe Russen
Details on test animals 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:
primary dermal irritation index (PDII)
Basis:
mean
Time point:
other: 24 + 48 + 72 hr
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:
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:
other: 24 + 48 + 72 hr
Score:
0
Max. score:
4
Irritation parameter:
iris score
Basis:
mean
Time point:
other: 24 + 48 + 72 hr
Score:
0.1
Max. score:
2
Reversibility:
fully reversible within: 48 hr
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: 24 + 48 + 72 hr
Score:
0.4
Max. score:
3
Reversibility:
fully reversible within: 96 hr
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: 24 + 48 + 72 hr
Score:
0
Max. score:
4
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 MPG, 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 MPG 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

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.

There are no human reports that propylene glycol causes respiratory irritation in humans. There are occasional human complaints of sensory irritation following its inappropriate use as theater fog but no clinical evidence of human respiratory irritation has been reported. There are two animal studies that evaluated respiratory tract effects to be considered.

A subchronic inhalation toxicity study with rats exposed to propylene glycol aerosol at dose levels of 160, 1000 and 2200 mg/m3 for 6 hr/day, 5 days/week for 90 days was reported by Suber et al. (1989). This study found treatment-related nasal haemorrhages which began during the second week of exposure and persisted throughout the study; recovery from these clinical signs occurred during the non-exposure weekend periods. The frequency of this reported nasal haemorrhages remained constant throughout the study and was highest (65-75%) in the medium-and high-concentration groups. Similar trends were observed for ocular discharge, with incidences of 16% in low-exposure males, 40% in medium and high exposure males and 5% in controls. There was generally less ocular discharge in females, who had incidences of 8% in controls, 14% in the low-exposure group, 28% in the medium-exposure group and 35% in the high-exposure group. Minute volume, tidal volume and respiratory rates were not significantly altered at any dose levels. Pathology examination did not confirm haemorrhages in the nasal cavity but did report an increase in the number of goblet cells or an increase in the mucin content of the existing goblet cells in the nasal passages. There was no other pathological changes reported in the upper or lower respiratory tract of these animals. Without confirmatory pathology changes, the clinical observation is questionable. An alternative explanation is that the reported “haemorrhage” was pigment/ porphyrin staining following an increase in lacrimal secretion caused by a drying effect of propylene glycol aerosols on mucous membranes. The reported pathology changes of increase in stored mucus in the nasal airway epithelium is a normal physiologic adaptive response that occurs with changes in humidity, temperature etc. This is observed with filtered air control animals as well - so it is not a specific "lesion" but an adaptive response. There was no evidence of inflammation or cytotoxicity that would indicate a pathologic response in the respiratory tissue to the propylene glycol exposure. The increase in an adaptive response associated with propylene glycol could also be explained by drying of the tissue but in any case should not be considered adverse or an irritant response.

The second study is a limited and non-standard study of rabbits that were exposed to very high atmospheres (10%) of propylene glycol aerosol for 20 or 120 minutes and the trachea epithelia examined (Konradova et al., 1979). This study found goblet cell changes and again these should be considered as adaptive responses and not as adverse changes or respiratory irritation

The present animal evidence therefore indicates mild clinical and adaptive changes in respiratory mucosa to propylene glycol aerosol exposure. Without reported evidence in animal studies of inflammation or cytotoxicity associated with propylene glycol, this substance does not warrant a label of respiratory irritancy according to the criteria laid down in regulation 1272/2008. The intent of the STOT Category 3 respiratory tract classification is to warn on effects which are of an adverse nature that impair function and are accompanied by objective measurements of irritation that would affect a population rather than induce idiosyncratic reactions in individuals with hypersensitive airways. These reported adaptive effects to propylene glycol exposure do not meet the classification criteria and therefore classification is not warranted.