Registration Dossier

Administrative data

Description of key information

Although no animal studies on skin irritation, performed up to modern standards, were available for assessment, the evidence from available human studies suggests that tripropylene glycol is not irritating to skin. Tripropylene glycol is not an eye irritant based on the results of an in vitro study using the SkinEthic Reconstituted Human Corneal Model and an in vivo OECD Guideline 405 study with rabbits. 

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: Study predates OECD guidelines and GLP, not performed in accordance with modern guideline standards, but contributing to overall assessment.
Principles of method if other than guideline:
0.01 ml of undiluted tripropylene glycol was applied to clipped uncovered intact skin of 5 rabbit bellies. Results were scored after 24 hours using a 10 grades system (no injury from undiluted substance = grade 1).
GLP compliance:
no
Species:
rabbit
Strain:
not specified
Details on test animals and environmental conditions:
The nonfasted animals were maintained on appropriate Rockland diets and water ad libitum except during period of manipulation or confinement.
Type of coverage:
open
Preparation of test site:
other: clipped
Vehicle:
unchanged (no vehicle)
Controls:
not specified
Amount / concentration applied:
0.01 ml
Duration of treatment / exposure:
24 hours
Observation period:
24 hours
Number of animals:
5
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
other: 24 h
Score:
2
Max. score:
10
Reversibility:
no data
Irritant / corrosive response data:
No irritation was observed in 1 animals; moderate capillary injection was observed on 4 rabbits. The overal irritation score was 2 out of 10 (1 = no irritation from undiluted substance).
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:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-compliant guideline study, available as unpublished report, no restrictions, fully adequate for assessment.
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Qualifier:
according to
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
GLP compliance:
yes (incl. certificate)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories U.K. Ltd, Hillcrest, Belton, Loughborough, UK.
- Age at study initiation: 12 - 20 weeks
- Weight at study initiation: 2.16 - 2.34 kg
- Housing: individually in suspended cages
- Diet: 2030 Teklad Global Rabbit diet supplied by Harlan Teklad, Blackthorn, Bicester, Oxon, UK ad libitum
- Water: drinking water ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17-23 °C
- Humidity (%): 30-70
- Air changes (per hr): at least 15 changes per hour
- Photoperiod (hrs dark / hrs light): 12/12
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
0.1 ml
Duration of treatment / exposure:
Once, eye closed for 1 second
Observation period (in vivo):
1hour, 24, 48 and 72 hours following treatment
Number of animals or in vitro replicates:
2
Details on study design:
SCORING SYSTEM: Draize

TOOL USED TO ASSESS SCORE: standard ophthalmoscope
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
Max. score:
2
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: 24 + 48 + 72 hr
Score:
0
Max. score:
3
Reversibility:
fully reversible within: 24 hr
Remarks on result:
other: slight redness (score 1) was observed in both animals 1 hr post-instillation
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: 24 + 48 + 72 hr
Score:
0
Max. score:
4
Reversibility:
fully reversible within: 24 hr
Remarks on result:
other: slight chemosis (score 1) was observed in both animals 1 hr post-instillation
Irritant / corrosive response data:
No corneal or iridial effects were noted during the study.
Moderate conjunctival irritation was noted in both treated eyes one hour after treatment.
Both treated eyes appeared normal at the 24-Hour observation.
Initial pain response upon substance instillation into the eye of the first animal was 3 by 6-point scale. Therefore one drop of local anaesthetic (Tetracaine hydrochloride 0.5%, Chauvin Pharmaceuticals, Romford, Essex, UK) was instilled into both eyes of the second animal 1 to 2 minutes before treatment.
Other effects:
Both animals showed expected gain in bodyweight during the study.

Table 1               Individual Scores and Individual Total Scores for Ocular Irritation

Rabbit Number and Sex

69070 Male

69079 Male

IPR=3

IPR=0+

Time After Treatment

1

Hour

24

Hours

48

Hours

72

Hours

1

Hour

24

Hours

48

Hours

72

Hours

CORNEA

E = Degree of Opacity

F = Area of Cornea Involved

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Score(ExF)x5

0

0

0

0

0

0

0

0

IRIS

D

0

0

0

0

0

0

0

0

Score (D x 5)

0

0

0

0

0

0

0

0

CONJUNCTIVAE

A= Redness

B= Chemosis

C=Discharge

1

1

2

0

0

0

0

0

0

0

0

0

1

1

2

0

0

0

0

0

0

0

0

0

Score (A + B + C) x 2

8

0

0

0

8

0

0

0

Total Score

8

0

0

0

8

0

0

0

IPR = Initial pain reaction

+ = One drop of local anaesthetic instilled into both eyes 1 to 2 minutes before treatment

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

Respiratory irritation

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

Additional information

Two studies with human volunteers were available for assessment. The first one, a 24-h semi-occluded patch study, was conducted to compare the skin irritancy potential of several test articles, including tripropylene glycol (Hill Top Research, Inc., 1995). The test substance was prepared as a 25% solution in distilled water and 0.2 ml of the solution was placed on the patch pad and applied on the paraspinal region of the back of 33 subjects. The results were compared with 2 negative controls (water and USP oil) and a positive control (0.5% sodium lauryl sulfate). All skin sites were scored prior to the application, 30 min after the removal of the 24 h application and again 24 h following patch removal.

Two subjects exhibited mild erythema at the 30 min evaluation, these responses were resolved by the 24-hr evaluation. The irritation was at a level equal to that of the negative control (distilled water). No further signs of irritation were noted in any of the subjects.

In the second study (Consumer Product Testing Co., 1997), a 14-day cumulative irritation test, approximately 0.2 ml of the test material was applied neat and as 50% solution under occlusive dressing to the upper back of 26 human volunteers. The test material was applied Monday through Friday. Patches applied on Friday remained in place until the following Monday for a total of 14 days of skin contact. None of the subjects showed any signs of skin irritation at any time during the test both with neat tripropylene glycol and its 50% solution.

In addition, one study with rabbits, predating OECD guidelines and GLP, was available for assessment (Chemical Hygiene Fellowship, 1974). 0.01 ml of undiluted tripropylene glycol was applied to clipped uncovered intact skin of 5 rabbit bellies. Results were scored after 24 hours using a 10 grades system (no injury from undiluted substance = grade 1). No irritation was observed in 1 animal, while moderate capillary injection was observed on 4 rabbits. The overall irritation score was 2 out of 10. Although no data after 48 and 72 hours were reported, and the animals were not observed for 14 days, the results appear to confirm the conclusion from human studies that tripropylene glycol is not irritating to skin. It should also be noted that the time of exposure (24 hours) vastly exceeded the limit of 4 hours recommended by OECD Guideline 404 and thus the results of the test present a worse case scenario.

Eye irritation potential of tripropylene glycol was studied in two GLP-compliant studies, one in vitro and one in vivo. In the in vitro study (Harlan Laboratories Ltd., 2010a), using the SkinEthic Reconstituted Human Corneal model, triplicate SkinEthic tissues were treated with 30 µl of the test material for 10 minutes. Triplicate tissues treated with 30 µl of 1% w/v sodium dodecyl sulphate served as the positive control. The test is based on the hypothesis that irritant chemicals are able to penetrate the corneal epithelial tissue and are sufficiently cytotoxic to cause cell death. If the percentage relative mean tissue viability was >=60% the test material was considered to be non-irritant; if the percentage relative mean tissue viability was <60% the test material was considered to be an irritant. The relative mean viability of the test material treated tissues after a 10 minute exposure was 85.9%. Based on these results, tripropylene glycol was considered to be non-irritating to eyes.

In the in vivo study with rabbits, performed according to OECD Guideline 405 (Harlan Laboratories Ltd., 2010b), the single eyes of two rabbits were instilled with 0.1 ml of the test substance, while another eye served as untreated control. The reactions were scored 1, 24, 48 and 72 hours post-instillation according to the system of Draize. A pH of the test substance was determined prior to the beginning of the study and was 6.8 for undiluted substance and ca. 7.5 for 95% solution. Immediately after the substance instillation, an assessment of the initial pain response was made according to a 6-point scale.

No corneal or iridial effects were noted during the study. Moderate conjunctival irritation was noted in both treated eyes one hour after treatment (score 1). Both treated eyes appeared normal at the 24-hour observation. Initial pain response upon substance instillation into the eye of the first animal was 3 by 6-point scale. Therefore one drop of local anaesthetic was instilled into both eyes of the second animal 1 to 2 minutes before treatment. Based on the results of the study, tripropylene glycol is considered to be not an eye irritant.

Justification for classification or non-classification

SKIN IRRITATION

Based on the overall evidence from available human studies and one available animal study, tripropylene glycol is not irritating to skin.

Therefore classification for skin irritation is not warranted in accordance with Directive 67/548/EEC andEU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.

EYE IRRITATION

Results of the available in vitro and in vivo eye irritation studies indicate that tripropylene glycol is not an eye irritant. Therefore classification for eye irritation is not warranted in accordance with Directive 67/548/EEC and EU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/200.