Registration Dossier

Administrative data

Description of key information

Skin and eye irritation studies on HG performed according to test guidelines, have demonstrated that the compound is a slight skin and eye irritant in rabbits. However, a former study has reported eye irritation but no irritation of the nose or throat in human volunteers exposed to HG vapors.

Skin Irritation/Corrosion

Skin irritation studies on hexylene glycol (HG) in rabbits, one of which was performed according to test guidelines, have demonstrated that the compound is a very slight skin irritant. 
A skin irritation study on HG has been performed in accordance with OECD Guidelines for the Testing of Chemicals No. 404 and in compliance with GLP (Parcell, 1995). In this study, 3 New Zealand White rabbits were exposed to 0.5 mL of undiluted HG on the clipped dorsal lumbar region under semi-occlusive conditions. Animals were exposed to HG for 4 hours and observations were recorded at 1, 24, 48, and 72 hours after removal of the patch and residual test substance. Additional observations were made on Day 5 for one animal. Skin reactions were scored according to a prescribed numerical system. Very slight transient erythema was observed in 2 animals, and was fully reversible by Day 3 in one animal and by Day 5 in the other. The third rabbit did not display any dermal reactions. In addition, no signs of toxicity or ill health were observed in any rabbit during the observational period. Individual mean scores over 24, 48 and 72h were 1, 0.7 and 0.7 for erythema and 0, 0 and 0 for oedema. Based on the results of this study, HG elicited very slight transient dermal irritation to intact rabbit skin.
The low potential of HG to cause skin irritation is supported by other skin irritation tests. HG was determined to be non-irritating to rabbit skin following an acute exposure to undiluted test substance under occlusive conditions (Guillotet al., 1982).
A 6-week cumulative irritation test also was conducted in rabbits (Guillotet al., 1982). In this test, 2 mL of undiluted or diluted HG in water (10% HG) was applied to the skin of 3 rabbits. The mean irritation index for each animal was calculated by adding up the erythema and oedema scores obtained each week (from five daily readings) and the mean maximum irritation index (MMII) was reported. Scarcely visible erythema was observed following application of the diluted test substance. Erythema was more apparent in animals exposed to undiluted HG. Although a 7-day recovery period was included in this study, the reversibility of the observed effects was not reported. Based on the results of this study, no significant adverse reaction was macroscopically or histologically observed after daily dermal application of HG (undiluted and diluted) for 6 weeks in rabbits.

Eye Irritation

In an eye irritation study performed in accordance with OECD Guidelines for the Testing of Chemicals No. 405 and in compliance with GLP (Gardner, 1996), HG was found to be slightly irritatioing to the eye.
In this study, 0.1 mL of undiluted HG was instilled into one conjunctival sac of each of 3 New Zealand White rabbits. Ocular changes were assessed 0.5, 1, 4, 24, 48, 72 hours, and 7 days after treatment, and scoring was performed according to guideline methods. No clinical signs of systemic toxicity or ill health were observed in any rabbit during the course of the study. Instillation of HG caused practically no initial sting responses. All rabbits developed corneal and conjunctival irritation within 1 hour of instillation of the test substance. These changes did not exceed diffuse opacity and stippling of the cornea (a crimson appearance of the conjunctivae), chemosis sufficient to cause partial eversion of the eyelids, or an ocular discharge. The conjunctival reactions in one rabbit intensified such that, four hours after treatment, the conjunctivae were crimson, chemosis was sufficient to obscure approximately one-half of the eye, and a marked ocular discharge was observed. Iridial inflammation also was apparent in this eye at the same examination. On the following day, all rabbits showed diffuse corneal opacity and conjunctival reactions not exceeding a crimson appearance, chemosis sufficient to cause partial eversion of the eyelids, or an ocular discharge. Corneal absorption of fluorescein applied to the tear film confirmed disruption of the corneal epithelium. Progressive resolution of the observed effects was apparent from Day 2 and was complete by Day 4 (in 2 rabbits) or Day 8. Individual mean scores over 14, 48 and 72 hours were 1, 0.7 and 0.7 for cornea opacity, 0, 0 and 0 for iritis, 1, 0.7 and 1 for conjunctival irritation and 1.3, 0.3 and 1 for chemosis. Therefore, a single instillation of HG into the conjunctival sac of 3 rabbits caused changes of the cornea, iris, and conjunctivae that resolved within seven days of treatment.

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
Study period:
1995
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Interfauna U.K. Ltd., Huntingdon, Cambridgeshire, England.
- Age at study initiation: approximately 11 to 12 weeks of age
- Weight at study initiation: range of 2.6 to 2.9 kg
- Housing: Individually housed in plastic cages with perforated floors
- Diet (e.g. ad libitum): standard laboratory diet SDS Stanrab (P) Rabbit diet ad libitum
- Water (e.g. ad libitum): drinking water ad libitum
- Acclimation period: Rabbits were reported to be acclimated, but number of days not reported

ENVIRONMENTAL CONDITIONS
- Temperature (°C): approximately 19°C
- Humidity (%): 30 - 70%
- Air changes (per hr): approximately 19 air changes per hour
- Photoperiod (hrs dark / hrs light): 12/12


Type of coverage:
semiocclusive
Preparation of test site:
other: clipped
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 mL
Duration of treatment / exposure:
4 hours
Observation period:
1 hour after removal of test substance and thereafter 24, 48, and 72 hours after exposure. Additional observations were made on Day 5 for one animal.
Number of animals:
3
Details on study design:
TEST SITE
- Area of exposure: dorso-lumbar region
- % coverage: not reported
- Type of wrap if used: Each treatment site was covered with "Elastoplast" elastic adhesive dressing.


REMOVAL OF TEST SUBSTANCE
- Washing (if done): the treatment site was washed with warm water (30° to 40°C) to remove any residual test substance .
- Time after start of exposure: 4 hours


SCORING SYSTEM: Local dermal irritation was assessed using the prescribed numerical system

Erythema and eschar formation:

No erythema 0
Very slight erythema (barely perceptible) ' 1
Well-defined erythema 2
Moderate to severe erythema 3
Severe erythema (beet redness) to slight eschar formation
(injuries in depth) preventing erythema reading 4



Oedema formation:

No oedema 0
Very slight oedema (barely perceptible) 1
Slight oedema (edges of area well-defined by definite raising) 2
Moderate oedema (raised approximately 1 millimetre) 3
Severe oedema (raised more than 1 millimetre and extending
beyond the area of exposure) 4

Irritation parameter:
erythema score
Basis:
animal #1
Remarks:
mean
Time point:
other: 24, 48, 72 hours
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 4 days
Irritation parameter:
edema score
Basis:
animal #1
Remarks:
mean
Time point:
other: 24, 48, 72 hours
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Irritation parameter:
erythema score
Basis:
animal #2
Remarks:
mean
Time point:
other: 24, 48, 72 hours
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 2 days
Irritation parameter:
edema score
Basis:
animal #2
Remarks:
mean
Time point:
other: 24, 48, 72 hours
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Irritation parameter:
erythema score
Basis:
animal #3
Remarks:
mean
Time point:
other: 24, 48, 72 hours
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Irritation parameter:
edema score
Basis:
animal #3
Remarks:
mean
Time point:
other: 24, 48, 72 hours
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Irritant / corrosive response data:
DERMAL RESPONSES
Very slight transient erythema was seen in two animals. The skin was normal in one of these animals on Day 3 and in the other on Day 5. The third rabbit showed no dermal response to treatment with HEXYLENE GLYCOL PURE.
Other effects:
CLINICAL SIGNS
There were no signs of toxicity or ill health in any rabbit during the observation period.
Interpretation of results:
slightly irritating
Remarks:
Migrated information not classified Criteria used for interpretation of results: other: CLP (EC 1278/2008)
Conclusions:
A single semi-occlusive application of HEXYLENE GLYCOL PURE to intact rabbit skin for four hours elicited very slight transient dermal irritation.
Executive summary:

A skin irritation study on hexylene glycol has been performed in accordance with OECD Guidelines for the Testing of Chemicals No. 404 and in compliance with GLP. In this study, 3 New Zealand White rabbits were exposed to 0.5 mL of undiluted hexylene on the clipped dorsal lumbar region under semi-occlusive conditions. Animals were exposed to the test compound for 4 hours and observations were recorded at 1, 24, 48, and 72 hours after removal of the patch and residual test substance. Additional observations were made on Day 5 for one animal. Skin reactions were scored according to a prescribed numerical system. Very slight transient erythema was observed in 2 animals, and was fully reversible by Day 3 in one animal and by Day 5 in the other. The third rabbit did not display any dermal reactions. In addition, no signs of toxicity or ill health were observed in any rabbit during the observational period. Individual mean scores over 24, 48 and 72h were 1, 0.7 and 0.7 for erythema and 0, 0 and 0 for oedema. Based on the results of this study, hexylene glycol elicited very slight transient dermal irritation to intact 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
Study period:
1996
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Charles River UK Ltd., Margate
- Age at study initiation: 13 to 16 weeks
- Weight at study initiation: 2.55 to 2.62 kg
- Housing: individually in floor-pens
- Diet (e.g. ad libitum): SQC TRB Rabbit Diet 9603 (pelleted) from Harlan Teklad, Bicester, available ad libitum
- Water (e.g. ad libitum): Mains water
- Acclimation period: approximately 3 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16 to 22
- Humidity (%): 40 to 80
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL
Duration of treatment / exposure:
Single administration
Observation period (in vivo):
0.5, 1, 4, 24, 48, 72 hours and 7 days after treatment.
Number of animals or in vitro replicates:
3 animals
Details on study design:

SCORING SYSTEM: as in guideline (see attached scoring scale)


TOOL USED TO ASSESS SCORE: Either visually or with a pencil-beam torch or similar to illuminate and magnify the eye. Fluorescein staining was used as considered appropriate with a UV lamp.
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
other: 24, 48, and 72 hours
Score:
1
Max. score:
4
Reversibility:
other: reversible in 4 days
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
other: 24, 48, and 72 hours
Score:
0.7
Max. score:
4
Reversibility:
other: reversible in 4 days
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
other: 24, 48, and 72 hours
Score:
0.7
Max. score:
4
Reversibility:
other: reversible in 4 days
Irritation parameter:
iris score
Basis:
animal #1
Time point:
other: 24, 48, and 72 hours
Score:
0
Max. score:
2
Reversibility:
other: not applicable
Irritation parameter:
iris score
Basis:
animal #2
Time point:
other: 24, 48, and 72 hours
Score:
0
Max. score:
2
Reversibility:
other: not applicable
Irritation parameter:
iris score
Basis:
animal #3
Time point:
other: 24, 48, and 72 hours
Score:
0
Max. score:
2
Reversibility:
other: not applicable
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
other: 24, 48, and 72 hours
Score:
1
Max. score:
3
Reversibility:
other: reversible in 4 days
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
other: 24, 48, and 72 hours
Score:
0.7
Max. score:
3
Reversibility:
other: reversible in 4 days
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
other: 24, 48, and 72 hours
Score:
1
Max. score:
3
Reversibility:
other: reversible in 4 days
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
other: 24, 48, and 72 hours
Score:
1.3
Max. score:
4
Reversibility:
other: reversible in 4 days
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
other: 24, 48, and 72 hours
Score:
0.3
Max. score:
4
Reversibility:
other: reversible in 4 days
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
other: 24, 48, and 72 hours
Score:
1
Max. score:
4
Reversibility:
other: reversible in 4 days
Irritant / corrosive response data:
See attached Table 1 for results

No clinical signs of systemic toxicity or ill health were noted for any rabbits during the course of the study. The individual scores for ocular reactions elicited by hexylene glycol are given in Table 1. Instillation of hexylene glycol caused practically no initial sting responses. All rabbits developed corneal and conjunctival irritation within one hour of instillation of the test article. These changes did not exceed diffuse opacity and stippling of the cornea, a crimson appearance of the conjunctivae, chemosis sufficient to cause partial eversion of the eyelids and an ocular discharge. The conjunctival reactions for one rabbit intensified such that four hours after treatment the conjunctivae were crimson, chemosis was sufficient to obscure approximately one-half of the eye and there was a marked ocular discharge. Iridial inflammation was also apparent in this eye at the same examination. On the following day, all rabbits showed diffuse corneal opacity and conjunctival reactions not exceeding a crimson appearance, chemosis sufficient to cause partial eversion of the eyelids and an ocular discharge. Corneal absorption of fluorescein applied to the tear film confirmed disruption of the corneal epithelium. Progressive resolution of the effects of hexylene glycol was apparent from Day 2 and was complete by Day 4 (two rabbits) or Day 8.

Interpretation of results:
slightly irritating
Remarks:
Migrated information not classified Criteria used for interpretation of results: other: CLP (EC 1278/2008)
Executive summary:

An eye irritation study on hexylene glycol has been performed in accordance with OECD Guidelines for the Testing of Chemicals No. 405 and in compliance with GLP. In this study, 0.1 mL of undiluted hexylene was instilled into one conjunctival sac of each of 3 New Zealand White rabbits. Ocular changes were assessed 0.5, 1, 4, 24, 48, 72 hours, and 7 days after treatment, and scoring was performed according to guideline methods. No clinical signs of systemic toxicity or ill health were observed in any rabbit during the course of the study. Instillation of hexylene glycol caused practically no initial sting responses.  All rabbits developed corneal and conjunctival irritation within 1 hour of instillation of the test substance. These changes did not exceed diffuse opacity and stippling of the cornea (a crimson appearance of the conjunctivae), chemosis sufficient to cause partial eversion of the eyelids, or an ocular discharge. The conjunctival reactions in one rabbit intensified such that, four hours after treatment, the conjunctivae were crimson, chemosis was sufficient to obscure approximately one-half of the eye, and a marked ocular discharge was observed. Iridial inflammation also was apparent in this eye at the same examination. On the following day, all rabbits showed diffuse corneal opacity and conjunctival reactions not exceeding a crimson appearance, chemosis sufficient to cause partial eversion of the eyelids, or an ocular discharge. Corneal absorption of fluorescein applied to the tear film confirmed disruption of the corneal epithelium. Progressive resolution of the observed effects was apparent from Day 2 and was complete by Day 4 (in 2 rabbits) or Day 8. Individual mean scores over 14, 48 and 72 hours were 1, 0.7 and 0.7 for cornea opacity, 0, 0 and 0 for iritis, 1, 0.7 and 1 for conjunctival irritation and 1.3, 0.3 and 1 for chemosis. Therefore, a single instillation of hexylene glycol into the conjunctival sac of 3 rabbits caused changes of the cornea, iris, and conjunctivae that resolved within seven days of 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

Justification for classification or non-classification

Regulation (EC) No 1272/2008 Annex VI Table 3.1

Eye Irrit. 2, H319

Skin Irrit.2, H315

Self classification

Not classified for skin and eye irritation according to CLP (EC 1272/2008) criteria is warranted according to the studies performed in the rabbits. However, a former study has reported eye irritation in human volunteers exposed to hexylene glycol vapors. Therefore, a classification as Eye irritant category 2 (H319) under CLP is proposed.