Registration Dossier

Toxicological information

Eye irritation

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Administrative data

Endpoint:
eye irritation: in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The source substances tetraethylene glycol butyl ether (TEGBE) and "Ethanol, 2-butoxy- , manufacture of, by-products from" are either a main component or a very similar material compared to the UVCB target substance. The majority of the other components of the registered UCVB are the higher molecular weight members in the homologous series. The hypothesis is that the toxicity of the substance can be estimated based on the toxicity of the components and that there is no interaction between them that increases the toxicity disproportionately

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Source: Tetraethylene glycol butyl ether and "Ethanol, 2-butoxy- , manufacture of, by-products from"
Target: UCVB substance Triethylene Glycol Ether Highers (NLPBuHeavies).
Impurities: Both the source and target substances will contain the same impurities as they are produced in the same process, therefore they will have similar impurity profiles and impurities will not impact on the validity of the read across.

3. ANALOGUE APPROACH JUSTIFICATION
The eye irritation potential of the ethylene glycol ether butyl series increases with increasing molecular weight. Therefore, TetraEGBE and "Ethanol, 2-butoxy- , manufacture of, by-products from" are expected to have similar or slightly lower irritation than the other higher EO components of the UCVB substances of NLPBuHeavies. This is supported by the data from an eye irritation study using the registered UCVB substance (cas 9004-77-7).

It seems reasonable to use these two read across substances to support the weight of evidence study on the registered UCVB substance (cas 9004-77-7) and therefore the UCVB substance NLPBuHeavies will also show severe eye irritation potential and will be classified accordingly.
Cross-referenceopen allclose all
Reason / purpose:
read-across source
Reference
Endpoint:
eye irritation: in vitro / ex vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Meets generally accepted scientific standards, well documented and acceptable for assessment.
Qualifier:
no guideline available
Principles of method if other than guideline:
Method: other: HET-CAM in vitro corrosion test
GLP compliance:
no
Species:
other: hen egg chorioallantoic membrane
Duration of treatment / exposure:
5 minute(s)
Irritation parameter:
other:
Remarks on result:
other: Results not indicative of substance being a severe irritant
Remarks:
See 'other effects/acceptance of results'field below
Other effects / acceptance of results:
- undiluted test substance (pH ca. 5.5):
- Haemorrhagia: appearance after 19 seconds
- Coagulation: appearance after 31.7 seconds
- test substance 10% in doubly distilled water (pH ca. 5)
- Haemorrhagia: no effect within 300 seconds
- Coagulation: no effect within 300 seconds
- evaluation: did not produce changes indicative for severe eye irritation (for the evaluation of eye irritation see eye irritation test in rabbits - 11H0181/032047)
Executive summary:

In an in vitro assay designed to assess the irritation potential for severe eye damage, 3,6,9,12-tetraoxahexadecan-1-ol was testsed in the HET-CAM = (Hen Egg Test - Chorioallantoic Membrane) assay. The level of response seen was not indicative of a severe eye irritant.

Reason / purpose:
read-across source
Reference
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
2003
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: OECD guideline study + GLP
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Centre Lago S.A., 01540 Vonnas, France
- Age at study initiation: About 5 - 6 months
- Weight at study initiation: 3.57 - 4.16 kg
- Housing: The animais were housed in fully air-conditioned rooms in stainless steel wire mesh cages with grating, floor area: 3000 CM2
- Diet: Kliba-Labordiät, Provimi Kliba SA, Kaiseraugst, Switzerland (about 130 glanimal per day)
- Water: ad libitum
- Acclimation period: At least 5 days before the beginning of the study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12/12

Vehicle:
unchanged (no vehicle)
Controls:
other: untreated left eye
Amount / concentration applied:
0.1 ml of test substance was applied in a single dose to the conjunctival sac of the right eyelid.
Duration of treatment / exposure:
About 24 hours after application of the liquid test substance the treated eye of the animal(s) was rinsed with 3 to 6 ml of hand warm tap water for 1 to 2 minutes using a syringe with a blunt probe.
Observation period (in vivo):
14 days
Number of animals or in vitro replicates:
3
Details on study design:
The evaluation of eye irritation is pertormed according to the quoted guidelines. In addition to specific observations recommended by the regulatory authorities, evaluations were madle of discharge from the eye and the area of carnea affected by the lesions.
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
all three animals
Time point:
other: 24-72 h
Score:
4
Reversibility:
not fully reversible within: 14 days
Irritation parameter:
iris score
Basis:
mean
Remarks:
all three animals
Time point:
other: 24-72 h
Score:
0.1
Max. score:
2
Reversibility:
fully reversible within: 7 days
Irritation parameter:
conjunctivae score
Basis:
mean
Remarks:
all three animals
Time point:
other: 24-72 h
Score:
2.2
Max. score:
3
Reversibility:
fully reversible within: 14 days
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
all three animals
Time point:
other: 24-72 h
Score:
1.6
Max. score:
4
Reversibility:
not fully reversible within: 14 days
Irritant / corrosive response data:
Slight corneal opacity (grade 1) was observed in all animals 24 hours after application and persisted in one animal up to 72 hours and in two animals up to day 7. Moderate iritis was seen in one animal 72 hours after application only. Slight to moderate conjunctival redness (grade 1 - 2), moderate to marked conjunctival chemosis (grade 2 - 3) and moderate discharge (grade 2) were observed in all animals 1 hour after application.
Moderate or severe conjunctival redness (grade 2 or 3) was observed in all animals after 24 hours up to 72 hours and decreased to slight (grade 1) after 7 days. Moderate conjunctival chemosis (grade 2), noted in all animals 24 hours after application, persisted in one animal up to 72 hours and decreased to slight after 7 days, whereas in the ether twe animais chemesis decreased to slight after 48 up to 72 hours after application. Slight or moderate discharge (grade 1 or 2) was seen in all animals 24 hours after application. Slight discharge was noted in twe animals from 48 hours up to 72 hours. In addition small retraction in the eyelid, suppuratien, centracted pupil, discharge of blood, injected scleral vessels, circular or in a circumscribed area and marginal vascularization of the cornea in a circumscribed area were observed ever the study period.

In a guideline OECD205 study, the substance tetrathylene glycol monobutyl ether was found cause slight corneal opacity that persistend for up to day 7. Moderate iritis was seen in one animal 72 hours after application only. Moderate or severe conjunctival redness was observed in all animals after 24 hours up to 72 hours and decreased to slight after 7 days. Moderate conjunctival chemosis was noted in all animals 24 hours after application, persisted in one animal up to 72 hours and decreased to slight after 7 days, whereas in the ether two animals chemosis decreased to slight after 48 up to 72 hours after application. Slight or moderate discharge was seen in all animals 24 hours after application. In addition small retraction in the eyelid, suppuratien, centracted pupil, discharge of blood, injected scleral vessels, circular or in a circumscribed area and marginal vascularization of the cornea in a circumscribed area were observed ever the study period. The study was only continued for up to 14 days after which not all symptoms had reversed.

Interpretation of results:
Category 2A (irritating to eyes)
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Considering the described ocular reactions as well as the average score for irritation, Tetraethylenglykolmonobutylether shows a slight eye Irritation potential under the test conditions chosen.
Reason / purpose:
read-across source
Reference
Endpoint:
eye irritation: in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: 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
Qualifier:
according to
Guideline:
EPA OPPTS 870.2400 (Acute Eye Irritation)
Deviations:
no
Qualifier:
according to
Guideline:
other: Japan MAFF Testing Guideline of 12 Nousan No. 8147, November 24, 2003
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Centre Lago S.A., 01540 Vonnas, France
- Age at study initiation: 5-6 month
- Weight at study initiation: 3.57-4.16 kg
- Housing: single housing, stainless steel wire mesh cages, floor area 3000 cm²
- Diet (e.g. ad libitum): Kliba-Labordiät, Provimi Kliba, SA, Kaiseraugust, Swiss about 130g/animal/day
- Water (e.g. ad libitum): Tap water ad libitum
- Acclimation period: at least 5 days before beginning of the experiment


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 30-70%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12h/12h


Vehicle:
unchanged (no vehicle)
Controls:
not specified
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 ml
- Concentration (if solution): undiluted
Duration of treatment / exposure:
24 hours
Observation period (in vivo):
14 days
Number of animals or in vitro replicates:
3
Details on study design:
Comment: rinsed after 24 hours

REMOVAL OF TEST SUBSTANCE
- Washing (if done): rinsing with 3-6 ml of hand warm tap water for 1 to 2 min using a syringe with a blunt probe
- Time after start of exposure: 24 hours


SCORING SYSTEM:
Cornea opacity (op):
Degree of density (the most dense area is taken for reading)
0 = no ulceration or opacity
1 = Scattered or diffuse areas ot opacity (other than slight dulling of normal lustre), details of iris clearly visible;
2 = Easily discernible translucent area, details of iris slightly obscured
3 = Necreous area, no details of iris visible, size of pupil barely discernible
4 = Opaque cornea, iris not discernible through the opacity

Area of cornea involved (ar): (The assessment of these ocular reactions is performed independent of the quoted guidelines)
1 = 0 < =1/4
2 = >1/4<1/2
3 = 2<3/
4 = >3/4

Iris:
0 = Normal
1 = Markedly deepened rugae, congestion, swelling, moderate circumcorneal hyperaemia or injection, any of these observations or combination of any thereof, Iris still reacting to light (sluggish reaction is positive)
2 = No reaction to light, haemorrhage, gross destruction (any or all of these)

Conjunctivae redness (red):
(Refers to palpebral and bulbar conjunctivae, not to cornea and iris)
o = Blood vessels normal
1 = Some blood vessels definitely hyperaemic (injected)
2 = Diffuse, crimson colour, individual vessels not easily discernible
3 = Diffuse beefy red


Chemosis (sw):
Lids and/or nictitating membrane
0 = No swelling
1 = Any swelling above normal (includes nictitating membranes)
2 = Obvious swelling with partial eversion of lids
3 = Swelling with lids about half closed
4 = Swelling with lids more than half closed

Discharge (di): (The assessment of these ocular reactions is performed independent of the quoted guidelines)
0 = No discharge
1 = Any amount different from normal (does not include small amounts observed in inner canthus of normal animals)
2 = Discharge with moistening of the lids and hairs just adjacent to Iids
3 = Discharge with moistening of the lids and hairs, and considerable area around the eye
Description of any ocular findings not covered by this scale were recorded.

Key:
h = hour
d = day
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 14 days
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Score:
0.11
Max. score:
2
Reversibility:
fully reversible within: 7 days
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
24/48/72 h
Score:
2.22
Max. score:
3
Reversibility:
fully reversible within: 14 days
Irritation parameter:
chemosis score
Basis:
mean
Time point:
24/48/72 h
Score:
1.55
Max. score:
4

Clinical examinations and assessment of ocular findings

Slight corneal opacity (grade 1) was observed in all animals 24 hours after application and persisted in one animal up to 72 hours and in two animals up to day 7. Moderate iritis was seen in one animal 72 hours after application only. Slight to moderate conjunctival redness (grade 1 - 2), moderate to marked conjunctival chemosis (grade 2 - 3) and moderate discharge (grade 2) were observed in all animals 1 hour after application. Moderate or severe conjunctival redness (grade 2 or 3) was observed in all animals after 24 hours up to 72 hours and decreased to slight (grade 1) after 7 days. Moderate conjunctival chemosis (grade 2), noted in all animals 24 hours after application, persisted in one animal up to 72 hours and decreased to slight after 7 days, whereas in the other two animals chemosis decreased to slight after 48 up to 72 hours after application. Slight or moderate discharge (grade 1 or 2) was seen in all animals 24 hours after application. Slight discharge was noted in two animals from 48 hours up to 72 hours. In addition small retraction in the eyelid, suppuration, contracted pupil, discharge of blood, injected scleral vessels, circular or in a circumscribed area and marginal vascularization of the cornea in a circumscribed area were observed over the study period. The ocular reactions were reversible in all animals within 14 days after application. Mean scores calculated for each animal over 24, 48 and 72 hours were 1.0 for corneal opacity, 0.0, 0.3 and 0.0 for iris lesions, 2.0, 2.7 and 2.0 for redness of the conjunctiva and 1.3, 1.3 and 2.0 for chemosis.

Readings

Animal

Cornea

Iris

Conjunctiva

Additional findings

Opacity

Area of cornea involved

Redness

Chemosis

Discharge

1h

1

0

0

0

2

3

2

PC

2

0

0

0

2

2

2

49

3

0

0

0

1

3

2

24h

1

1

2

0

2

2

1

DB, 48

2

1

4

0

2

2

2

49

3

1

4

0

2

2

1

49

48h

1

1

1

0

2

1

0

48

2

1

4

0

3

1

1

S, 49

3

1

4

0

2

2

1

49

72h

1

1

1

0

2

1

0

48

2

1

4

1

3

1

1

49

3

1

4

0

2

2

1

49

7d

1

0

0

0

1

0

0

44

2

1

1

0

1

0

0

48

3

1

2

0

1

1

0

SR,PC,44,48

14d

1

0

0

0

0

0

0

2

0

0

0

0

0

0

3

0

0

0

0

0

0

Mean

1

1

0

1.3

1.3

2

1

0.3

1.3

1.3

3

1

0

2

2.0

Mean

1

0.1

1.6

1.6

Explanation of findings:

SR = Small retraction in the eyelid

S = Suppuration

PC = Pupil contracted

DB = Discharge of blood

44 = Vascularization of the cornea, circumscribed area, marginal

48 = Scleral vessels injected, circumscribed area

49 = Scleral vessels injected, circular

Interpretation of results:
Category 2A (irritating to eyes) based on GHS criteria
Remarks:
Migrated information
Conclusions:
EU Classification: not irritating
GHS Classification: Causes severe eye irritation (Cat 2A)
Executive summary:

In a guideline GLP eye irritation study, the substance 3,6,9,12-tetraoxahexadecan-1-ol was tested in rabbit eyes to assess the level of eye irritancy produced. The eyes were washed after 24 hours as permitted under the guideline. This can be considered more representative of the hazard in man as humans have a lachrymatory response to irritants (a response lacking in rabbits.) Under the conditions of the test, moderate eye irritation was observed, the most acute response being moderate to severe conjunctival erythema. All symptoms disappeared within 14 days. The response was not sufficiently severe to warrant classifying the substance as an eye irritant under the EU classification according to the Dangerous Substances Directive, but the conjunctival response does meet the criteria for classification under the GHS as a severe eye irritant (Cat 2A).

Reason / purpose:
read-across source
Reference
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP and guideline study
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.2400 (Acute Eye Irritation)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Deviations:
no
Qualifier:
according to
Guideline:
other: Japan MAFF Testing Guideline of 12 Nosan No. 8147
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
testing lab.
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
Identification of the animals: Ear tattoo
Age at the beginning of the study: About 4 - 5 months
Body weight range at the beginning of the study: 2.82 - 3.30 kg
Air-conditioning: The animals were housed in fully air-conditioned rooms, in which a central air-conditioning system ensured a temperature in the range of 20 - 24°C and a relative humidity in the range of 30 - 70%. Deviations from these specifications that would have had an adverse effect on the test results did not occur.
Illumination period: 12 h light (6:00 a.m. - 6.00 p.m .) / 12 h darkness (6.00 p.m. - 6.00 a.m.)
No. of animals per cage: Single housing
Type of diet: Kliba-Labordiaet, Provimi Kliba SA, Kaiseraugst, Switzerland (about 130 g/animal per day)
Watering: Tap water ad libitum
Acclimatization period: At least 5 days before the beginning of the study.
Only animals with intact cornea and conjunctiva were used.
Vehicle:
unchanged (no vehicle)
Controls:
other: untreated eye of the same animal
Amount / concentration applied:
0.1 ml
Duration of treatment / exposure:
The test substance was applied in a single dose to the conjunctival sac of the right eyelid; the substance was washed out with tap water about 24 hours after application (before 24 hour reading).
Observation period (in vivo):
Observation period: 21 days (animal No. 01) resp. 14 days (animal Nos. 02, 03)
Number of animals or in vitro replicates:
3
Details on study design:
About 24 hours after application the eye was rinsed with tap water.
Body weight determination : Just before application of the test substance.
Readings: About 1 h, 24 h, 48 h, 72 h, 7, 14 and 21 days after application.
Check for dead or moribund animals: Twice each workday (beginning and end) and once on Saturdays, Sundays and on public holidays.
For evaluation, the calculation of the mean values of corneal opacity, iris, conjunctival redness and chemosis for readings 24, 48 and 72 hours were quoted. Additionally, the reversibility of the observed findings was taken into account. The evaluation is based on the criteria of Annex VI of the Commission Directive 67/548/EEC that were in place on the date of report signature.
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Score:
1
Max. score:
4
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Score:
0.2
Max. score:
2
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
24/48/72 h
Score:
2.7
Max. score:
3
Irritation parameter:
chemosis score
Basis:
mean
Time point:
24/48/72 h
Score:
1.8
Max. score:
4
Irritant / corrosive response data:
Slight to moderate conjunctival redness (grade 1-2) , moderate to marked conjunctival chemosis (grade 2 - 3) and moderate to severe discharge (grade 2 - 3) were observed in all animals 1 hour after application. Moderate or severe conjunctival redness (grade 2 or 3), observed in all animals at 24 hours until 72 hours after application, persisted in 1 animal until day 7 and decreased in 2 animals to slight conjunctival redness (grade 1) within 7 days. Slight conjunctival redness was still seen in 1 animal on day 14. Moderate to marked conjunctival chemosis (grade 2 - 3), noted in all animals 24 hours after application, decreased to slight or moderate (grade 1- 2) after 48 hours. At 72 hours after application all animals showed slight conjunctival chemosis, which persisted in 1 animal up to day 7. Slight to severe discharge (grade 1- 3), observed in all animals 24 hours after application, decreased to slight or moderate (grade 1- 2) at 48 hours after application. 72 hours after application slight discharge was observed in 1 animal only. Slight corneal opacity was observed in all animals 24 hours until 72 hours after application and persisted in 2 animals until day 7. Slight corneal opacity was still observed in 1 animal on day 14 after application. Moderate iritis (grade 1) was observed in 2 animals 24 hours after application only. Moreover, small retraction in the eyelid, suppuration, contracted pupil, discharge of blood, loss of corneal tissue, marginal vascularization of the cornea or injected scleral vessels in a circumscribed or circular area each, were observed during the observation period. The ocular reactions relevant for evaluation were reversible in 2 animals within 14 days and in 1 animal after 21 days. Mean scores calculated for each animal over 24, 48 and 72 hours were 1.0 in each animal for corneal opacity, 0.0, 0.3 and 0.3 for iris lesions, 2.0, 3.0 and 3.0 for redness of the conjunctiva and 1.7, 1.7 and 2.0 for chemosis.
Interpretation of results:
irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Considering the described ocular reactions as well as the average score for irritation, Butyltriglykol gives indication of an irritant property to the eye under the test conditions chosen.
Executive summary:

In a guideline OECD405 eye irritancy study, a substance meeting the description "Ethanol, 2-butoxy- ,manufacture of, by-products from" produced marked irritation in rabbit eyes. The most severe reaction was conjunctival erythema, which averaged a response of 2.7 across all animals tested and the 24, 48 and 72 hour observations. This reaction is sufficiently severe to warrant classification as an eye irritant. Whilst the way the subsequent observations were reported is not entirely clear, it would appear that most effects had disappeared within 14 days apart from possibly slight conjunctival redness in one animal only. On the basis of these results, the substance does not warrant classification as a severe eye irritant.

Reason / purpose:
read-across source
Reference
Endpoint:
eye irritation: in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
1994
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study to GLP for which original study report is available.
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
Each animal was given a number unique within the study which was written with a black indelible marker-pen on the inner surface of the ear and on a cage label.

TEST ANIMALS
- Source: David Percival Ltd., Moston, Sandbach, Cheshire, U.K.
- Age at study initiation: 12 -16 weeks old.
- Weight at study initiation: 2.46 – 2.62 kg
- Housing: Animals were individually housed in suspended metal cages.
- Diet: STANRAB SQC Rabbit Diet, Special Diets Services Ltd., Witham, Essex, U.K. ad libitum.
- Water: Ad libitum
- Acclimation period: five days

ENVIRONMENTAL CONDITIONS
- Temperature: 17-20°C
- Humidity: 49 – 59%
- Air changes: 15 changes per hour
- Photoperiod: 12 hour light/12 hour dark cycle.

IN-LIFE DATES: From: 13 December 1993 To: 6 January 1994
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- For the purpose of this study the test material was used as supplied.
- Amount(s) applied (volume or weight with unit): 0.1 ml
Duration of treatment / exposure:
One rabbit was initially treated.  A volume of 0.1 ml of the test material was instilled into the conjucntival sac of the right eye, formed by gently pulling the lower lid away from the eyeball.  The upper and lower eyelids were held together for about one second immediately after instillations, to prevent loss of the test material, and then released.  The left eye remained untreated and was used for control purposes.  Immediately after administration of the test material, an assessment of the initial pain reaction was made.
Observation period (in vivo):
Assessment of ocular damage/irritation was made approximately 1 hour and 24, 48, and 72 hours following treatment, according to the numerical evaluation given in Appendix I, (from Draize J.H. 1959, Association of Food and Drug Officials of the United States, Austin, Texas, “The Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics”).
Additional observations were made on days 7, 14 and 21 to assess the reversibility of the ocular effects.
Number of animals or in vitro replicates:
Three.
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): no

SCORING SYSTEM: Draize

TOOL USED TO ASSESS SCORE: Examination of the eye was facilitated by use of the light source from a standard ophthalmoscope.
Irritation parameter:
maximum mean total score (MMTS)
Time point:
48 h
Score:
41
Max. score:
110
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Score:
1.2
Max. score:
4
Reversibility:
not fully reversible within: 21 days.
Remarks on result:
other: No corneal opacity remaining but one animal still showing vascularisation.
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Score:
1
Max. score:
2
Reversibility:
fully reversible within: 7 days
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
24/48/72 h
Score:
2.1
Max. score:
3
Reversibility:
fully reversible within: 21 days
Irritation parameter:
chemosis score
Basis:
mean
Time point:
24/48/72 h
Score:
1.9
Max. score:
4
Reversibility:
fully reversible within: 21 days
Irritant / corrosive response data:
Dulling of the normal luster of the cornea was noted in all treated eyes one hour after treatment.  Areas of diffuse corneal opacity were noted in all treated eyes at the 24 hour observation with areas of diffuse to translucent corneal opacity at the 48 and 72-hour observations.  Areas of diffuse corneal opacity were noted in two treated eyes at the 7-day observation.  Vascularisation of the cornea was noted in all treated eyes at the 7-day observation and in one treated eye at the 14 and 21-day observations.

Iridial inflammation was noted in all treated eyes one hour after treatment and at the 24, 48 and 72-hour observations.  No other iridial effects were noted.

Moderate conjunctival irritation was noted in all treated eyes one hour after treatment and at the 24 and 48-hour observations with minimal to moderate conjunctival irritation at the 72 hour and 7 day observations.  Minimal conjunctival redness was noted in one treated eye at the 14-day observation. Two treated eyes appeared normal fourteen days after treatment.

Individual total scores and group mean scores for ocular irritation.

 Rabbit # and Sex

 1 hour

 24 hour

 48 hour

 72 hour

 7 days

 45 male  19  37  49  39  4
 44 male  19  37  37  37  25
 200 male  19  37  37  26  7
 Group Total  57 111   123  102  36

 Group Mean Score

 19.0  37.0 41.0 34.0  12.0

14 days - all scored zero, full recovery

Individual scores for animals for key end and time points used for classification:

Readings

Animal

Cornea Opacity

Iris

Conjunctiva

Redness

Chemosis

24h

1

1

1

2

2

2

1

1

2

2

3

1

1

2

2

48h

1

2

1

2

2

2

1

1

2

2

3

1

1

2

2

72h

1

2

1

3

2

2

1

1

2

2

3

1

1

2

1

Interpretation of results:
Category 1 (irreversible effects on the eye) based on GHS criteria
Remarks:
Migrated information
Conclusions:
The test material, "Ethanol, 2-butoxy- ,manufacture of, by-products from", produced a maximum group mean score of 41.0 and was classified as a MODERATE IRRITANT (CLASS 5 ON A 1 TO 8 SCALE) to the rabbit eye according to a modified Kay and Calandra classification system. However, because of the irreversible nature of some effects, the test material was also classified as an irreversible eye irritant according to EEC labelling regulations.
Executive summary:

In a guideline (OECD 405) and GLP eye irritancy study, the substance "Ethanol, 2-butoxy- ,manufacture of, by-products from" was found to be an irreversible eye irritant. Whilst the immediate acute irritancy response was sufficient to trigger classification as a reversible eye irritant, the lesions seen were particularly persistent and vascularisation in one animal did not fully reverse during the observation period. Information on preparations containing this substance suggest that the effects consistently become reversible at concentrations below 30%.

Data source

Materials and methods

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
not specified

Results and discussion

In vivo

Results
Remarks on result:
probability of severe irritation

Applicant's summary and conclusion