2-[2-(2-methylpropoxy)ethoxy]ethanol

Eye irritation

Administrative data

Endpoint:

eye irritation: in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Justification for type of information:

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The source substance is a structural isomer of the target substance. The two differ only in the degree of branching of the terminal alkyl chain. The structural difference is not expected to confer any significant difference in terms of the eye irritancy potential of the target from the source substance.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Source: 2-(2-n-butoxyethoxy)ethanol. Smiles CCCCOCCOCCO (DEGBE)
Target: 2-(2-isobutoxyethoxy)ethanol. Smiles CC(C)COCCOCCO (DEGiBE)
Impurities: Both substances are mono-constituent in nature. There are no impurities in either that would invalidate the read across

3. ANALOGUE APPROACH JUSTIFICATION
See hypothesis above. The eye irritation of the target substance can be predicted from the experimentally determined eye irritation potential of the source component , which is identical apart from the branching of the terminal alkyl chain. Branched chain structures tend to be less lipophilic and therefore have lower eye irritation potential, as exemplified by the lower logKow. (This is supported by the overall tendency for eye irritation potential shown by this series of glycol ethers which increases with increasing length of the alkyl chain and increasing partition coefficient (logKow)

4. DATA MATRIX.
Experimentally determined physicochemical characteristics:
- Boiling point: target substance 240C, source substance 230C.
- Density: target substance 0.942 , source substance 0.955.
- Flash point: target substance 99C , source substance 115C
QSAR values for logKow
- LogKowwin: target substance 0.22, source substance 0.29.
Other: both fully water miscible.
DEGBE: Experimental result: Irritating

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

read-across source

Reference

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1984

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: A well reported study recorded in detail. Not all of the end points were recorded to enable a full and definitive comparison with classification criteria.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

yes

Remarks:

, not all required parameters reported

GLP compliance:

not specified

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Strain: abino
- Housing: individual in wire mesh floor cages.
- Acclimation period: 1 week
- Other: animals checked for prior eye injury before tests.


ENVIRONMENTAL CONDITIONS
- no data

Vehicle:

water

Controls:

other: second eye of each animal used as a control

Amount / concentration applied:

0.1ml of 5%, 10%, 20%, 50% and undiluted

Duration of treatment / exposure:

single exposure. No washout reported.

Observation period (in vivo):

14 days

Number of animals or in vitro replicates:

6 per concentration

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): No washout reported


SCORING SYSTEM:
Grade 0: no effect
Grade 1: barely detectable effect
Grade 2: mild effect
Grade 3: moderate effect
Grade 4: severe effect
Grade 5: severe effect with complication


TOOL USED TO ASSESS SCORE: hand-slit lamp / biomicroscope / fluorescein
- 2% fluorescein siodium and a biomicroscope.

Irritation parameter:

chemosis score

Basis:

mean

Time point:

other: 24 hour

Score:

1.5

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

chemosis score

Basis:

mean

Time point:

other: 48 hour

Score:

1

Max. score:

4

Reversibility:

fully reversible

Remarks on result:

other: Fully reversed by day 5

Irritation parameter:

iris score

Basis:

mean

Time point:

other: 24 hours

Score:

1

Max. score:

2

Reversibility:

fully reversible

Remarks on result:

other: fully reversed by day 7

Irritation parameter:

iris score

Basis:

mean

Time point:

other: 72 hours

Score:

0.5

Max. score:

2

Reversibility:

fully reversible

Remarks on result:

other: fully reversed by day 7

Irritant / corrosive response data:

See table in remarks field below.

Other effects:

See table in remarks field below.

Other end points mean (max):

Time (days)	Lachrymation	Congestion	Chemosis	Blepharitis	Iritis	Keratitis
1	1.8 (2)	2. 7(3)	1.5 (2)	1.2 (2)	1.0 (2)	1.2 (2)
2	0.7 (2)	2.5 (3)	1.0 (1)	1.5 (2)	0.5 (2)	1.0 (2)
3	0.4 (1)	2.2 (3)	0.4 (1)	1.5 (2)	0.5 (1)	1.3 (2)
Fully reversed day	5	14	5	10	7	14

Results for dilutions. 50% solution, mean (max):

Time (days)	Lachrymation	Congestion	Chemosis	Blepharitis	Iritis	Keratitis
1	1.5 (2)	2. 5(3)	0.7 (1)	1.7 (2)	0.7 (1)	1.2 (2)
2	0.3 (1)	2.3 (3)	0.5 (1)	1.2 (2)	0.2 (1)	0.7 (1)
3	0	0.5 (1)	0	0.7 (1)	0	0
Fully reversed day	3	5	3	5	3	3

Results for dilutions. 25% solution, mean (max):

Time (days)	Lachrymation	Congestion	Chemosis	Blepharitis	Iritis	Keratitis
1	0.5 (2)	2. 5(3)	0.2 (1)	1.5 (3)	0	0.8 (1)
2	0	1.7 (3)	0	0.6 (2)	0	0
3	0	0	0	0	0	0
Fully reversed day	2	3	2	3	-	2

Results for dilutions. 10% solution, mean (max): Only effects seen were mild congestion which had fully reversed within 24 hours.

Testing of intra-occular pressure (IOP) could only be carried out with solutions up to 10% in strength as the chemosis caused by stronger solutions interfered with measurements. A statistically significant but moderate increase in IOP was seen for solution strengths of 5% or more and volumes greater than 0.04ml, but these returned to normal values within an hour.

Interpretation of results:

moderately irritating

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

2-(2-butoxyethoxy)ethanol causes moderately severe conjunctivitis and mild corneal injury which resolves spontaneously within 14 days. The thresholds for effects are 25% for mild keratatitis and 10% for conjunctivitis. The transient increase in intra-occular pressure seen are typical of materials which do not cause severe corneal injury.

Executive summary:

In a study that was broadly similar to the requirements of an OECD guideline study, the eye irritation potential of 2 -(2 -butoxyethoxy)ethanol was examined in the rabbit. Both pure substance and various dilutions in water were examined. The study did not report on all end points normally used to determine eye irritancy classification against EU criteria and did not use the Draize scoring system. This makes a definitive interpretation difficult. The reported effects for chemosis and iritis do not appear to be severe enough to warrant classification under the EU criteria for these two end points.

Results synopsis

Classification uncertain.

Cross-reference 2

Reason / purpose for cross-reference:

read-across source

Reference

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

10.02.1987-03.03.1987

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Basic daten given. Report which meets basic scientific criteria.

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

yes

Remarks:

, washing not done until 72 hours after application when fluoroscine reading had been performed.

GLP compliance:

no

Species:

rabbit

Strain:

other: Small white russian, Chbb-SPF

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Dr. Karl Thomae GmbH, Biberach, Germany
- Weight at study initiation: 2,3-2,5 kg
- Housing: stainless steel cages (one animal each)
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 14 days
-sex: femal

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


IN-LIFE DATES: From: To:

Vehicle:

unchanged (no vehicle)

Controls:

other: The untreated eye served as control.

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0,1 cm3

Duration of treatment / exposure:

0,1 cm3 of the test substance were applied to the conjunctival sac of one eye of the animals. Treated eyes were assessed using fluoroscine after72hours, following which the eyes were washed out.

Observation period (in vivo):

The animals were observed 1, 24, 48 and 72 hrs as well as 6,8,10,13, 17 an 21 days after application.

Number of animals or in vitro replicates:

3

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): warm saline after fluoroscine assessment.
- Time after start of exposure: 72 hrs


SCORING SYSTEM: according to Draize, 1959


TOOL USED TO ASSESS SCORE: fluorescein

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

other: 24, 48, 72 hrs

Score:

1.22

Max. score:

4

Reversibility:

not fully reversible within: 21 days

Irritation parameter:

iris score

Basis:

mean

Time point:

other: 24, 48, 72 hrs

Score:

1

Max. score:

2

Reversibility:

not fully reversible within: 21 days

Remarks on result:

other: circumcorneal injection noted along with slight to marked reddening of the iris in all animals.

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

other: 24, 48, 72 hrs

Score:

3

Max. score:

3

Reversibility:

fully reversible within: 13 days

Remarks on result:

other: Bloody mucous noted in 2 of 3 animals at 48 and 72hrs.

Irritation parameter:

chemosis score

Basis:

mean

Time point:

other: 24, 48, 72 hrs

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 8 days

Interpretation of results:

highly irritating

Remarks:

Criteria used for interpretation of results: EU

Executive summary:

In an eye irritancy study that closely followed guidelines, 2 -(2 -butoxyethoxy)ethanol was found to cause significant eye irritation. Some of the lesions, notably the iris and corneal effects persisted until the end of the 21 day study, whilst conjunctival redness and odema had fully disappeared within 14 days. Although effects which remain persistent up to the end of the observation period (21 days) should be regarded as irreversible effects and warrant classification of the substance as a serious eye irritant (H318 and R41 respectively), this should not automatically be the conclusion in this case because washing was done until 72 hours after application. According to the OECD guideline, washing is normally performed 24 hours after application and delayed washing is likely to delay recovery. Although this study clearly shows that this substance warrants classification as an eye irritant, the degree of severity of the irritant effects should be based on all the available data and not just this single study.

Materials and methods

Test material

Test material information

Constituent 1

Reference substance name:

2-[2-(2-methylpropoxy)ethoxy]ethanol

EC Number:

242-665-1

EC Name:

2-[2-(2-methylpropoxy)ethoxy]ethanol

Cas Number:

18912-80-6

Molecular formula:

C8H18O3

IUPAC Name:

2-[2-(2-methylpropoxy)ethoxy]ethan-1-ol

Test material form:

liquid

Results and discussion

In vivo

Results

Remarks on result:

probability of severe irritation

Remarks:

Sufficient to warrant classification