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Administrative data

Description of key information

The submission substance is irritating to skin and eyes and a risk for respiratory irritation was identified.

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:
1987-09-01 until 1987-09-15
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study.
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
GLP compliance:
no
Species:
rabbit
Strain:
other: Small Russian
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Dr. Karl Thomae GmbH, Biberach, Germany
- Weight at study initiation: 2.4 - 2.5 kg
- Housing: singly in stainless steel cages
- Diet: rabbit diet K4, Ssniff Spezialfutter GmbH, Soest, germany, ad libitum
- Water tap water ad libitum
- Acclimation period: 14 days


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



IN-LIFE DATES: From: 1987-09-01 To: 1987-09-15
Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount applied: 500 µL
Duration of treatment / exposure:
4 hrs
Observation period:
14 days
Number of animals:
3
Details on study design:
TEST SITE
- Area of exposure: 6 cm²
- Type of wrap if used: the application site was covered with a gauze patch (2.5 x 2.5 cm) followed by an impervious polyethylene foil. The patch was help in place by a flexible cotton wrap.


REMOVAL OF TEST SUBSTANCE
- Washing: yes, with water
- Time after start of exposure: 4 hrs


SCORING SYSTEM: according to OECD 404 test guideline
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
other: 1, 24, 48, 72 hrs
Score:
6.75
Max. score:
8
Reversibility:
not reversible
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 24, 48, 72 hrs
Score:
3.33
Max. score:
4
Reversibility:
not reversible
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 24, 48, 72 hrs
Score:
4
Max. score:
4
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
other: 24, 48, 72 h
Score:
3.33
Max. score:
4
Reversibility:
not reversible
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
other: 24, 48, 72 h
Score:
3.33
Max. score:
4
Reversibility:
not reversible
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
other: 24, 48, 72 h
Score:
3.33
Max. score:
4
Reversibility:
not reversible
Irritation parameter:
edema score
Basis:
animal #1
Time point:
other: 24, 48, 72 h
Score:
4
Max. score:
4
Irritation parameter:
edema score
Basis:
animal #2
Time point:
other: 24, 48, 72 h
Score:
4
Max. score:
4
Irritation parameter:
edema score
Basis:
animal #3
Time point:
other: 24, 48, 72 h
Score:
4
Max. score:
4

Individual test results were as tabulated below. In addition, the skin was coloured in all animals at 24 hrs (yellow) and at 48 hrs (brown).

Animal

No.

1 h

24 h

48 h

72 h

6 d

8 d

10 d

14 d

ery

ede

ery

ede

ery

ede

ery

ede

ery

ede

ery

ede

ery

ede

ery

ede

1

2

3

3

4

3

4

4

4

scab

Scab, des

des, scar

scar

2

2

3

3

4

3

4

4

4

scab

scab, rup

scab, rup

scab, des, scar

3

2

3

3

4

3

4

4

4

scab, rup

scab, rup

scab, rup

scab, des, scar

Abbreviations:

Ery: erythema; ede: edema; figures: scores according to OECD 404

scab: scab formation; rup: ruptured; des: desquamation; scar: scar formation

No necrosis of the epidermis was reported.

A mean irritation index of 6.75 (maximum possible: 8) was calculated as the sum of all erythema and edema scores of all animals at 1, 24, 48, and 72 hours after patch removal, divided the number of animals (3) and time points (4).

The evaluation according to the directive 79/831/EEC gave means for each animal of 3.33 (erythema) and 4.0 (edema).

Interpretation of results:
highly irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
2-EH was highly irritating, as severe irreversible skin reactions were noted in all treated animals during 24 through 72 hours after patch removal which developed into formation of new skin and scars within 2 weeks after patch removal.

Executive summary:

The skin irritation potential of 2 -EH, purity 99.5%, was tested in a valid non-GLP OECD 404 study using 3 rabbits. Severe erythema and edema was noted in all treated animals at 24 hours after treatment which persisted until 72 hours. The skin reactions caused irreversible changes and resulted in scab formation, desquamation, formation of new skin in all animals during days 6 through 14 after patch removal. Scars and peeling scabs were observed on day 14 in all animals. The observed effects including the late scarification are consistent with a strong irritant, but not a corrosive agent.

2 -EH was irritating according to EU legislation (Council directive 67/548/EEC and its amendment 79/831/EEC),

requiring the label Xi and R38 (Hüls AG, 1987). With respect to the CLP regulation (Regulation (EC) no 1272/2008) a classification in Skin Irritation category 2 seems justified.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (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:
1987-09-01 until 1987-09-22
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
GLP compliance:
no
Species:
rabbit
Strain:
other: Small Russian
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Karl Thomae GmbH, Biberach, Germany
- Weight at study initiation: 2.3 - 2.5 kg
- Housing: singly in stainless steel cages
- Diet: diet K4, Ssniff Spezialfutter GmbH, Soest, Germany, ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: 14 days


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


IN-LIFE DATES: From: day 0 (initiation) To: day 21 after treatment
Vehicle:
unchanged (no vehicle)
Controls:
other: untreated eyes
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL
Duration of treatment / exposure:
single application
Observation period (in vivo):
21 days
Number of animals or in vitro replicates:
3
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing: no

SCORING SYSTEM: according to Draize (OECD 405)

TOOL USED TO ASSESS SCORE: fluorescein

EVALUATION:
1) Modified Maximum Average Score (MMAS) according to Draize (1944; cf. ECETOC (1998), company study T01716)
2) Average scores according to EU (79/831/EEC)
Irritation parameter:
other: MMAS
Basis:
mean
Remarks:
3 animals
Time point:
other: 24, 48, and 72 hrs
Score:
28.59
Max. score:
110
Reversibility:
fully reversible within: 21 days
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
3 animals
Time point:
other: 24, 48, 72 hrs
Score:
1.44
Max. score:
4
Reversibility:
fully reversible within: 17 days
Irritation parameter:
iris score
Basis:
mean
Remarks:
3 animals
Time point:
other: 24, 48, 72 hrs
Score:
0.89
Max. score:
2
Reversibility:
fully reversible within: 21 days
Irritation parameter:
conjunctivae score
Remarks:
(redness)
Basis:
mean
Remarks:
3 animals
Time point:
other: 24, 48, 72 hrs
Score:
2.56
Max. score:
3
Reversibility:
fully reversible within: 21 days
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
3 animals
Time point:
other: 24, 48, 72 hrs
Score:
0.78
Max. score:
4
Reversibility:
fully reversible within: 8 days
Irritant / corrosive response data:
Single animal data are given below. For each score the data is given for the respective animal on reading at 24/48/72 hours after test material instillation (number in brackets indicates the time period within which the effect was fully reversible).

- Cornea score: animal #1: 2/2/2 (17 days); animal #2: 1/2/0; animal #3: 2/2/0
- Iris score: animal #1: 1/1/1 (21 d); animal #2: 1/1/1 (6 d); animal #3: 1/1/0
- Conjunctivae (redness) score: animal #1: 3/3/3 (21 d); animal #2: 3/2/2 (8 d); animal #3: 3/3/1 (6 d)
- Chemosis score: animal #1: 1/1/1 (8 d); animal #2: 1/1/0; animal #3: 1/1/0
Interpretation of results:
other: Category 2 (irritating to eyes)
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
2-EH was markedly irritant to the rabbit's eye in a valid OECD 405 test. The effects were fully reversible within 21 days.
Executive summary:

2-EH was markedly irritant to the rabbit's eye in a valid OECD 405 test using 3 male Small russian rabbits. Reading for relevant effects were performed on 1, 24, 48 and 72 hours after instillation of 0.1 mL test material into the left conjunctival sac of each animal. Effects were observed for up to 21 days after instillation. Moderate corneal opacity was seen in all animals at 24 and 48 hours after treatment. The effect was absent in 2 animals at 72 hours after treatment and at 17 days in the third animal (mean animal #1: 2; animal #2: 1; animal #3: 1.3). Grade 1 iritis was noted in all animals. The effect was absent in two animals on day 6, and on day 21 in the third animal (mean animal #1: 1; animal #2: 1; animal #3: 0.67)

Moderate reddening of the conjunctivae was seen in all animals at 24 and 48 hours after treatment. Two animals were free of this effect on day 8, the third on day 21 (mean animal #1: 3; animal #2: 3; animal #3: 2.3). Chemosis was slight in two animals, and on day 8 all animals were free of this effect (mean animal #1: 1; animal #2: 0.67; animal #3: 0.67).

To conclude, 2-EH caused moderate eye irritation in all 3 treated animals. The effects were fully reversible within 21 days. The MMAS (Mean Modified Average Score) according to Draize was 28.59 (maximum possible score: 110).

The mean cornea score of all animals, the mean iris score of animal #1 and #2 and the mean conjunctivae score (reddening) of all animals exceeded slightly the EU criteria for classification as irritant category 2 according to Regulation (EC) no. 1272/2008 (H319). The mean conjunctivae score (reddening) of all animals was 2.56 and exceeded slightly the EU criterion for classification according to Directive 67/548/EEG (R36) (Hüls AG, 1987).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Additional information

Skin irritation

The skin irritation potential of 2 -EH, purity 99.5%, was tested in a valid non-GLP OECD 404 study using 3 rabbits. Severe erythema and edema was noted in all treated animals at 24 hours after treatment which persisted until 72 hours. The skin reactions caused irreversible changes and resulted in scab formation, desquamation, formation of new skin in all animals during days 6 through 14 after patch removal. Scars and peeling scabs were observed on day 14 in all animals.The observed effects including the late scarification are consistent with a strong irritant, but not a corrosive agent.

2 -EH was irritating according to EU legislation (Council directive 67/548/EEC and its amendment79/831/EEC),

requiring the label Xi and R38 (Hüls AG, 1987). With respect to the CLP regulation (Regulation (EC) no 1272/2008) a classification in Skin Irritation category 2 seems justified.

In various studies of low reliability (RL 3 or RL 4, original data and data from secondary sources) depending on the study design slight to marked irritation was observed. In one study using only 4% test substance in petrolatum no irritation was observed after 48 hours. In a developmental toxicity study (dermal exposure for 6 h/d) in rats the authors reported a NOEL of 252 mg/kg per day based on skin irritation (exfoliation and encrustation was noted).

Eye irritation

2-EH was markedly irritant to the rabbit's eye in a valid OECD 405 test using 3 male Small russian rabbits. Reading for relevant effects were performed on 1, 24, 48 and 72 hours after instillation of 0.1 mL test material into the left conjunctival sac of each animal. Effects were observed for up to 21 days after instillation. Moderate corneal opacity was seen in all animals at 24 and 48 hours after treatment. The effect was absent in 2 animals at 72 hours after treatment and at 17 days in the third animal (mean animal #1: 2; animal #2: 1; animal #3: 1.3). Grade 1 iritis was noted in all animals. The effect was absent in two animals on day 6, and on day 21 in the third animal (mean animal #1: 1; animal #2: 1; animal #3: 0.67)

Moderate reddening of the conjunctivae was seen in all animals at 24 and 48 hours after treatment. Two animals were free of this effect on day 8, the third on day 21 (mean animal #1: 3; animal #2: 3; animal #3: 2.3). Chemosis was slight in two animals, and on day 8 all animals were free of this effect (mean animal #1: 1; animal #2: 0.67; animal #3: 0.67).

To conclude, 2-EH caused moderate eye irritation in all 3 treated animals. The effects were fully reversible within 21 days. The MMAS (Mean Modified Average Score) according to Draize was 28.59 (maximum possible score: 110).

The mean cornea score of all animals, the mean iris score of animal #1 and #2 and the mean conjunctivae score (reddening) of all animals exceeded the EU criteria for classification as irritant category 2 according to Regulation (EC) no. 1272/2008 (H319). The mean conjunctivae score (reddening) of all animals was 2.56 and exceeded slightly the EU criterion for classification according to Directive67/548/EEC(R36)(Hüls AG, 1987).

The eye irritating properties of 2 -EH were examined in 4 New Zealand White rabbits according to the OECD 405 test guideline (1987) and under GLP. The eye reactions were examined until day 14 after the instillation of 0.1 mL into the conjunctival sac. The effects were scored according to the tables contained in OECD 405. For evaluation purposes the modified mean average score (MMAS) was calculated. For comparison with the EU classification criteria according to Directive 67/548/EEC the means of the eye reactions of all animals at the examinations at 24, 48, and 72 hours after treatment were additionally calculated.

Slight to marked effects of the cornea, iris, and conjunctivae (redness and chemosis) were seen in all animals 24 hours after treatment. The effects were fully reversible in 3 animals within 10 days, and in all animals within 14 days, after treatment.

The MMAS was 51.3, indicating a risk of serious eye damage.

The mean cornea score of all animals, the mean conjunctivae score (reddening) of all animals #3 and #4 and the mean chemosis score of animals # 1, #2, 1nd #3 exceeded the EU criteria for classification as irritant category 2 according to Regulation (EC) no 1272/2008 (H319).

The mean scores calculated according to the provisons of the Council Directive 67/548/EEC do not indicate a classification requirement (ECETOC, 1998).

These findings were supported by four other in vivo studies in rabbits of low reliability (RL3 or RL 4, mostly due to insufficient reporting of individual animal data which would allow for classification). Moreover there is an in vitro eye irritation test available. Within the Short Time Exposure (STE) test eye irritation is assessed by measuring the cytotoxicity in SIRC cells (rabbit corneal cell line) following a 5 min dose treatment. When applying 5% (w/w) of 2-ethylhexanol in mineral oil the relative viability of the cells was 44%. When applying 0.05% (w/w) of 2-ethylhexanol the relative viability of tested cells was 93.4%. 2-ethylhexanol thus was correctly identified as irritant and was ranked as moderately irritant.

Respiratory irritation

Irritating effects on eyes and the respiratory tract were investigated in controlled experimental human studies. In these studies by Kieswetter et al. (2005) and van Thriel et al. (2003, 2005, 2007) (reported in IUCLID section 7.10) volunteers were exposed for 4 h to concentrations up to 20 ppm. It was stated that higher concentrations caused irritation. At 20 ppm and 4 h exposure the following effects were observed: increased eye blinking, higher scores for self-reported chemosensory irritation, higher concentrations of substance P in nasal fluid and reduced nasal airflow.


Justification for selection of skin irritation / corrosion endpoint:
Adequate study available of high reliability (Klimisch score 1)

Justification for selection of eye irritation endpoint:
Adequate study available of high reliability (Klimisch score 1)

Effects on skin irritation/corrosion: irritating

Effects on eye irritation: irritating

Effects on respiratory irritation: irritating

Justification for classification or non-classification

Skin irritation

A classification in Skin Irritation category 2 for 2 -EH is justified with respect to the CLP regulation (Regulation (EC) no 1272/2008 based on the results of the key study given in detail above (Hüls AG, 1987).

Eye irritation

As presented in detail above 2 -EH was identified as being irritant to the eyes (Eye Irritation category 2) according to Regulation (EC) no 1272/2008 within two reliable key studies (OECD 405 guideline conform studies in rabbits (Hüls AG, 1987; ECETOC, 1998).

Respiratory irritation

2 -EH may cause respiratory irritation at concentrations of 50 ppm or higher. Signs of respiratory irritation of unclear adversity were observed in human experimental studies at 20 ppm (Kiesswetter et al., 2005; van Thriel et al., 2005). Based on the available data on respiratory irritation in humans the test substance has to be classified into specific target organ toxicity category 3 (STOT 3, H335) according to Regulation (EC) No 1272/2008.