Dihexyl ether

Endpoint summary

Description of key information

skin irritation (human): slightly irritating
eye irritating (rabbit): not irritating

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Reference 1

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1998

Reliability:

1 (reliable without restriction)

Qualifier:

no guideline available

Principles of method if other than guideline:

Human Patch Test, GCP compliant

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material (as cited in study report): Cetiol OE
- Lot/batch No.: 1029/8
- Physical state: Colorless liquid
- Purity: 99.9%

Species:

human

Strain:

other: caucasian

Type of coverage:

occlusive

Preparation of test site:

not specified

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

70 µL

Duration of treatment / exposure:

4 hours

Observation period:

72 hours

Number of animals:

19 volunteers

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

1.39

Max. score:

2

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

0

Interpretation of results:

GHS criteria not met

Conclusions:

The substances was rated as beeing non-irritant to humans.

Executive summary:

Dioctylether was tested in an occlusive 4-hr patch test. 19 volunteers were treated with the undiluted test substance and with a 50% concentration of dioctylether in 2-hexyl decanol. As a positive standard 2% Sodium Dodecyl Sulfate (SDS) was used which is classified as an irritant substance at a concentration of 2 %. The positive standard SDS 2% caused slight, moderate, strong and very strong reactions in 16 out of 19 volunteers, while the undiluted dioctylether caused slight and single moderate erythema in 8 out of 19 volunteers. The 50% concentration of dioctylether caused single slight erythema in 2 out of 19 volunteers. Thus, the reactions caused by dioctylether were significantly lower than the reactions caused by SDS 2%.

Reference 2

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Klimisch criteria

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

GLP compliance:

yes

Species:

rabbit

Strain:

other: Kleinrussen Chbb:HM

Details on test animals or test system and environmental conditions:

according to guideline

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

not required

Amount / concentration applied:

0.5 mL

Duration of treatment / exposure:

4 h

Observation period:

21 days after patch removal

Number of animals:

3

Details on study design:

according to guideline

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

>= 2

Reversibility:

fully reversible

Remarks:

within: 21 days

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

>= 2

Reversibility:

fully reversible

Remarks:

within 21 days

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

3

Max. score:

3

Reversibility:

fully reversible within: 21 days

Remarks on result:

positive indication of irritation

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

2.67

Max. score:

3

Reversibility:

fully reversible within: 21 days

Remarks on result:

positive indication of irritation

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

2.33

Max. score:

3

Reversibility:

fully reversible within: 21 days

Remarks on result:

positive indication of irritation

Irritation parameter:

edema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

2.67

Max. score:

3

Reversibility:

fully reversible within: 21 days

Remarks on result:

positive indication of irritation

Irritation parameter:

edema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

2.33

Max. score:

3

Reversibility:

fully reversible within: 21 days

Remarks on result:

positive indication of irritation

Irritation parameter:

edema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

2

Max. score:

2

Reversibility:

fully reversible within: 21 days

Remarks on result:

positive indication of irritation

Other effects:

none

Interpretation of results:

moderately irritating

Conclusions:

Based on the results of this study, the substance is considered to be moderately irritating.

Executive summary:

The acute dermal irritation of the test substance was tested undiluted (100% active matter) in 3 albino rabbits, strain New Zealand White. The contact time under semi-occlusive conditions was four hours. The 24/48/72 hours scores were 2.7 for the erythema and 2.3 for the oedema. The reactions disappeared totally within 21 days.

Reference 3

Endpoint:

skin 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:

Dioctyl ether is a structural closely-reated dialkyl ether with only slightly longer C-chains. The toxicological profile of the read-across substance show a high similarity to dihexyl ether.

Reason / purpose for cross-reference:

read-across source

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

24/48/72 h

Score:

ca. 1.39

Reversibility:

fully reversible

Remarks on result:

other: test in human

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

1.39

Max. score:

2

Reversibility:

fully reversible

Remarks on result:

other: test in human

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

0

Remarks on result:

other: test in human

Other effects:

none

Interpretation of results:

GHS criteria not met

Executive summary:

The test substance was tested in an occlusive 4-hr human patch test. 19 volunteers were treated with the undiluted test substance and with a 50% concentration of dioctylether in 2-hexyl decanol. As a positive standard 2% Sodium Dodecyl Sulfate (SDS) was used which is classified as an irritant substance at a concentration of 2 %. The positive standard SDS 2% caused slight, moderate, strong and very strong reactions in 16 out of 19 volunteers, while the undiluted dioctylether caused only slight and single moderate erythema in 8 out of 19 volunteers. The 50% concentration of dioctylether caused single slight erythema in 2 out of 19 volunteers. Thus, the reactions caused by dioctylether were significantly lower than the reactions caused by SDS 2%.

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:

July 26 to Sugust 31, 2018

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

The study was conducted for the notification in China where authorities do not accept non-animal nor read-across data for the endpoint eye irritation.

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

GLP compliance:

yes (incl. QA statement)

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland, 97633 Sulzfeld, Germany
- Age at study initiation: 46 weeks (animal 1) and 54 weeks (animal 2)
- Weight at study initiation: 3.7 kg (animal 1) and 3.8 kg (animal 2)
- Housing: ABS-plastic or Noryl rabbit cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 +/- 3 °C
- Humidity (%): 55 +/- 10%
- Air changes (per hr): at least 10x/h
- Photoperiod (hrs dark / hrs light): 12 dark/ 12 h light)

Vehicle:

unchanged (no vehicle)

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 ml

Duration of treatment / exposure:

24 h

Observation period (in vivo):

72 hours

Number of animals or in vitro replicates:

2

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): with 0.9 % NaCl
- Time after start of exposure: after 24 h

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

0

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

0

Remarks on result:

no indication of irritation

Irritation parameter:

conjunctivae score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0.33

Max. score:

1

Reversibility:

fully reversible within: 48 hours

Remarks on result:

probability of weak irritation

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

0

Remarks on result:

no indication of irritation

Irritation parameter:

cornea opacity score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

0

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

0

Remarks on result:

no indication of irritation

Irritation parameter:

conjunctivae score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0.33

Max. score:

1

Reversibility:

fully reversible within: 48 hours

Remarks on result:

probability of weak irritation

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

0

Remarks on result:

no indication of irritation

Other effects:

- Lesions and clinical observations: none

Animal no. 1 showed conjunctival redness score 1 from 1 hour to 24 hours after application. Chemosis score 1 was observed in this animal 1 hour after application.

Application of the test item in the eye of animal no. 2 led to conjunctival redness score 2 after 1 hour and decreased to score 1 24 hours post-application. Chemosis score 1 was recorded 1 hour after application. In both animals the effects were reversible within up to 48 hours post-application.

Neither mortalities nor significant clinical signs of toxicity or local effects were observed. However, animal no. 1 reacted very sensitive 1 hour after application, when touching the treated eye.

Upon fluorescein examinations at the end of the observation period of 72 hours no corneal lesions were found in any animal.

Interpretation of results:

GHS criteria not met

Conclusions:

Based on the result of this study, the substance dihexyl ether is not irritating to the eyes.

Executive summary:

An acute eye irritation study was performed according to OECD Test Guideline 405.

After the application into the eyes of two male NZW rabbits the test item produced slightly irritant but not corrosive effects in two animals.

Animal no. 1 showed conjunctival redness score 1 from 1 hour to 24 hours after application. Chemosis score 1 was observed in this animal 1 hour after application.

Application of the test item in the eye of animal no. 2 led to conjunctival redness score 2 after 1 hour and decreased to score 1 24 hours post-application. Chemosis score 1 was recorded 1 hour after application. In both animals the effects were reversible within up to 48 hours post-application.

Upon fluorescein examinations at the end of the observation period of 72 hours no corneal lesions were found in any animal.

Neither mortalities nor significant clinical signs of toxicity or local effects were observed. However, animal no. 1 reacted very sensitive 1 hour after application, when touching the treated eye.

Based on the result of this study, the substance dihexyl ether is not irritating to the eyes.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Acute skin irritation:

No skin irritation study is available for the substance dihexyl ether. In an acute dermal toxicity study in rats no local effects were observed at the application area after the exposure time of 24 hours.

In addition the data of the structurally related substance dioctyl ether (see below) can be used for read-across to assess the skin irritant properties of dihexyl ether. The dialkylether dioctyl ether shows a comparable toxicological profile as dihexyl ether. The data on eye irritation show the same low potential for eye irritation in rabbits as dihexyl ether. Dihexyl ether shows even less effects in the rabbit eye than the read-across substance dioctyl ether.

There are two studies with the read-across substance dioctyl ether.

In the first study the acute dermal irritation of dioctyl ether was tested undiluted (100% active matter) in 3 albino rabbits, strain New Zealand White. The contact time under semi-occlusive conditions was four hours. The 24/48/72 hours scores were 2.7 for the erythema and 2.3 for the oedema. The reactions disappeared totally within 21 days.

Dioctylether was also tested in an occlusive 4-hr patch test in humans. 19 volunteers were treated with the dioctyl ether and with a 50% dilution of dioctylether in 2-hexyl decanol. As a positive standard 2% Sodium Dodecyl Sulfate (SDS) was used which is classified as an irritant substance at this concentration. The positive standard SDS 2% caused slight, moderate, strong and very strong reactions in 16 out of 19 volunteers, while the undiluted dioctylether caused slight and single moderate erythema in 8 out of 19 volunteers. The 50% concentration of dioctylether caused single slight erythema in 2 out of 19 volunteers. Thus, the reactions caused by dioctylether were significantly lower than the reactions caused by SDS 2%. Therefore, dioctylether was rated to be slightly irritating. A classification is not justified.

Based on the higher relevance of the test result obtained in the human study compared to the animal test, the human patch test has been used as key study.

Acute eye irritation:

An aliquot of 0.1 ml aqueous solution of dihexyl ether was instilled by a single application for a 24h contact into the eyes of 3 rabbits. The eyes were scored 24, 48 and 72 hours after application. The 24/48/72 hours mean scores were 0 for the cornea, 0 for the iris, 0.33 for the conjunctival erythema and 0.11 for the conjunctival oedema. The conjunctiva reactions abated completely within 72 hours. In summary, only mild effects were observed that were fully reversible. Therefore, the substance is considered to be slightly irritating.

Justification for classification or non-classification

Based on data on the structurally-related substance dioctyl ether for skin irritation and a study on eye irritation, the substance dihexyl ether does not need to be classified according to GHS (Regulation (EU) 1272/2008).