Hexanoic acid, 3,5,5-trimethyl-, 1,1'-[2-ethyl-2-[[(3,5,5-trimethyl-1-oxohexyl)oxy]methyl]-1,3-propanediyl] ester

Endpoint summary

Description of key information

Skin Irritation
Key (test item), Sanders, 2013, Skin irritation - not irritating
Supporting (EC 234-392-1), Clouzeau, 1990, Skin irritation – not irritating
Supporting (CAS 68424-31-7), Robinson, 1991 Skin irritation – not irritating
Eye Irritation
Key (test item), Sanders, 2013, Eye irritation - not irritating
Supporting (EC 234-392-1), Clouzeau, 1990, Eye irritation – not irritating
Supporting (CAS 68424-31-7), Robinson, 1991, Eye irritation – not irritating

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:

2013-05-21 to 2013-05-24

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to other study

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)

Deviations:

no

Principles of method if other than guideline:

Not applicable

GLP compliance:

yes (incl. QA statement)

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Laboratories UK Ltd., Leicestershire, UK.
- Age at study initiation: 12-20 weeks
- Weight at study initiation: 2.26-2.33 kg
- Housing: Animals were individually housed in suspended cages.
- Diet: Food (2930C Teklad Global Rabbit diet supplied by Harlan Laboratories UK Ltd., Oxon, UK), ad libitum
- Water: Mains drinking water, ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 17-23 °C
- Humidity: 30-70 %
- Air changes: 15 air changes/hour
- Photoperiod: 12 h dark / 12 h light

IN-LIFE DATES: From: 2013-05-21 To: 2013-05-24

Type of coverage:

semiocclusive

Preparation of test site:

clipped

Vehicle:

unchanged (no vehicle)

Controls:

not required

Amount / concentration applied:

TEST MATERIAL
- Test item was used as supplied (undiluted)
- pH of the undiluted test item: 6.0
- Amount(s) applied (volume or weight with unit): 0.5 mL

Duration of treatment / exposure:

4 h

Observation period:

Immediately following removal of the patches and approximately 1, 24, 48 and 72 h later, the sites were examined for evidence of primary irritation.

Number of animals:

3 males

Details on study design:

TEST SITE
- Area of exposure: On the day of the test a suitable site was selected on the back of each rabbit. A quantity of 0.5 mL of the test item was applied directly to the skin under a 2.5 cm x 2.5 cm cotton gauze patch.
- Type of wrap if used: Treatment site was secured in position with a strip of surgical adhesive tape. To prevent the animals interfering with the patches, the trunk of each rabbit was wrapped in an elasticated corset and the animals were returned to their cages for the duration of the exposure period.

REMOVAL OF TEST SUBSTANCE
- Washing: Four hours after application the corset and patches were removed from animals and any residual test item removed by gentle swabbing with cotton wool soaked in distilled water.
- Time after start of exposure: 4 h

SCORING SYSTEM: Draize method

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

0.22

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

erythema score

Basis:

animal #1

Remarks:

mean individual score

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritation parameter:

edema score

Basis:

animal #1

Remarks:

mean individual score

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritation parameter:

erythema score

Basis:

animal #2

Remarks:

mean individual score

Time point:

24/48/72 h

Score:

0.3

Max. score:

4

Reversibility:

fully reversible within: 48 h

Irritation parameter:

edema score

Basis:

animal #2

Remarks:

mean individual score

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritation parameter:

erythema score

Basis:

animal #3

Remarks:

mean individual score

Time point:

24/48/72 h

Score:

0.3

Max. score:

4

Reversibility:

fully reversible within: 48 h

Irritation parameter:

edema score

Basis:

animal #3

Remarks:

mean individual score

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritant / corrosive response data:

Very slight erythema was noted at two treated skin sites 1 and 24 h after patch removal.
No evidence of skin irritation was noted at one treated skin site during the study.

Other effects:

All animals showed expected gain in body weight during the study.

Table 7.3.1/1: Individual Skin Reactions

Skin Reaction	Observation Time (following patch removal)	Individual Scores – Rabbit Number and Sex
		73197 Male	73198 Male	73199 Male
Erythema/Eschar Formation	Immediately	0	0	0
	1 h	0	1	1
	24 h	0	1	1
	48 h	0	0	0
	72 h	0	0	0
	Mean (24, 48 and 72 h)	0.0	0.3	0.3
Oedema Formation	Immediately	0	0	0
	1 h	0	0	0
	24 h	0	0	0
	48 h	0	0	0
	72 h	0	0	0
	Mean (24, 48 and 72 h)	0.0	0.0	0.0

Individual body weights and body weight change:

Rabbit Number	Individual body weight (kg)		Body weight change (kg)
	Day 0	Day 3
73197	2.33	2.40	0.07
73198	2.27	2.29	0.02
73199	2.26	2.29	0.03

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Under the test conditions the substance is not classified as irritating to skin according to the criteria of CLP Regulation (EC) No. 1272/2008.

Executive summary:

Test Guidance

OECD guideline 404 and EC Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion).

Method and materials

Three New Zealand White male rabbits were dermally exposed to 0.5 mL of the test material for 4 h under a semi-occlusive dressing. After removal of the residual test item, irritation was scored immediately following removal of the patches and approximately 1, 24, 48 and 72 h later, according to Draize method.

Results

Very slight erythema was noted at two treated skin sites 1 and 24 h after patch removal. No evidence of skin irritation was noted at one treated skin site during the study. All animals showed expected gain in body weight during the study. Mean individual scores at 24, 48 and 72 h after exposure for the 3 animals were 0.0, 0.3, 0.3 for erythema and 0.0, 0.0, 0.0 for oedema score, respectively. The mean erythema and oedema scores at 24, 48 and 72 h were 0.22 and 0.0 respectively. The substance is not a skin irritant in male rabbits.

Conclusion

Under the test conditions the substance is not classified as irritating to skin according to CLP Regulation (EC) No. 1272/2008.

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:

2013-05-28 to 2013-06-20

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)

Deviations:

no

Principles of method if other than guideline:

Not applicable

GLP compliance:

yes (incl. QA statement)

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Harlan Laboratories UK Ltd., Leicestershire, UK.
- Age at study initiation: 12-20 weeks
- Weight at study initiation: 2.37-2.70 kg
- Housing: Animals were individually housed in suspended cages.
- Diet: Food (2930C Teklad Global Rabbit diet supplied by Harlan Laboratories UK Ltd., Oxon, UK), ad libitum
- Water: Mains drinking water, ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 17-23 °C
- Humidity: 30-70 %
- Air changes: 15 air changes/hour
- Photoperiod: 12 h dark / 12 h light

IN-LIFE DATES: From: 2013-05-28 To: 2013-06-20

Vehicle:

unchanged (no vehicle)

Controls:

not required

Amount / concentration applied:

TEST MATERIAL
- Test item was used as supplied (undiluted)
- pH of undiluted test item: 6.0
- Amount(s) applied (volume or weight with unit): 0.1 mL

Duration of treatment / exposure:

Eyes were not rinsed throughout study

Observation period (in vivo):

Assessment of ocular damage/irritation was made approximately 1, 24, 48 and 72 h following treatment.

Number of animals or in vitro replicates:

3 males

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing: No

SCORING SYSTEM: Draize method

TOOL USED TO ASSESS SCORE: Examination of the eye was facilitated by the use of the light source from a standard ophthalmoscope.

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

fully reversible

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

24/48/72 h

Score:

0.33

Max. score:

3

Reversibility:

fully reversible

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Score:

0.33

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

cornea opacity score

Basis:

animal #1

Remarks:

mean individual score

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritation parameter:

iris score

Basis:

animal #1

Remarks:

mean individual score

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

other: not applicable

Irritation parameter:

conjunctivae score

Basis:

animal #1

Remarks:

mean individual score

Time point:

24/48/72 h

Score:

0.3

Max. score:

3

Reversibility:

fully reversible within: 48 h

Irritation parameter:

chemosis score

Basis:

animal #1

Remarks:

mean individual score

Time point:

24/48/72 h

Score:

0.3

Max. score:

4

Reversibility:

fully reversible within: 48 h

Irritation parameter:

cornea opacity score

Basis:

animal #2

Remarks:

mean individual score

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritation parameter:

iris score

Basis:

animal #2

Remarks:

mean individual score

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

other: not applicable

Irritation parameter:

conjunctivae score

Basis:

animal #2

Remarks:

mean individual score

Time point:

24/48/72 h

Score:

0.3

Max. score:

3

Reversibility:

fully reversible within: 48 h

Irritation parameter:

chemosis score

Basis:

animal #2

Remarks:

mean individual score

Time point:

24/48/72 h

Score:

0.3

Max. score:

4

Reversibility:

fully reversible within: 48 h

Irritation parameter:

cornea opacity score

Basis:

animal #3

Remarks:

mean individual score

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritation parameter:

iris score

Basis:

animal #3

Remarks:

mean individual score

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

other: not applicable

Irritation parameter:

conjunctivae score

Basis:

animal #3

Remarks:

mean individual score

Time point:

24/48/72 h

Score:

0.3

Max. score:

3

Reversibility:

fully reversible within: 48 h

Irritation parameter:

chemosis score

Basis:

animal #3

Remarks:

mean individual score

Time point:

24/48/72 h

Score:

0.3

Max. score:

4

Reversibility:

fully reversible within: 48 h

Irritant / corrosive response data:

No corneal or iridial effects were noted during the study.
Moderate conjunctival irritation was noted in all treated eyes one hour after treatment with minimal conjunctival irritation noted at the 24 h observation.
- All treated eyes appeared normal at the 48 h observation.

Other effects:

One animal showed body weight loss, one animal showed no gain in body weight and the remaining animal showed expected gain in body weight during the study.

Table 1: Results

Rabbit	1				2				3
	Initial Pain Reaction = 0				Initial Pain Reaction = 0				Initial Pain Reaction = 0
Time After Treatment (hrs)	1	24	48	72	1	24	48	72	1	24	48	72
Cornea
E = Degree of Opacity	0	0	0	0	0	0	0	0	0	0	0	0
F = Area of Cornea involved	0	0	0	0	0	0	0	0	0	0	0	0
Score (ExF)x5	0	0	0	0	0	0	0	0	0	0	0	0
Iris
D	0	0	0	0	0	0	0	0	0	0	0	0
Score (Dx5)	0	0	0	0	0	0	0	0	0	0	0	0
Conjunctivae
A = Redness	2	1	0	0	2	1	0	0	2	1	0	0
B = Chemosis	2	1	0	0	1	1	0	0	1	1	0	0
C = Discharge	2	0	0	0	1	1	0	0	2	1	0	0
Score (A+B+C)x2	12	4	0	0	8	6	0	0	10	6	0	0
Total Score	12	4	0	0	8	6	0	0	10	6	0	0

 

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Under the test conditions the substance is not classified as irritating to eyes according to the criteria of CLP Regulation (EC) No. 1272/2008.

Executive summary:

Test Guidance

OECD guideline 405 and EC Method B.5 (Acute Toxicity: Eye Irritation / Corrosion).

Method and materials

Three New Zealand White male rabbits were exposed to 0.1 mL of test item in the right eye while the left eye remained untreated and served as control. The eyelids were then gently held together for one second before releasing. The eyes were examined and the changes were observed at 1, 24, 48 and 72 h after treatment and graded according to the Draize method.

Results

No corneal or iridial effects were noted during the study. Moderate conjunctival irritation was noted in all treated eyes one hour after treatment with minimal conjunctival irritation noted at the 24 h observation. All treated eyes appeared normal at the 48 h observation. One animal showed body weight loss, one animal showed no gain in body weight and the remaining animal showed expected gain in body weight during the study. Mean individual scores at 24, 48 and 72 h after exposure for the 3 animals were 0.0, 0.0, 0.0 for cornea score; 0.0, 0.0, 0.0 for iris score; 0.3, 0.3, 0.3 for conjunctivae score and 0.3, 0.3, 0.3 for chemosis score. In this study, the test substance is not an eye irritant in male rabbits.

Conclusion

Under the test conditions, the substance is not classified as irritating to eyes according to CLP Regulation (EC) No. 1272/2008.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Data for skin and eye irritation are available from studies performed using the substance itself. In addition, read-across data are available and these data are used to support the studies on the substance itself.

Read-across to the toxicological properties of fatty acid polyols (Fatty acids, C5-9, esters with pentaerythritol (EC 270-290-3, CAS 68424-30-6) and Decanoic acid, ester with 2-ethyl-2-(hydroxymethyl)-1,3-propanediol octanoate (EC 234-392-1, CAS 11138-60-6)) and their analogues is applicable based on the similarity in structure and physico-chemical properties. The substance with the CAS No. 131459-39-7 is a structural analogue of one of the read-across substances (CAS No. 68424-30-6) and can therefore be used for read-across. The justification for read-across is presented in Section 13 Assessment reports- Read-across justification.

Skin Irritation

One reliable study is available. In this study (Sanders, 2013) performed under GLP according to OECD TG 404 and EC Method B.4, three male New Zealand White rabbits were exposed to 0.5 mL of the substance for 4 hours under semi-occlusive conditions. After removal of the residual test item, irritation was scored immediately following removal of the patches and approximately 1, 24, 48 and 72 h later, according to Draize method. Very slight erythema was noted at two treated skin sites 1 and 24 h after patch removal. No evidence of skin irritation was noted at one treated skin site during the study. All animals showed expected gain in body weight during the study. Mean individual scores at 24, 48 and 72 h after exposure for the 3 animals were 0.0, 0.3, 0.3 for erythema and 0.0, 0.0, 0.0 for oedema score, respectively. The mean erythema and oedema scores at 24, 48 and 72 h were 0.22 and 0.0 respectively. The substance is not a skin irritant in male rabbits.

 

In a supporting study, 2,2-bis[(octanoyloxy)methyl]butyl decanoate (CAS No. 11138-60-6) was tested for its skin irritation potential according to OECD Guideline 404 (Clouzeau, 1990): The shaved back of three New Zealand White rabbits was exposed to 0.5 mL test material for 4 hours under semi-occlusive conditions. The rabbits were observed for 3 d after exposure and skin reactions were assessed using the Draize scheme periodically (24, 48 and 72 hours) after removal of the test substance. No cutaneous reactions were observed in any of the tested animals at any observation interval.

Furthermore, the result of an acute dermal toxicity study on CAS 131459-39-7 which was conducted according to OECD 402 (Allen, 1999) can be used for risk evaluation of the irritation potential and supports the view that a non-classification of fatty acid polyol esters with short chain length of the fatty acids is warranted for skin irritation. This fatty acid polyol is composed of C5 -C9 fatty acids with pentaerythritol. A single dose of 2000 mg/kg bw of the test material was applied on the shaved skin of five Sprague-Dawley rats for 24 h under semiocclusive conditions and, in addition to mortality and systemic effects, the skin reactions were observed for up to 14 days after exposure. None of the animals showed any signs of skin reaction (erythema/edema/scale) after exposure to this limit dose.

Eye Irritation

One reliable study is available. In this study (Sanders, 2013) performed under GLP according to OCED TG 405 and EC Method B.5, three male New Zealand White rabbits were exposed to 0.1 mL of the substance in the right eye while the left eye remained untreated and served as control. The eyes were examined and the changes were observed at 1, 24, 48 and 72 h after treatment and graded according to the Draize method. No corneal or iridial effects were noted during the study. Moderate conjunctival irritation was noted in all treated eyes one hour after treatment with minimal conjunctival irritation noted at the 24 h observation. All treated eyes appeared normal at the 48 h observation. One animal showed body weight loss, one animal showed no gain in body weight and the remaining animal showed expected gain in body weight during the study. Mean individual scores at 24, 48 and 72 h after exposure for the 3 animals were 0.0, 0.0, 0.0 for cornea score; 0.0, 0.0, 0.0 for iris score; 0.3, 0.3, 0.3 for conjunctivae score and 0.3, 0.3, 0.3 for chemosis score. In this study, the substance is not an eye irritant in male rabbits.

 

In a supporting study, 2,2-bis[(octanoyloxy)methyl]butyl decanoate (CAS No. 11138-60-6) was tested for its eye irritation potential according to OECD Guideline 405 (Clouzeau, 1990): 0.1 mL of the test material were instilled into the conjunctival sac of one eye of three New Zealand White rabbits. Animals were observed for 72 hours and observed effects were scored 24, 48 and 72 hours after instillation according to 84/499/EEC appendix V B5 (Draize). No effects, except for one animal with a very slight exudation reaction at the 24 h time point, were observed in any of the tested animals at any relevant observation interval.

Fatty acids, C5-10, esters with pentaerythritol (CAS No. 68424-31-7) were tested for eye irritation potential according to OECD Guideline 405 (Robinson, 1991): 0.1 mL of the test material was instilled into the conjunctival sac of one eye of three New Zealand White rabbits. Animals were observed for 72 hours. Irritation was scored 24, 48 and 72 hours after instillation according to the method of Draize. No corneal or iridial effects were observed. Conjunctival effects included slight redness (one animal) and slight discharge (one animal) were transiently seen approx. one hour after dosing but were completely reversible within the first 24 h.

Justification for selection of skin irritation / corrosion endpoint:
Reliable (k=1) study performed on the substance itself

Justification for selection of eye irritation endpoint:
Reliable (k=1) study performed on the substance itself

Justification for classification or non-classification

According to the CLP criteria for classification and labelling of dangerous substances the test item is not classified as a skin or eye irritant.