3,6,9-trioxaundecamethylene bis(2-ethylhexanoate)

Endpoint summary

Description of key information

The primary skin irritancy of the undiluted test substance in New Zealand White rabbits was evaluated in compliance with the conditions specified in the regulation for the enforcement of the Federal Insecticide, Fungicide, and Rodent icide Act (40 CFR), the Toxic Substances Control Act (40 CFR), and the OECD Guidelines. Moderate irritation persisted 72 hours following applications. All animals were held for 7 days at which time all irriatation had cleared. The Primary Irritation Index (PII) was found to be 2.8 based on erythema and edema. The only change noted in the coloration and/or texture of the skin was desquamation that persisted in 2 of the 6 test animals. No evidence of corrosion was found.

The primary eye irritancy of the undiluted test substance in New Zealand White rabbits was evaluated in compliance with the conditions specified in the regulation for the enforcement of the Federal Insecticide, Fungicide, and Rodenticide Act (40 CFR), the Toxic Substances Control Act (40 CFR), and the OECD Guidelines. The test material produced conjunctival irritation, which had cleared by the 72 hour reading. Maximum total irritation scores for individual animals ranged from 4 to 8. There was no evidence of corrosion noted.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vivo

Remarks:

Primary skin irritation study in rabbits

Type of information:

experimental study

Adequacy of study:

key study

Study period:

November 18 1992 to December 8 1992

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Justification for type of information:

A study conducted under Good Laboratory Practice Standards (40 CFR) and conforming with internationally recognized protocols and in particular satisfying criteria of the Federal Insecticide, Fungicide, and Rodenticide Act (40 CFR), the Toxic Substances Control Act (40 CFR), and OECD Guidelines.

Qualifier:

equivalent or similar to guideline

Guideline:

other: The protocol satisfies the criteria established by the Federal Insecticide, Fungicide, and Ro denticide Act (40 CFR), the Toxic Substances Control Act (40 CFR), and the OECD Guidelines.

Deviations:

no

Principles of method if other than guideline:

Young adult, male and female New Zealand White rabbits were used. The test material was administered as received.

GLP compliance:

yes (incl. QA statement)

Remarks:

All aspects of this study, as defined in the Protocol and the Project Instruction Sheet, were conducted in accordance with Good Laboratory Practice Standards (40 CFR).

Specific details on test material used for the study:

The test material was a clear, golden-yellow liquid and was stored at room temperature throughout the study in two clear, glass jars.

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

Young adult male and female New Zealand White rabbits were used. The animals were purchased from a U.S.D.A. approved supplier.

All animals were acclimated to the laboratory for one day before use. Animals were housed singly in wire mesh suspension cages and were supplied PURINA LABORATORY RABBIT CHOW (or other comparable diet) and tap water ad libitum except for the withholding of food overnight prior to dosing. The animals were maintained in 12-hour light/12-hour dark cycles.

Type of coverage:

semiocclusive

Preparation of test site:

clipped

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

0.5 g undiluted

Duration of treatment / exposure:

4 hours

Observation period:

72 hours

Number of animals:

3 male and 3 female

Details on study design:

On the day prior to the dosing the application sites were prepared by clipping the hair from the dorsal surface of each animal.

A 0.5 gram aliquot of the undiluted test material was applied to to each animal under a one inch X one inch gauze patch, two layers thick. Each patch was held in place with adhesive tape. After application of the patch, the trunk of each animal was wrapped with rubber dental dam and this secured with staples. An outer layer of gauze was wrapped around the trunk of each animal and secured with tape. Each animal was fitted with an appropriate restraining device to prevent wrapping and patch removal. Following approximately 4 hours of exposure, the wrapping and patches were removed. The test sites were wiped free of residual test material by gentle sponging using a moistened towel.

The application sites were scored for each rabbit according to Draize at approximately 1/2 to 1 hour, 24 hours, 48 hours and 72 hours. Any other notable responses were recorded.

Irritation parameter:

primary dermal irritation index (PDII)

Basis:

mean

Time point:

24/48/72 h

Score:

2.8

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24 h

Score:

2

Max. score:

4

Reversibility:

fully reversible

Remarks on result:

probability of weak irritation

Remarks:

Hair on site and minor desquamation at 168 hr

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

48 h

Score:

2

Max. score:

4

Reversibility:

fully reversible

Remarks on result:

probability of weak irritation

Remarks:

Hair on site and minor desquamation at 168 hr

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible

Remarks on result:

probability of weak irritation

Remarks:

Hair on site and minor desquamation at 168 hr

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24 h

Score:

2

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

48 h

Score:

1

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

24 h

Score:

2

Max. score:

4

Reversibility:

fully reversible

Remarks on result:

probability of weak irritation

Remarks:

Hair on site at 168 hr

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

48 h

Score:

2

Max. score:

4

Reversibility:

fully reversible

Remarks on result:

probability of weak irritation

Remarks:

Hair on site at 168 hr

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible

Remarks on result:

probability of weak irritation

Remarks:

Hair on site at 168 hr

Irritation parameter:

erythema score

Basis:

animal #4

Time point:

24 h

Score:

2

Max. score:

4

Reversibility:

fully reversible

Remarks on result:

probability of weak irritation

Remarks:

Minor desquamation at site at 168 hr

Irritation parameter:

erythema score

Basis:

animal #4

Time point:

48 h

Score:

2

Max. score:

4

Reversibility:

fully reversible

Remarks on result:

probability of weak irritation

Remarks:

Minor desquamation at site at 168 hr

Irritation parameter:

erythema score

Basis:

animal #4

Time point:

72 h

Score:

2

Max. score:

4

Reversibility:

fully reversible

Remarks on result:

probability of weak irritation

Remarks:

Minor desquamation at site at 168 hr

Irritation parameter:

erythema score

Basis:

animal #5

Time point:

24 h

Score:

2

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

erythema score

Basis:

animal #5

Time point:

48 h

Score:

2

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

erythema score

Basis:

animal #5

Time point:

72 h

Score:

0

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

erythema score

Basis:

animal #6

Time point:

24 h

Score:

2

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

erythema score

Basis:

animal #6

Time point:

48 h

Score:

1

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

erythema score

Basis:

animal #6

Time point:

72 h

Score:

0

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

edema score

Basis:

animal #1

Time point:

24 h

Score:

2

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

edema score

Basis:

animal #1

Time point:

48 h

Score:

2

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

edema score

Basis:

animal #1

Time point:

72 h

Score:

0

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

edema score

Basis:

animal #2

Time point:

24 h

Score:

1

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

edema score

Basis:

animal #2

Time point:

48 h

Score:

1

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

edema score

Basis:

animal #2

Time point:

72 h

Score:

0

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

edema score

Basis:

animal #3

Time point:

24 h

Score:

2

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

edema score

Basis:

animal #3

Time point:

48 h

Score:

1

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

edema score

Basis:

animal #3

Time point:

72 h

Score:

0

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

edema score

Basis:

animal #4

Time point:

24 h

Score:

1

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

edema score

Basis:

animal #4

Time point:

48 h

Score:

1

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

edema score

Basis:

animal #4

Time point:

72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

edema score

Basis:

animal #5

Time point:

24 h

Score:

2

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

edema score

Basis:

animal #5

Time point:

48 h

Score:

1

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

edema score

Basis:

animal #5

Time point:

72 h

Score:

0

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

edema score

Basis:

animal #6

Time point:

24 h

Score:

1

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

edema score

Basis:

animal #6

Time point:

48 h

Score:

0

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

edema score

Basis:

animal #6

Time point:

72 h

Score:

0

Max. score:

4

Reversibility:

fully reversible

		Skin Irritation Test Ref.: 92-8820-21 C
Intact Skin
Rabbit No.	Erythema Score	Oedema Score	Comments
/Observation Time
No. 1
1 hour	2	2	Hair on site
24 hour	2	2	Hair on site
48 hour	2	2	Hair on site
72 hour	1	0	Hair on site
168 hour	0	0	Hair on site - Desq.
Mean 24,48, 72	1.67	1.33
No. 2
1 hour	1	1
24 hour	2	1
48 hour	1	1
72 hour	1	0
168 hour	0	0
Mean 24,48, 72	1.33	0.67
No. 3
1 hour	2	2	Hair on site
24 hour	2	2	Hair on site
48 hour	2	1	Hair on site
72 hour	1	0	Hair on site
168 hour	0	0	Hair on site
Mean 24,48, 72	1.67	1.00
No. 4
1 hour	2	2
24 hour	2	1
48 hour	2	1
72 hour	2	1	Desq. At site
168 hour	0	0	Desq. At site
Mean 24,48, 72	2.00	1.00
No. 5
1 hour	1	1
24 hour	2	2
48 hour	2	1
72 hour	0	0
168 hour	0	0
Mean 24,48, 72	1.33	1.00
No. 6
1 hour	2	1
24 hour	2	1
48 hour	1	0
72 hour	0	0
168 hour	0	0
Mean 24,48, 72	1.00	0.33

For each rabbit, erythema and eschar formation scores were recorded at 1/2 to 1 hours, 24 hours, 48 hours and 72 hours and these values totaled for each rabbit. The eight averaged scores from this were added together and the sum divided by 4 to obtain a Primary Irritation Index (PII).

Interpretation of results:

other: Category III accordiing to 40 CFR 156.10

Remarks:

Moderate irritation at 72 hours.

Conclusions:

The primary skin irritancy of undiluted test material was evaluated in compliance with the conditions specified in the regulation for the enforcement of the Federal Insecticide, Fungicide, and Rodenticide Act (40 CFR), the Toxic Substances Control Act (40 CFR), and the OECD Guidelines.

Moderate irritation persisted 72 hours following applications. All animals were held for 7 days at which time all irriatation had cleared.

The Primary Irritation Index (PII) was found to be 2.8 based on erythema and edema.

The only change noted in the coloration and/or texture of the skin was desquamation that persisted in 2 of the 6 test animals.

No evidence of corrosion was found.

Based on mean 24, 48 and 72 hour scores for erythema/eschar or for oedema, TegMeR(R) 804 would not be classified as a skin irritant under the EU CLP Regulation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation: in vivo

Remarks:

Primary eye irritation study in rabbits

Type of information:

experimental study

Adequacy of study:

key study

Study period:

November 18 1992 to December 8 1992

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Justification for type of information:

A study conducted under Good Laboratory Practice Standards (40 CFR) and conforming with internationally recognized protocols and in particular satisfying criteria of the Federal Insecticide, Fungicide, and Rodenticide Act (40 CFR), the Toxic Substances Control Act (40 CFR), and OECD Guidelines.

Qualifier:

equivalent or similar to guideline

Guideline:

other: The protocol satisfies the criteria established by the Federal Insecticide, Fungicide, and Ro denticide Act (40 CFR), the Toxic Substances Control Act (40 CFR), and the OECD Guidelines.

Deviations:

no

Principles of method if other than guideline:

Young adult, male and female New Zealand White rabbits were used. The test material was administered as received.

GLP compliance:

yes (incl. QA statement)

Remarks:

All aspects of this study, as defined in the Protocol and the Project Instruction Sheet, were conducted in accordance with Good Laboratory Practice Standards (40 CFR).

Specific details on test material used for the study:

The test material was a clear, golden-yellow liquid and was stored at room temperature throughout the study in two clear, glass jars.

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

Young adult male and female New Zealand White rabbits were used. The animals were purchased from a U.S.D.A. approved supplier

All animals were acclimated to the laboratory for one day before use. Animals were housed singly in wire mesh suspension cages and were supplied PURINA LABORATORY RABBIT CHOW (or other comparable diet) and tap water ad libitum except for the withholding of food overnight prior to dosing. The animals were maintained in 12-hour light/12-hour dark cycles.

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

0.1 mL undiluted

Duration of treatment / exposure:

The undiluted test material was placed into one eye of each rabbit. The untreated eye served as control.

Observation period (in vivo):

approximately 1 hour and at 24, 48 and 72 hours

Number of animals or in vitro replicates:

3 males and 3 females

Details on study design:

The eyes were examined and graded for ocular reaction at approximately 1 hour and at 24, 48 and 72 hours after appliecation using the Draize method. Except for the 1 hour scoring, the eyes were scored again for corneal opacity intensity and area using fluorescein.

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

24/48/72 h

Score:

0.33

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Table 1: Primary Eye Irritation in Rabbits Following an Ocular Application of Test Material

Rabbit		Cornea		Iris	Conjunctivae			Total
Number	Hr/Day	(Opacity)	(Area)		Erythema	Swelling	Discharge	Score
1	1 hours	0	0	0	1	1	0	4
(male)	24 hours	0	0	0	1	0	0	2/2
	48 hours	0	0	0	0	0	0	0/0
	72 hours	0	0	0	0	0	0	0/0
Mean/An 1	(24,48 and 72 hr)	0.00		0.00	0.33	0.00
2	1 hours	0	0	0	2	2	0	8
(male)	24 hours	0	0	0	1	0	0	2/2
	48 hours	0	0	0	1	0	0	2/2
	72 hours	0	0	0	0	0	0	0/0
Mean/An 2	(24,48 and 72 hr)	0.00		0.00	0.67	0.00
3	1 hours	0	0	0	1	1	0	4
(male)	24 hours	0	0	0	0	0	0	0/0
	48 hours	0	0	0	0	0	0	0/0
	72 hours	0	0	0	0	0	0	0/0
Mean/An 3	(24,48 and 72 hr)	0.00		0.00	0.00	0.00
4	1 hours	0	0	0	2	2	0	8
(female)	24 hours	0	0	0	1	1	0	4/4
	48 hours	0	0	0	0	0	0	0/0
	72 hours	0	0	0	0	0	0	0/0
Mean/An 4	(24,48 and 72 hr)	0.00		0.00	0.33	0.33
5	1 hours	0	0	0	1	1	0	4
(female)	24 hours	0	0	0	1	0	0	2/2
	48 hours	0	0	0	0	0	0	0/0
	72 hours	0	0	0	0	0	0	0/0
Mean/An 5	(24,48 and 72 hr)	0.00		0.00	0.33	0.00
6	1 hours	0	0	0	1	1	0	4
(female)	24 hours	0	0	0	1	0	0	2/2
	48 hours	0	0	0	0	0	0	0/0
	72 hours	0	0	0	0	0	0	0/0
Mean/An 6	(24,48 and 72 hr)	0.00		0.00	0.33	0.00

The total score is the sum of the following three sub-totals, with a maximum score of 110; (/) = score without/with sodium fluorescein.

1. Decgree of opacity x area x 5

2. Iris score x 5

3. (Sum of scores for erythema, swelling and discharge) x 2

Interpretation of results:

other: The undiluted test material is classified in Toxicity Category III (40 CFR 156.10) by ocular administration.

Conclusions:

The primary eye irritancy of undiluted test material was evaluated in compliance with the conditions specified in the regulation for the enforcement of the Federal Insecticide, Fungicide, and Rodenticide Act (40 CFR), the Toxic Substances Control Act (40 CFR), and the OECD Guidelines.

The test material produced conjunctival irritation, which had cleared by 72 hour reading.

Maximum total irritation scores for individual animals ranged from 4 to 8.

There was no evidence of corrosion noted.

Based on mean scores following grading at 24, 48 and 72 hours after instillation of the test material, TegMeR(R) 804 would not be classified as an eye irritant due to the minimal sores observed for corneal opacity, iritis, conjunctival redness or conjunctival oedema.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

The test substance is a member of a category of aliphatic esters submitted by The American Chemistry Council's (ACC) Aliphatic Esters Panel (Panel) under the High Production Volume (HPV) Chemical Challenge Program (ACC, 2003). The structurally similar material, decanoic acid, mixed diesters with octanoic acid and triethylene glycol (CAS 68583 -52 -8) elicited minimal to mild skin irritation when tested in 6 rabbits. Two (2) application sites exhibited minimal erythema at 14 days. All other sites exhibited no signs of irritation at 14 days. The eye irritation potential of CAS 68583 -52 -8 was also tested in 6 rabbits. Under the conditions of this test, this test article displayed only minimal ocular irritant. All animals returned to normal before 7 days.

Justification for classification or non-classification

Based on mean 24, 48 and 72 hour scores for erythema/eschar or for oedema, the test substance would not be classified as a skin irritant according to the European Regulation (EC) No. 1272/2008 on classification and labelling of chemicals.

Based on the results of testing in rabbits, the test substance would not be classified as an eye irritant according to the European Regulation (EC) No. 1272/2008 on classification and labelling of chemicals.