Amines, C11-14-branched alkyl, monohexyl and dihexyl phosphates

Endpoint summary

Description of key information

The potential of test substance to cause acute dermal irritation was evaluated in two studies. The potential of the test substance to cause damage to the conjunctiva, iris or cornea was evaluated in one study. The test substance showed a skin and eye irritation potential under the test conditions chosen.

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:

November 23, 1981 - December 7, 1981

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study with restrictions (study was performed under QAU): - occlusive conditions - exposure period of 24 hours

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

yes

Remarks:

(occlusive conditions, exposure period of 24 hours)

Qualifier:

according to guideline

Guideline:

other: United States Environmental Agency (EPA) § 163.81-5 "Primary dermal irritation study". Federal Register, Vol. 43, No. 163, August 22, 1978

GLP compliance:

no

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Kleintierfarm Madoerin AG, CH-4414 Fuellinsdorf
- Weight at study initiation: 2 to 3 kg
- Housing: individually in metal cages
- Diet (ad libitum): standard rabbit food - NAFAG, No. 814
- Water (ad libitum): drinking water
- Acclimation period: min. of 4 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2
- Humidity (%): 55 +/- 10
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

occlusive

Preparation of test site:

other: shaved (one flank), shaved and scarified (other flank)

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 ml

Duration of treatment / exposure:

24 hours

Observation period:

14 days

Number of animals:

3 male ande 3 female animals

Details on study design:

TEST SITE
- Area of exposure: both side flanks (one side was just shaved, the other one was shaved and scarified)
- Type of wrap if used: gauze patch (2.5x2.5 cm), patches were covered with an impermeable material and were fastened to the body of the rabbit with adhesive tape.

SCORING SYSTEM:
Erythema and eschar formation
No erythema 0
Very slight erythema (barely perceptible) 1
Well defined erythema 2
Moderate to severe erythema 3
Severe erythema (beet redness) to slight eschar
formation (injuries in depth) 4
Total possible erythema score: 4

Edema formation
No edema 0
Very slight edema (barely perceptible) 1
Slight edema (edges of area well defined by definite raising) 2
Moderate edema (raised approximately 1 mm) 3
Severe edema (raised more than 1 mm and extending beyond area of exposure) 4
Total possible edema score: 4

Irritation parameter:

erythema score

Basis:

mean

Time point:

other: 24 h- 48 h - 72 h

Score:

2.83

Max. score:

4

Reversibility:

not fully reversible within: 14 days (all animals were affected)

Irritation parameter:

edema score

Basis:

mean

Time point:

other: 24 h - 48 h - 72 h

Score:

2.5

Max. score:

4

Reversibility:

not fully reversible within: 14 days (all animals were affected)

Irritation parameter:

primary dermal irritation index (PDII)

Score:

5

Max. score:

8

Remarks on result:

other: The scores read after 24 and 72 hours for erythema and edema for the intact as well as for the abraded skin were summed up and divided by 4 (FHSLA § 191.11): The test substance caused a marked irritation when applied to intact and abraded rabbit skin.

Irritant / corrosive response data:

The following observations were made in practically all the application sites in the course of the experiment, in addition to the scores: erythema greater than the surface of compound patch, ischaemic areas, cracked skin, scales formation.

Other effects:

Besides transient periods of anorexia in few animals no other symptoms were observed. One female animal died at day 8 of test independently of the compound administration. No gross lesions were found.

In the following tables, only the results of the treatment of the intact skin side is given, as testing on intact skin is recommended by OECD guideline 404 and the basis for skin irritation assessment.

Table 1: Evaluation of erythema an edema in male animals after a 24 hours treatment under occlusive conditions:

Observation time	Animal	Erythema	Edema
24 hours	1	3	3
	2	2	2
	3	3	3
48 hours	1	3	3
	2	3	2
	3	3	3
72 hours	1	4	4
	2	3	2
	3	4	3
14 days	1	4	4
	2	3	2
	3	4	3
Mean (24-48-72h)	1	3.33	3.33
	2	2.66	2
	3	3.33	3
Mean		3.11	2.78

Table 2: Evaluation of erythema an edema in female animals after a 24 hours treatment under occlusive conditions:

Observation time	Animal	Erythema	Edema
24 hours	1	2	2
	2	2	2
	3	3	2
48 hours	1	2	2
	2	3	3
	3	3	2
72 hours	1	2	2
	2	3	3
	3	3	2
14 days	1	dead	dead
	2	4	3
	3	4	3
Mean (24-48-72h)	1	2	2
	2	2.66	2.66
	3	3	2
Mean		2.55	2.22

Interpretation of results:

irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Under the conditions of the present experiment the test article was found to cause a marked irritation when applied to intact and abraded rabbit skin.

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:

November 23, 1981 - December 7, 1981

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study with restrictions: - observation period of 14 days, but reversibility of the effects was not completed - no detailed information of the test substance

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

yes

Remarks:

(observation period of 14 days, but reversibility of the effects was not completed, no detailed information of the test substance)

GLP compliance:

no

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Kleintierfarm Madoerin AG, CH-4414 Fuellinsdorf
- Weight at study initiation: 2 to 3 kg
- Housing: individually in metal cages
- Diet (ad libitum): standard rabbit food - NAFAG, No. 814
- Water (ad libitum): drinking water
- Acclimation period: min. of 4 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2
- Humidity (%): 55 +/- 10
- Photoperiod (hrs dark / hrs light): 12/12

Vehicle:

unchanged (no vehicle)

Controls:

other: the right eye was not treated and served as control

Amount / concentration applied:

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

Duration of treatment / exposure:

single treatment of all animals; in 3 of the 9 rabbits approximately 30 seconds after treatment the treated eye was flushed with 10 ml of physiological saline.

Observation period (in vivo):

14 days

Number of animals or in vitro replicates:

6 males and 3 females

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): In 3 of the 9 rabbits approximately 30 seconds after treatment the treated eye was flushed with 10 ml of physiological saline.

SCORING SYSTEM: as described in OECD Guideline 405

TOOL USED TO ASSESS SCORE: hand-slit lamp

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

other: 24 - 48 - 72 h

Score:

0.67

Max. score:

4

Reversibility:

fully reversible within: 14 days

Irritation parameter:

iris score

Basis:

mean

Time point:

other: 24 - 48 -72 h

Score:

0

Max. score:

2

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

other: 24 -48 -72 h

Score:

2.28

Max. score:

3

Reversibility:

not fully reversible within: 14 days (in 2 of 5 animals)

Irritation parameter:

chemosis score

Basis:

mean

Time point:

other: 24 - 48 - 72 h

Score:

2.11

Max. score:

4

Reversibility:

not fully reversible within: 14 days (in 3 of 5 animals)

Other effects:

Besides a transient anorexia of one animal on day 11, no symptoms were observed.
One female animal died on day 8 independently of the compound administration.
Besides spotted lungs no gross lesion were found.

Table 1: Rabbit eye irritation scores after single treatment with the test substance (m=males, f=females), here the results of the treated eyes, that were not rinsed, are given:

Observation time	Animal	Cornea		Iris	Conjuctiva
		OP	AR		RED	SW	DI
24 H	1 (m)	0	0	0	2	1	0
	2 (m)	1	4	0	3	3	1
	3 (m)	1	1	0	2	2	2
	4 (f)	1	3	0	2	2	1
	5 (f)	0	0	0	2	2	1
	6 (f)	1	2	0	2	3	2
48 H	1 (m)	0	0	0	2	1	0
	2 (m)	1	3	0	3	2	1
	3 (m)	0	0	0	2	1	1
	4 (f)	1	1	0	2	2	1
	5 (f)	0	0	0	2	2	1
	6 (f)	2	2	0	3	3	2
72 H	1 (m)	0	0	0	2	2	0
	2 (m)	1	1	0	2	2	1
	3 (m)	0	0	0	2	2	0
	4 (f)	1	1	0	3	3	2
	5 (f)	0	0	0	2	2	0
	6 (f)	2	2	0	3	3	2
7 days	1 (m)	0	0	0	1	2	0
	2 (m)	0	0	0	2	2	0
	3 (m)	0	0	0	1	1	0
	4 (f)	0	0	0	2	2	0
	5 (f)	0	0	0	1	2	1
	6 (f)	1	1	0	2	2	1
14 days	1 (m)	0	0	0	1	1	4
	2 (m)	0	0	0	0	1	2
	3 (m)	0	0	0	0	0	0
	4 (f)	-	-	-	-	-	-
	5 (f)	0	0	0	0	0	0
	6 (f)	0	0	0	1	1	4
Mean (24-48-72 h)	1 (m)	0.00	0.00	0.00	2.00	1.33	0.00
	2 (m)	1.00	2.67	0.00	2.67	2.33	1.00
	3 (m)	0.33	0.33	0.00	2.00	1.67	1.00
	4 (f)	1.00	1.67	0.00	2.33	2.33	1.33
	5 (f)	0.00	0.00	0.00	2.00	2.00	0.67
	6 (f)	1.67	2.00	0.00	2.67	3.00	2.00
Mean		0.67	1.11	0.00	2.28	2.11	1.00

Interpretation of results:

irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Under the conditions of this experiment the test material was found to cause irritation when applied to the rabbit eye mucosa.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin Irritation

Two studies are avaible, that investigated the skin irritationg potential of the test substance.

In the first available study, the potential of the test substance to cause acute dermal irritation or corrosion was assessed by single topical application of an amount of 0.5 ml of the unchanged test substance for 24 hours to the intact skin of 3 male and 3 female White New Zealand rabbits using a gauze patch of 2.5 x 2.5 cm, covered with an impermeable material and fastened to the body of the animals with adhesive tape. The cutaneous reactions were assessed 24, 48 and 72 hours after removal of the patch.

Erythema greater than the surface of compound patch, ischaemic areas, cracked skin, scales formation and transient periods of anorexia in few animals was observed in the animals during the course of the study. One female animal died at day 8 of test independently of the compound administration. Mean 24-48-72-hour scores were 2.83 and 2.5 for erythema and edema, respectively (intact skin sites). The effects were not fully reversible within 14 days in all animals. The test was also conducted on the abraded skin.

In the second available study, the potential of the test substance to cause acute dermal irritation or corrosion was assessed by single topical application of an amount of 0.5 ml of the test substance (1 % solution; vehicle was undefined) for 24 hours to the intact skin of 3 male and 3 female White New Zealand rabbits using a gauze patch of 2.5 x 2.5 cm, covered with an impermeable material and fastened to the body of the animals with adhesive tape. The cutaneous reactions were assessed 24, 48 and 72 hours after removal of the patch. Under the conditions of this study, an erythema score of 0.58 and an edema score of 0.1 was found based on the mean values of 6 animals at 24/48/72 hours (intact skin). The effects were fully reversible within 7 days in all animals. The test was also conducted on the abraded skin.

Taking these two studies into consideration, the findings after 24 hours occluded application with the unchanged test substance were used for evaluation. The conclusion may be more stringent than one dervied from a 4 h semi-occluded application required by the current OECD guideline. Therefore, the test substance has to be classfied as skin irritant.

 

Eye Irritation

In this study, the potential of the test substance to cause damage to the conjunctiva, iris or cornea was assessed by a single ocular application of 0.1 ml bulk volume of the test substance to one eye of each 6 male and 3 female White New Zealand rabbits (in 3 males of the overall 9 rabbits, approximately 30 seconds after treatment the treated eye was flushed with 10 ml of physiological saline). The ocular reactions were assessed approximately 24, 48 and 72 hours after application.

One female animal died on day 8 independently of the compound administration. Mean 24-48-72-hour scores for the 6 animals (eyes were not washed out) were 0.67, 0.00, 2.28 and 2.11 for corneal opacity, iris lesions, redness of the conjunctiva and chemosis. Effects on the cornea were fully reversible within 14 days, effects on the conjunctivae and chemosis were not fully reversible within 14 days in 2 and 3 animals of 5, respectively, but with a clear tendency of reversibility. Overall, the test substance does show an eye irritation potential under the test conditions chosen.

 

Respiratory irritation

No data available

Justification for selection of skin irritation / corrosion endpoint:
Study performed similar to guideline under quality control

Justification for selection of eye irritation endpoint:
Study performed similar to guideline under quality control

Effects on skin irritation/corrosion: irritating

Effects on eye irritation: irritating

Justification for classification or non-classification

Dangerous Substance Directive (67/548/EEC)

The available experimental test data is reliable and suitable for the purpose of classification under Directive 67/548/EEC. 

Based on the data, the test subtance has to be classified as skin irritant (Xi, R38) and as irritating to the eyes (Xi, R36).

 

Classification, Labeling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data are reliable and suitable for the purpose of classification under Regulation (EC) No.1272/2008. Based on the data, the test subtance has to be classified as skin irritant (Cat. 2) and as irritating to the eyes (Cat. 2).