N,N-dimethyltetradecylamine N-oxide

Endpoint summary

Description of key information

There are several key and supporting studies available for C14 AO indicating that the substance is irritating to the skin and corrosive to the eyes of rabbits. These results are supported by the available studies on C12-14 AO.

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:

1997-10-22 to 1997-11-07

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline study to GLP.

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

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: Kulper Rabbitry, Gary, Indiana USA
- Age at study initiation: 8 - 10 weeks
- Weight at study initiation: 2120 - 2370 g
- Housing: stainless steel cages
- Diet (e.g. ad libitum): Purina rabbit Chow ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 4 days

ENVIRONMENTAL CONDITIONS
Environmental conditions were not specified but cages were maintained in a temperature, humidity and light controlled room.

IN-LIFE DATES: From: 1997_10_22 To: 1997_11_6

Type of coverage:

semiocclusive

Preparation of test site:

other: clipped

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:

4 hours

Observation period:

14 days

Number of animals:

6 male

Details on study design:

TEST SITE
- Area of exposure: 6 cm square
- % coverage: no data
- Type of wrap if used: 2 layer gauze patch held in place with non-irritating Kendall Curity Standard Porous Tape and then covered with a semi-occlusive plastic overwrap secured in place with Kendall Curity Standarf Porous Tape.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Yes
- Time after start of exposure: 4 hours

SCORING SYSTEM: Draize

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

other: mean of 24, 48 & 72 hrs

Score:

3

Max. score:

4

Reversibility:

fully reversible within: 14 days

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

other: mean of 24, 48 & 72 hrs

Score:

3

Max. score:

4

Reversibility:

fully reversible within: 14 days

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

other: mean of 24, 48 & 72 hrs

Score:

3

Max. score:

4

Reversibility:

fully reversible within: 14 days

Irritation parameter:

erythema score

Basis:

animal #4

Time point:

other: mean of 24, 48 & 72 hrs

Score:

3

Max. score:

4

Reversibility:

fully reversible within: 14 days

Irritation parameter:

erythema score

Basis:

animal #5

Time point:

other: mean of 24, 48 &72 hrs

Score:

3

Max. score:

4

Reversibility:

fully reversible within: 14 days

Irritation parameter:

erythema score

Basis:

animal #6

Time point:

other: mean of 24, 48 & 72 hrs

Score:

3

Max. score:

4

Reversibility:

fully reversible within: 14 days

Irritation parameter:

edema score

Basis:

animal #1

Time point:

other: mean of 24, 48 &72 hrs

Score:

2.33

Max. score:

4

Reversibility:

fully reversible within: 7 days

Irritation parameter:

edema score

Basis:

animal #2

Time point:

other: mean of 24, 48 & 72 hrs

Score:

1.33

Max. score:

4

Reversibility:

fully reversible within: 7 days

Irritation parameter:

edema score

Basis:

animal #3

Time point:

other: mean of 24, 48 & 72 hrs

Score:

1.66

Max. score:

4

Reversibility:

fully reversible within: 7 days

Irritation parameter:

edema score

Basis:

animal #4

Time point:

other: mean of 24, 48 & 72 hrs

Score:

2

Max. score:

4

Reversibility:

fully reversible within: 7 days

Irritation parameter:

edema score

Basis:

animal #5

Time point:

other: mean of 24, 48 & 72 hrs

Score:

1.66

Max. score:

4

Reversibility:

fully reversible within: 7 days

Irritation parameter:

edema score

Basis:

animal #6

Time point:

other: mean of 24, 48 & 72 hrs

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 7 days

Other effects:

Coriaceousness and slight fissuring on all at 48 hours
Coriaceousness and slight fissuring on all at 72 hours
Some scaling of epidermis on all at 168 hours.

Rabbit #	Initial bwt (g)	Final bwt (g)	Sex	ER 4.5	ED 4.5	ER 24	ED 24	ER 48	ED 48	ER 72	ED 72	ER 168	ED 168	ER 336	ED 336
403	2040	2260	M	2	1	2	3	3	3	4	1	1	0	0	0
404	2120	2375	M	2	0	2	1	3	2	4	1	2	0	0	0
405	2200	2490	M	1	0	2	2	3	2	4	1	1	0	0	0
406	2070	2250	M	1	1	2	2	3	2	4	2	1	0	0	0
407	2140	2400	M	2	1	2	2	3	2	4	1	2	0	0	0
408	2155	2480	M	1	1	2	1	3	1	4	1	2	0	0	0
		Ave:		1.5	0.67	2.0	1.83	3.0	2.0	4.0	1.17	1.5	0	0	0
		Total		2.17		3.83		5.0		5.17		1.50		0

ER: Erythema

ED: Oedema

Interpretation of results:

Category 2 (irritant)

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The substance is highly irritating to the skin of rabbits under the conditions of the study.

Executive summary:

In an OECD 404 Guideline study for acute skin irritation, the substance tested as provided was highly irritating to the skin of rabbits.

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:

1997-10-23 to 1997-11-13

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline study to GLP.

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: Kulper Rabbitry, Gary, Indiana USA
- Age at study initiation: 8 - 10 weeks
- Weight at study initiation: 2120 - 2370 g
- Housing: stainless steel cages
- Diet (e.g. ad libitum): Purina rabbit Chow ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 4 days

ENVIRONMENTAL CONDITIONS
Environmental conditions were not specified but cages were maintained in a temperature, humidity and light controlled room.

IN-LIFE DATES: From: 1997_10_23 To: 1997_11_13

Vehicle:

unchanged (no vehicle)

Controls:

other: untreated eye acted as control

Amount / concentration applied:

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

Duration of treatment / exposure:

21 days (no rinsing)

Observation period (in vivo):

21 days

Number of animals or in vitro replicates:

6

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): No

SCORING SYSTEM: Draize

TOOL USED TO ASSESS SCORE: fluorescein

Irritation parameter:

cornea opacity score

Basis:

mean

Remarks:

of six animals

Time point:

other: mean of 24, 48 & 72 hrs

Score:

1.33

Max. score:

4

Reversibility:

not fully reversible within: 21 days

Remarks on result:

other: highest individual mean score = 1.67 (3/6 animals)

Irritation parameter:

iris score

Basis:

mean

Remarks:

of six animals

Time point:

other: mean of 24, 48 & 72 hrs

Score:

1

Max. score:

2

Reversibility:

not fully reversible within: 21 days

Remarks on result:

other: highest individual mean score =1 (all animals)

Irritation parameter:

conjunctivae score

Basis:

mean

Remarks:

of six animals

Time point:

other: mean of 24, 48 & 72 hrs

Score:

3

Max. score:

3

Reversibility:

not fully reversible within: 21 days

Remarks on result:

other: highest individual mean score =3 (all animals)

Irritation parameter:

chemosis score

Basis:

mean

Remarks:

of six animals

Time point:

other: mean of 24, 48 & 72 hrs

Score:

3

Max. score:

4

Reversibility:

not fully reversible within: 21 days

Remarks on result:

other: highest individual mean score = 3 (all animals)

Group Mean Eye Irritation Scores (Draize Values)

Treatment: No wash

	Observation Time – Hours
	1	24	48	72	168	336	504
Averages
Cornea	-	20.0	30.0	30.0	43.3	45.0	38.3
Iris	5.0	5.0	5.0	5.0	5.8	6.7	5.8
Conjunctiva	15.7	18.3	18.0	17.0	14.3	11.7	7.0
Total	20.7	43.3	53.0	52.0	63.4	63.4	51.1

Interpretation of results:

Category 1 (irreversible effects on the eye)

Remarks:

Migrated information Criteria used for interpretation of results: EU

Executive summary:

In an OECD 405 Guideline study for acute eye irritation, the substance tested as provided produced irreversible effects on the eye and is classified as Category 1.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin irritation:

In the key study for C14 AO, performed according to OECD TG 404 under GLP [Kukulinski M (1997b)], the test material (0.5 mL, 29.9 %AO) was applied to the intact skin of six male rabbits (New Zealand White) and covered with a semi-occlusive dressing for four hours. At the end of the exposure period the treatment sites were cleaned and reactions were noted over a 14 day period. Well-defined erythema was observed in all animals at 24 hours increasing to severe erythema at 72 hours. These reactions had completely cleared by 14 days. Very slight to moderate oedema was observed in all animals at 24 hours, decreasing to very slight to slight oedema at 72 hours. These reactions had completely cleared by 7 days.

The results of this study are supported by studies performed using another member of the amine oxide category – C12-14 AO. In a study, performed according to OECD TG 404 [Fulfs JC (1978b)], C12-14 AO (0.4 mL, 27.8 %AO) was applied to the intact and abraded skin of 3 female rabbits (New Zealand White) and covered with an occlusive dressing for 24 hours. At the end of the exposure period the treatment sites were wiped with a wet paper towel and reactions noted over a 72 hour period. Very slight to well defined erythema was observed at the intact and abraded sites of all the test animals at 24 hours. At 72 hours severe erythema (beet redness) to slight eschar formation were observed at the intact and abraded sites of all test animals. No oedema was observed at any time point. Similar results were obtained in a second supporting study [Dean WP (1978b)].

In three further supporting studies, performed according to US Federal Register, vol 41(188): 42572 (27^thSeptember 1976), C12-14 AO (0.5 mL, 30 % AO) was applied to the intact skin of 6 rabbits (albino) and covered with an occlusive dressing for 4 hours. At the end of the exposure period the test substance was removed by wiping with a paper towel moistened with sterile distilled water. The sites were scored immediately and after 48 hours. Erythema and oedema scores increased during the 48 hour observation period. No destruction of intact skin was observed after the four hour exposure [Haynes G (1982b,c); Sugar JR & Haynes G (1981)].

One study is available that was performed using a lower concentration of C14 AO. In this study, performed according to CFR 16.1500.41, the test material (0.5 mL, 5.0 %AO) was applied to the intact and abraded skin of 6 rabbits and covered with an occlusive dressing for 24 hours [LaCap & Frances (1986a)]. Reactions were scored after 24 and 72 hours. Very slight erythema and oedema were observed in two animals at 24 hours. All reactions had cleared by 72 hours.

Three further studies are available performed using lower concentrations of C12-14 AO. In the first of these [Nicholas P & Jones JR (1976)] performed according to US Federal Register Vol 38 (187): 1500:41 (1973) the substance (0.5 mL, 6 %w/w AO) was applied to the intact and abraded skin of 6 rabbits (New Zealand White) and covered with an occlusive dressing for 24 hours. Very slight to moderate to severe erythema and very slight to slight oedema was observed at the intact and abraded sites of all test animals at 24 hours. At 72 hours no to slight erythema and no to very slight oedema was observed at the intact and abraded sites of all test animals. In the second study the substance (0.5 mL, 0.6 % AO) was applied to the intact and abraded skin of 8 rabbits (New Zealand White) and covered with an occlusive dressing for 24 hours. No to very slight erythema and oedema was observed at the intact and abraded sites of all test animals at 24 and 72 hours [Heisler E et al (1975)]. In the third study [Kukulinski M (1997)] performed according to FHSA/CPSC Design, 16 CFR1500 the substance (0.5 mL, 2.5 or 5 %AO) was applied to the intact and abraded skin of 3 rabbits (New Zealand White). At 5 % AO one rabbit had no erythema at 24 hours on had very slight and the third had well defined erythema at the intact sites. At 72 hours two rabbits had no erythema and the third very slight erythema. No oedema was observed at either 24 or 72 hours. At 2.5 % AO very slight erythema was observed in one rabbit at 24 hours. All other scores were zero at both 24 and 72 hours.

Eye irritation:

In the key study for C14 AO, performed according to OECD TG 405 [Kukulinksi M (1997d)], the test material (0.1 mL, 29.9 % AO) was instilled into one eye of each of six female rabbits (New Zealand White). The eyes were not rinsed following instillation. The observable response included irreversible corneal opacity varying between grade 1 at 24 hours and grade 1-4 at 21 days. Grade 1 iridic response was observed in all animals at 24 hours and was still present in 5/6 animals at 21 days at grade 1-2. Irreversible conjunctival redness varying between grade 3 at 24 hours and grade 1or 2 at 21 days was observed in all animals. Conjunctival chemosis grade 3or 4 was observed at 24 hours and remained in 5/6 animals at 21 days at grade 1. From these observations it is concluded that C14 AO caused irreversible damage to the rabbit eye.

The results of this study are supported by studies performed using another member of the amine oxide category – C12-14 AO. In a study performed according to OECD TG 405 [Fulfs JC (1978c)] C12-14 AO (0.1 mL, 27.8 % AO) was instilled into the eyes of two groups of three rabbits (New Zealand White). The eyes of the first group of 3 rabbits were not rinsed and the eyes of the second group of 3 rabbits were rinsed, approximately 4 seconds following instillation of the test substance, with 20 ml of lukewarm distilled water. In the first group the maximum average score was 4.0 at one day. The observable response included irreversible corneal opacity in all three animals up to 35 days. No iridic response was observed. Conjunctival redness with grade 1 and conjunctival chemosis up to grade 2 were observed and fully reversed within 14 days. In the second group the maximum average score was 3.67 at one day. The observable response included irreversible corneal opacity in one animal up to 35 days. No iridic response was observed. Conjunctival redness with grade 1 and conjunctival chemosis up to grade 2 were observed and fully reversed within 2 days.

In a further supporting study performed according to OECD TG 405 [Dean WP (1978c)] C12-14 AO was instilled into the eyes of two groups of three rabbits (New Zealand White). Group I and Group II received 0.1 mL of 28 % AO. Group III received 0.1 mL of a 10 % dilution, i.e. 2.8 % AO. The eyes of the Group I and Group III rabbits were not rinsed and the eyes of the Group II rabbits were rinsed, approximately 4 seconds following instillation of the test material, with 20 mL of lukewarm distilled water. For Group I the maximum average score was 8.0 on 4th day. The observable response included irreversible corneal opacity in all three animals till 35 days. Iridic response with grade 1 was observed. Conjunctival redness up to grade 2 was observed and conjunctival chemosis up to grade 3 (swelling with lids about half closed) was observed. The reactions were not fully reversed up to 35 days. For Group II the maximum average score was 6.0 on the third day. The observable response included irreversible corneal opacity in one animal up to 35 days. Iridic response up to grade 1 was observed. Conjunctival redness up to grade 2.5 (more diffuse beefy red areas) and conjunctival chemosis up to grade 2.5 were observed which were not fully reversed within 35 days. For Group III the maximum average score was 4.8 on the second day. The observable response included corneal opacity which was reversed within 7 days. Iridic response up to grade 1 was observed. Conjunctival redness up to grade 2 (more diffuse crimson red areas) and conjunctival chemosis up to grade 2 were observed. All reactions were fully reversed within 21 days in all animals. In this group one rabbit was found dead and the cause of death was unable to be determined. From these observations it can be concluded that C12-14 AO at a concentration of 28 %AO caused irreversible damage to the rabbit eye. A 10 % dilution of the test substance (i.e. 2.8 % AO) caused irritation that was reversible within 21 days.

Two studies are available performed on a lower concentration of C14 AO (2.5 %AO). Both studies were performed according to CFR 16 1500.42. In the first study [Rothstein & Platt (1985)] the test material (0.1 mL) was instilled into the eyes of six rabbits. Reactions were observed at 24, 48 and 72 hours after treatment. Corneal opacity (grade 1) was observed in one animal at up to 48 hours but was reversed by the 72 hour observation. No iridic response was observed. Grade 1 conjunctival redness was observed in 4/6 animals up to 72 hours. Conjunctival chemosis (grade 2) was observed in two animals at 24 hours and remained present (grade 1) in one animal at the end of the observation period. In the second study [LaCap & Frances (1986b)] the test material (0.1 mL) was instilled into the eyes of 6 rabbits. Reactions were observed at 24, 48 and 72 hours after treatment. No corneal opacity or iridic response was observed in any of the animals at any time point. Conjunctival redness (grade 1) and chemosis (grade 1) was observed in three animals at 24 hours but was reversed by 48 hours. On the basis of these studies, it is concluded that C14 AO is non-irritant to rabbit eyes at a concentration of 2.5 %w/w.

Justification for selection of skin irritation / corrosion endpoint:
This study was performed to OECD guidelines under GLP and has a Klimisch score of 1.

Justification for selection of eye irritation endpoint:
This study was performed to OECD guidelines under GLP and has a Klimisch score of 1.

Effects on skin irritation/corrosion: highly irritating

Effects on eye irritation: corrosive

Justification for classification or non-classification

The substance is classified as Skin Irritant Category 2 on the basis of the reactions seen in the skin irritation studies.

The substance caused damage to the eyes of rabbits that did not fully reverse during the 21 day observation period. It is therefore classified as Eye Damage Category 1.