Amines, N-C12-18-alkyltrimethylenedi-

Endpoint summary

Description of key information

There are four studies available that all indicate corrosive properties following exposures of 3 minutes and longer, with the skin destruction becoming visible after some delay. Also one study is available demonstrating severe corrosive effects in eyes.

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:

2007-11-16 to 2008-04-04

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP-guideline 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

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2500 (Acute Dermal Irritation)

Deviations:

no

Principles of method if other than guideline:

not applicable

GLP compliance:

yes (incl. QA statement)

Species:

rabbit

Strain:

other: New Zealand White HsdIf:NZW

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Winkelmann GmbH, Borchen, Germany
- Weight at study initiation: 2.4 to 2.5kg
- Housing: in ABS - plastic rabbit cages, floor 4200cm²
- Diet (e.g. ad libitum): free access to Altromin 2123 maintenance diets for rabbits, rich in crude fibre
- Water (e.g. ad libitum): free access to tap water (microbiologically controlled periodically)
- 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): 12/12

Type of coverage:

other: initial test: gauze patch was held in place with a semiocclusive dressing; additional test: patch was held manually in place

Preparation of test site:

other: clipping

Vehicle:

unchanged (no vehicle)

Controls:

other: untreated skin areas of the test animal served as control

Amount / concentration applied:

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

Duration of treatment / exposure:

initial test: 4h
additional test: 3min

Observation period:

1, 24, 48, 72h after patch removal (for both tests)

Number of animals:

1 animal for each both test

Details on study design:

TEST SITE
- Area of exposure: dorsal area of the trunk
- % coverage: small area of approximately 6cm²

REMOVAL OF TEST SUBSTANCE
initial test:
- Washing (if done): rinsed by using tap water
- Time after start of exposure: at the end of the exposure period

additional test:
Test substance was not rinsed.

SCORING SYSTEM:
according to guideline

Irritation parameter:

other: PSI

Basis:

animal #1

Remarks:

initial test (exposure: 4h)

Time point:

other: average over 24/48/72h

Score:

8

Max. score:

4

Reversibility:

not reversible

Remarks:

within 72h

Remarks on result:

other: Necrosis covering the entire patch was observed at all times

Irritation parameter:

other: PSI

Basis:

animal #2

Remarks:

additional test (exposure: 3min)

Time point:

other: average over 24/48/72h

Score:

8

Max. score:

4

Reversibility:

not reversible

Remarks:

within 72h

Remarks on result:

other: Black necrosis covering the entire patch area was observed at all times

Irritant / corrosive response data:

Dermal irritation was scored and recorded according to the grades stated in the guidelines. Due to the severe reactions and animal welfare the animals were euthanized shortly after the last observation.

Other effects:

Necrosis was observed, refer to Table 1.

Table 1: Dermal irritation of animal 1 and 2

	1h		24h		48h		72h
Animal number	Erythema	Oedema	Erythema	Oedema	Erythema	Oedema	Erythema	Oedema
1	4*	4	4*	4	4*	4	4*	4
2	1	2	4*	4	4*	4	4*	4

* necrosis covering the whole patch area

Interpretation of results:

Category 1B (corrosive) based on GHS criteria

Remarks:

Migrated information

Conclusions:

According to the criteria of the Commission Directive 2001/59/EC, the test item N-Coco-1,3-diaminopropane has to be classified as corrosive.

Executive summary:

Acute dermal irritation/corrosion of N-Coco-1,3 -diaminopropane was investigated by administration of 0.5mL unchanged test substance. In the initial test, one female New Zealand White (NZW) rabbit was exposed 4h after removing fur from the dorsal area of the trunk. At the end of the exposure period, residual test substance was rinsed by using tap water. The animal was examined for signs of erythema and oedema at 1, 24, 48, 72h after patch removal. An additional test was requested by the sponsor. Therefore, another female NZW rabbit was exposed to the unchanged test substance for 3min. Residual test substance was not rinsed and the effects were also observed after 1, 24, 48 and 72h.

Calculation of Primary Irritation Scores (PIS) as an average value over 24h, 48h and 72h was calculated for each animal. This yielded a value of 8 for both tests. Necrosis covering the entire patch was observed at all times. These severely irritant effects were not reversible within 72h after patch removal. The animal of the initial test also showed weight loss during the observation period.

According to the EC criteria for classification and labelling requirements for dangerous substances and preparations (Guidelines in Commission Directive 2001/59/EC) the test item N-Coco-1,3-diamonipropane has to be classified as corrosive.

The test on acute dermal irritation/corrosion was performed under GLP and similar to guideline OECD Guideline 404, EU Method B.4 and EPA OPPTS 870.2500 without deviations.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (corrosive)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The study was performed pre-GLP and not according to standard protocol but comparable with OECD 405. Under current regulations an eye irritaion study would no be performed due to the observed corrosive effects on skin.

Reason / purpose for cross-reference:

reference to same study

Qualifier:

according to guideline

Guideline:

other: according to a modification of the procedure described in 16 CFR.1500.42.

Principles of method if other than guideline:

Under current regulations an eye irritaion study would no be performed due to the extremely irritating effects on skin.

GLP compliance:

no

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: from H.A.R.E.- Rabbits for Research, Hewi tt, N. J. (a USDA approved supplier)
- Age at study initiation: no data
- Weight at study initiation: 2-4 kg
- Housing: individually housed in wiremesh bottom cages
- Diet (e.g. ad libitum): Agway Charles River Rabbit Ration, ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days


ENVIRONMENTAL CONDITIONS
Animals were kept in an environmentally controlled room.
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data


IN-LIFE DATES: no data

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

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

Duration of treatment / exposure:

In total 9 animals were used. The eyes of 3 animals were washed out after 4 seconds. The eyes of the other 6 animals were not washed out at all.

Observation period (in vivo):

The eyes were examined with sodium fluorescein and an ultraviolet lamp at 24, 48 and 72 hours and at 7 days.

Number of animals or in vitro replicates:

In total 9 animals were used.

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): not performed

SCORING SYSTEM: The Draize Scale for Scoring Ocular Lesions

TOOL USED TO ASSESS SCORE: fluorescein and an ultraviolet lamp

Irritation parameter:

other: Corrositivity

Basis:

other: All animals

Time point:

other: 24 hours

Reversibility:

not reversible

Remarks on result:

other: Eyes toptally destroyed (eye and surrounding tissue necrossed and abcessed)

Irritant / corrosive response data:

In every case the corrosivity of Duomeen C was so severe that the treated eyes were totally destroyed (eye and surrounding tissue necrossed and abscessed) so t h a t no accurate readings could be taken. In every case the conjunctiva of the eye appeared to be bleached.

Interpretation of results:

highly corrosive

Remarks:

Migrated information Criteria used for interpretation of results: expert judgment

Conclusions:

Due to the corrosivity of the test article accurate readings were not possible. The eye and surrounding tissue were necrosed, abscessed and bleached.

Executive summary:

The irritant/corrosive properties of N-coco-1,3 diaminopropane to the eyes was evaluated in an OECD 404 guideline study in rabbit eyes.

A volume of 0.1 ml of the test article was instilled in one eye of each rabbit by gently pulling the lower lid away from the eyeball to form a cup into which the test substance was dropped. The lids were then held together for one second. The eyes of 6 animals were not washed out after instillation of the test article. The eyes of 3 animals were washed out, approximately 4 seconds after instillation of the test article, by flushing with distilled water for about 10 seconds or until all visible test article was removed.

Due to the corrosivity of the test article accurate readings were not possible. The eye and surrounding tissue were necrosed, abscessed and bleached. The test substance can therefore be considered to be highly corrosive to the eyes without and with washout 4-seconds after instillation.

 

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Dermal irritation:

There are four studies available for evaluation for dermal irritation /corrosion of N-Coco-1,3-diaminopropane CAS 61791-63-7 (recently redefined as Amines, N-C12-18-alkyltrimethylenedi-, CAS 68155-37-3), also referred to as Coco-diamine.

 

In the first study (BSL, 073802B, 2008), N-Coco-1,3 -diaminopropane was investigated in an in vivo OECD 404 guideline study under GLP. The test substance was investigated by administration of 0.5mL unchanged test substance. In the initial test, one female New Zealand White (NZW) rabbit was exposed 4h after removing fur from the dorsal area of the trunk, and another animal was exposed for 3 minutes. At the end of the 4 hour exposure period, residual test substance was rinsed by using tap water. No rinsing was performed after the 3 minute exposure.

Necrosis covering the entire patch was observed in both animals. Necrosis was already observed 1 hour after patch removal following 4 hours exposure, but following 3 minutes exposure, necrosis was visible the next day, but not yet at one hour after exposure.

The results following the 3 minute exposure can possibly be considered to represent a too severe evaluation. Without removal of the (sticky) test substance, there is in principle no difference expected between the results after 4 hour and 3-minute exposures. Indeed, the comparable observation times at 24 hours after exposure and later, show the same effects for both application schemes.

 

A next GLP OECD 404 study was performed at SafePharm (SafePharm, Cesio, 1991) to derive the correct classification for dermal irritation/corrosion. 0.5 ml of test substance was applied to one flank using a gauze patch held in place by a non-irritating semi-occlusive dressing and a restraining bandage. The animals were exposed for 3 minutes and after this period the dressing was removed and the skin was decontaminated by gentle swabbing with cotton wool soaked in sterile distilled water. Severe dermal responses were produced. Moderate to severe erythema, haemorrhage of the dermal capillaries and moderate oedema were noted one hour after patch removal. The responses increased in severity and at subsequent observations were identified as blanching of the skin, scabbing and thickening of the skin. Scar tissue indicative of dermal corrosion was noted in 3 out the 6 treated rabbits and the end of the observation period of 14 days. The other three animals showed scabs becoming detached revealing further deep scabbing.

 

In another GLP study (SafePharm, 1594-191/1-18, 1989) N-coco-1,3 diaminopropane was tested for dermal irritation/corrosion in an OECD 404 study, which was modified in order to compare the effects of treatment site decontamination using distilled water alone or with 3% (v/v) aqueous acetic acid followed by distilled water. Six rabbits were exposed to 0.5 ml of test substance on each of both flanks for 3 minutes after which the skin of both flanks was decontaminated with cotton wool soaked in sterile distilled water on one flank and a solution of 3% acetic acid on the other side. At one hour observation, all animals showed erythema 1 (very slight, barely perceptible) to 2 (well defined). Three animals showed on the side that followed decontamination with water additionally some petechial haemorrhage of dermal capillaries. One of the six animals showed scar tissue indicative of dermal corrosion fourteen days after treatment.

 

In one non-GLP study (F&D Res.Lab, SD-1684, 1981) Duomeen C (N-coco-1,3 diaminopropane) was tested for dermal irritation according to Draize. Six rabbits were exposed to 0.5 ml of material on both clipped intact and abraded skin during 24 hours under occlusion. Scoring was done 24 hours (half hour after removal) and 72 hours after start of exposure. All six animals scored 4 (maximum) for erythema and 3 for oedema at 24 and 72 hrs on both intact and abraded skin sites. The mean primary skin irritation score (empirical score) was determined to be 7.0. Also eschar formation was seen at all observation times and locations, indicative of corrosive activity. The test article was considered to be extremely irritating to the skin of rabbits. Results are not interpretable for classification due to deviations to standard testing.

Chain	Class	Study	Result
Coco	Cat. 1B	BSL 073802B, 2008	3 min: Corrosive after 24 hrs
	Cat. 1B	SPL 1594-191/1-18, 1989	3 min: Corrosive (skin decontaminated) effects indicative for corrosion were visible from 24 hours; 1/6 animals showed scar after 14 days
	Cat. 1B	SPL, Cesio, 1991	3 min: Corrosive (skin decontaminated) Scar tissue in 3/6 animals after 14 days, effects indicative for corrosion were visible from 24 hours
	n.a.	F&D Res.Lab, SD-1684, 1981	24 hrs: Corrosive (Eschar formation (dead skin) visible at 24 and 72 hrs. No later observations)

All available data indicate corrosive properties following exposures of 3 minutes and longer, with the skin destruction becoming visible after some delay.

 

Eye irritation:

Due to corrosive properties in de dermal irritation/corrosion studies with this substance testing in eyes would not be required. In an available older study the irritant/corrosive properties of N-coco-1,3 diaminopropane to the eyes (F&D Res.Lab, SD-1684, 1981) was evaluated in an OECD 404 guideline study in rabbit eyes.

A volume of 0.1 ml of the test article was instilled in one eye of each rabbit by gently pulling the lower lid away from the eyeball to form a cup into which the test substance was dropped. The lids were then held together for one second. The eyes of 6 animals were not washed out after instillation of the test article. The eyes of 3 animals were washed out, approximately 4 seconds after instillation of the test article, by flushing with distilled water for about 10 seconds or until all visible test article was removed.

Due to the corrosivity of the test article accurate readings were not possible. The eye and surrounding tissue were necrosed, abscessed and bleached. The test substance is therefore considered to be highly corrosive to the eyes without and with washout 4-seconds after instillation.

Justification for classification or non-classification

Available data indicate corrosive properties following exposures of 3 minutes and longer. Following exposure of 3 minutes, the skin destruction is observed at examination the next day, but not yet at the observation 1 hour after the exposure.Consequently, GHS classification Corrosive Category 1B is appropriate, with hazard statement H314 ‘Causes severe skin burns and eye damage’.

 

Also one study is available demonstrating severe corrosive effects in eyes. But under GHS with the hazard phrase ‘H314 Causes severe skin burns and eye damage’ additional classification for eyes is not necessary.

 

There is no information is available following exposure via inhalation. However, with a vapour pressureof 0.0015 Pa at 20°C (based on cross-reading from C12-14-diamine showing almost similar avarage molecular weight), the potential for inhalation of vapours is limited. Also the use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalation route will be unlikely to occur.Consequently, despite the irritant nature of the substance, respiratory irritation is not expected, and classification STOT-SE Cat.3 for respiratory irritation is not required.