Amines, N-(3-aminopropyl)-N’-[3-(C16-18 (even numbered) and C18 unsaturated alkyl amino)propyl]trimethylenedi- and amines, N-(3-aminopropyl)-N’-(C16-18 (even numbered) and C18 unsaturated alkyl)trimethylenedi-

Endpoint summary

Description of key information

Available information indicates that Tallow tripropylenetetramine is corrosive to skin.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Reference 1

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

7-05-1987 until 21-05-1987

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: No batch no. or composition, but test material data sheet included. All other data available. Study is GLP and according to guideline. Results potentially biased by cleaning procedure after exposure, see other available study on irritation.

Reason / purpose for cross-reference:

reference to other study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

yes

Remarks:

see remarks below

Principles of method if other than guideline:

Three test animals were exposed for 3 min, 1 hr and 4 hrs, at the same time and not sequentially.

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: David Percival, Moston, Sandbach, Chesire, United Kingdom
- Age at study initiation: 12 to 16 weeks
- Weight at study initiation: 2.51 - 2.95 kg
- Housing: individually in suspended metal cage
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: minimum five days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17 - 21
- Humidity (%): 60-68
- Air changes (per hr): 15 changes/hour
- Photoperiod (hrs dark / hrs light): 12 / 12

Type of coverage:

semiocclusive

Preparation of test site:

other: clipped

Vehicle:

unchanged (no vehicle)

Controls:

not required

Amount / concentration applied:

0.5 ml

Duration of treatment / exposure:

3 minutes, 1 hr and 4 hrs

Observation period:

1 hr after removal of patches and 24, 48 and 72 hours later. Additional observations were made after 7 and 14 days.

Number of animals:

3

Details on study design:

TEST SITE
- Area of exposure: 2.5cm x 2.5 cm
- Type of wrap if used: elasticated corset (tubigrip)

REMOVAL OF TEST SUBSTANCE
- Washing (if done): gentle swabbing with cotton wool soaked in acetone
- Time after start of exposure: 3 min, 1 hr and 4 hrs

SCORING SYSTEM:
- According to Draize (1959) Association of Food and Drug Officials of the United States, Austin, Texas, "The appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics", see table below.

Irritation parameter:

erythema score

Basis:

mean

Remarks:

all animals 4 hrs exposure

Time point:

other: 24, 48 and 72 hrs

Score:

4

Max. score:

4

Reversibility:

not fully reversible within: 14 days

Irritation parameter:

edema score

Basis:

mean

Remarks:

all animals 4 hrs exposure

Time point:

other: 24, 48 and 72 hrs

Score:

3.4

Max. score:

4

Reversibility:

fully reversible within: 7 days

Irritant / corrosive response data:

Four-hour Exposure
Well-defined erythema and moderate oedema , with slight haemorrhage of the dermal capillaries was noted at all test sites one hour after removal of the patches. Light-brown coloured slight eschar surrounded by moderate erythema, with slight to severe oedema were noted at subsequent 24, 48 and 72-hour observations. The eschar persisted at two test sites on day seven with or without desquamation. The skin at the remaining test site was shiny and pink-coloured with continued desquamation, The shiny, pink-coloured skin was noted at all test sites on day fourteen. Desquamation and abnormal fur growth persisted at two test sites on day fourteen.

Summary of dermal lesions (following 4-h application)

no.	Effect	Hour	Days after application						Mean score erythema 24/48/72 h	Mean score oedema 24/48/72 h
		1	1	2	3	7	14
60	Erythema/ eschar Oedema	2H 3	4E 4R	4E 2R	4E 2R	4ED 0	0DP 0		4	2.7
77	Erythema/ eschar Oedema	2H 3	4E 4R	4E 4R	4E 3R	0DP 0	0DP 0		4	3.7
81	Erythema/ eschar Oedema	2H 3	4E 4R	4E 4R	4E 4R	4ED 0	0P 0		4	4
Mean									4	3.4

Fa = abnormal fur growth; Fr = reduced fur growth; D = desquamation; T = thickening of skin; R= reactions extending beyond treatment site; Hy = hyperkeratinisation; Br = brown discolourisation of skin; L = loss of skin suppleness; H = haemorrhage of dermal capillaries; Gr = green discoulorisation of skin; Tf = transverse folding of skin; Fi = fissuring of skin; Sc = small scattered scabs; Gs = glossy skin, E = eschar, P = pink coloured and shiny skin

Interpretation of results:

Category 1C (corrosive) based on GHS criteria

Remarks:

Migrated information

Conclusions:

Maximum irritation with eschar and desquamation were observed which was not reversible within the 14 days observation period, but with signs of skin repair. Although there was no actual necrosis reported, classification as corrosive is prudent.

Executive summary:

A study was performed to assess the effects of Amine 760 on the irritancy potential to the skin of the New Zealand White rabbit. The method used was based on that described in the OECD Guidelines for Testing of Chemicals (1981) No. 404 "Acute Dermal Irritation/Corrosion".

A three minute, 1 hour and 4 hours, semi-occluded dermal application of the test material to the intact skin of three rabbits followed by a decontamination procedure with acetone produced irritation scores directly after patch removal and 1,2 and 3 days afterwards.

Results: Maximum scores for erythema were observed in all animals during first 3 days and in two animals accompanied by eschar formation even until day 7, with desquamation in all three animals. At end of observation period on day 14, all animals show pink and shiny skin and in two animals desquamation is still visible. Although the report indicate no visible necrosis, the seriousness of the effects, only partial recovery, and pink shiny colouration indicative of skin recovery after damage, it is probably prudent to classify as corrosive.

Reference 2

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1986

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Reported in French. GLP, standard test, exposure only 3 minutes and 1 hour.

Qualifier:

according to guideline

Guideline:

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

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

- Strain: New-Zealand
- Sex: male 
- Source: Abbaye de Bellefontaine (49122 Bégrolles-en-Mauges, France)
- Age: no data
- Mean weight at study initiation: 2.7 kg
- Controls: auto-control (left flank)

Type of coverage:

semiocclusive

Vehicle:

other: none

Controls:

not required

Amount / concentration applied:

500 mg
undiluted,
heated before application to 50 deg.C

Duration of treatment / exposure:

3 minutes and 1 hour(s)

Observation period:

Up to 11 days

Number of animals:

6: 3 animals for 3 minute exposure: rabbits 1, 2 and 3
3 animals for 1 hr exposure: rabbits 4, 5 and 6.

Details on study design:

ADMINISTRATION:
- Area of exposure: right flank
- Total quantity applied: 500 mg
- Administration frequency: once
- Removal of test substance: residual is wiped with a gauze patch  moistened with sterile water.
- Other: 3 rabbits were exposed for 3 minutes and 3 other rabbits were  exposed for 1 hour.

EXAMINATIONS: 
- Scoring system: Draize's score: max. score 4 for erythema or oedema.
- Examination time points: 1h, 24 h, 48 h and 72 hours after the patch  removal.

Irritation parameter:

erythema score

Basis:

animal #1

Remarks:

3 minutes exposure

Time point:

other: 24,48,72 hr

Score:

2

Max. score:

4

Reversibility:

fully reversible within: 5 days

Irritation parameter:

erythema score

Basis:

animal #2

Remarks:

3 minutes exposure

Time point:

other: 24,48,72 hr

Score:

0.67

Max. score:

4

Reversibility:

fully reversible within: 4 days

Irritation parameter:

erythema score

Basis:

animal #3

Remarks:

3 minutes exposure

Time point:

other: 24,48,72 hr

Score:

2

Max. score:

4

Reversibility:

fully reversible

Remarks:

9 days

Irritation parameter:

edema score

Basis:

animal #1

Remarks:

3 minutes exposure

Time point:

other: 24,48,72 hr

Score:

1.33

Max. score:

4

Reversibility:

fully reversible within: 5 days

Irritation parameter:

edema score

Basis:

animal #2

Remarks:

3 minutes exposure

Time point:

other: 24,48,72 hr

Score:

0

Max. score:

4

Irritation parameter:

edema score

Basis:

animal #3

Remarks:

3 minutes exposure

Time point:

other: 24,48,72 hr

Score:

2

Max. score:

4

Reversibility:

fully reversible within: 5 days

Irritation parameter:

erythema score

Basis:

animal #4

Remarks:

1 hour exposure

Time point:

other: 24,48,72 hr

Score:

1.33

Max. score:

4

Reversibility:

fully reversible within: 4 days

Remarks on result:

other: dry skin was observed untl day 11.

Irritation parameter:

erythema score

Basis:

animal #5

Remarks:

1 hour exposure

Time point:

other: 24,48,72 hr

Score:

3.67

Max. score:

4

Reversibility:

fully reversible within: 7 days

Remarks on result:

other: Crusts and dry skin remaind until end

Irritation parameter:

erythema score

Basis:

animal #6

Remarks:

1 hour exposure

Time point:

other: 24,48,72 hr

Score:

0

Max. score:

4

Irritation parameter:

edema score

Basis:

animal #4

Remarks:

1 hour exposure

Time point:

other: 24,48,72 hr

Score:

3.67

Max. score:

4

Reversibility:

fully reversible within: 10 days

Irritation parameter:

edema score

Basis:

animal #5

Remarks:

1 hour exposure

Time point:

other: 24,48,72 hr

Score:

3.67

Max. score:

4

Reversibility:

fully reversible

Remarks:

9 days

Irritation parameter:

edema score

Basis:

animal #6

Remarks:

1 hour exposure

Time point:

other: 24,48,72 hr

Score:

0

Max. score:

4

3-MINUTE EXPOSURE:
A very slight erythema was observed in 2 rabbits at 1 hour after the  patch removal.
At 24h, 48h and 72h, the above-mentioned 2 rabbits exhibited a  well-defined erythema (grade 2) that persisted up to day 5. 

The third  rabbit only presented a very slight erythema at 24h and 48h. This grade 1  erythema disappeared at 72h.
A very slight to slight oedema was noted at 24h, 48h and 72h in 2  rabbits. No oedema was found in the third rabbit.

1-HOUR EXPOSURE:
Whereas a very slight to slight (grade 1 and 2 respectively) or even no erythema was found in 2 rabbits, a moderate to severe (grade 3 to 4)  

erythema was observed in the third rabbit up to day 5.
A very slight to slight odemas were observed in 2 rabbits. They worsened  thereafter, reaching a grade 4 at 24h and 72h, 

and steadily retroceded  afterwards (up to completely disappear on day 8).

Irritation scoring:

	1hr		day 2		day 3		day 4		AVG 24/48/72		day 5		day 6		day 7		day 8		day 9		day 10		day 11
Rabbit	E	O	E	O	E	O	E	O	E	O	E	O	E	O	E	O	E	O	E	O	E	O	E	O
1	1E	0	2	2	2	1	2	1	2	1.333	2A	1	0A	0	0A	0	A	0	A	0	A	0	0	0
2	0E	0	1	0	1	0	0	0	0.667	0	-	-	-	-	-	-	-	-	-	-	-	-	-	-
3	1E	0	2	2	2	2	2	2	2	2	2	1	1	0	1	0	1	0	0	0	-	-	-	-
4	1E	2	2	4	2	4	0A	3	1.333	3.667	0A	3	0A	3	0A	2	0A	2	0A	1	0A	0	0A	0
5	3E	1	4*A	4	4*A	4	3*A	3	3.667	3.667	3+A	3	2+A	2	2+A	2	+A	2	0	0	-	-	-	-
6	0E	0	0	0	0	0	0	0	0	0	-	-	-	-	-	-	-	-	-	-	-	-	-	-

E Removal of excess product using a gauze pad soaked in distilled water

A Dry skin

* Reading the erythema around the application site; application site: beginning of necrosis - brown skin -

- No more scoring when signs of irritation disappeared

+ Torn crust

Interpretation of results:

Category 1C (corrosive) based on GHS criteria

Remarks:

Migrated information

Conclusions:

Classification: corrosive (causes burns)

Executive summary:

Reported in French. GLP, standard test: 3 rabbit exposed for 3 minutes and a further three rabbits were exposed for 1 hour. After exposure period excess material was wiped off with moistened cloth. Results: One hour after exposure are signs of dermal irritation very weak in the animals exposed for 3 minutes, and moderate in the others. After 24 hours are reactions increased in both groups. The report concludes that the substance is corrosive following 1 hour application. However, the effects of corrosion are not conclusive. Specifically, no ulcers, bleeding or bloody scabs were observed in any of the animals. Only 'top necrosis' is mentioned for one animal with crusts visible until day 9, after which all effects had cleared. However, considering the serious skin effects observed after one hour exposure, for which classification as corrosive is disputable, it is prudent to certainly assume corrosion following a four times longer exposure of 4 hours.

Reference 3

Endpoint:

skin irritation: in vivo

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

weight of evidence

Study period:

02 February 2010

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: This study has been performed according to OECD and/or EC guidelines and according to GLP principles. Read accross used from oleyl dipropylene triamine.

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
Cross-reading to data available on other polyamines is acceptable on the basis of identical alkyl-polyamine structure, resulting to the same functional groups with similar properties leading to common biological activity, and common metabolic degradation. Further information on the applicability of the read-across from various diamines to Tallow-diamine can be obtained from the document "Category polyamines - 20170518.pdf" added to IUCLID Ch. 13.
For the polyamines, the substance which was considered likely to have the least corrosive properties was selected for an in vivo confirmatory study. As experience (eg. from primary fatty amines, but also indicated by comparing cytotoxicity scores from genotoxicity studies with the various polyamines) indicate that corrosivity diminishes with increasing alkyl chain length, the substance oleyl tripropylene tetramine was selected, as this has the largest alkyl chain.

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

Qualifier:

according to guideline

Guideline:

other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 12 Nousan, Notification No 8147, November 2000, including the most recent partial revisions.

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, Belton, Leics, England.
- Age at study initiation: at least 6 weeks
- Weight at study initiation: at least 1.0 kg
- Housing: The animal was individually housed in a labeled cage with perforated floor and shelter
- Diet: ad libitum
- Water: ad libitum)
- Acclimation period: Acclimatization period was at least 5 days before start of treatment under laboratory conditions

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18.8 - 20.6ºC
- Humidity (%): 44 - 74%
- Air changes (per hr): approximately 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: 02 February 2010

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

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

pH (1% in water, indicative range): 10.2-10.7

Duration of treatment / exposure:

3 minutes, 1 hour and 4 hours:
The study was initiated by treatment of one rabbit. This animal received of 0.5 grams of the test substance to the intact, clipped skin of one flank using a Metalline patch of 2x3 cm. The patch was mounted on Micropore tape#, which was wrapped around the abdomen and secured with Coban elastic bandage. The dressing was removed 3 minutes after application. Since no signs of severe skin reactions (i.e. necrosis or corrosion) were observed and it was considered that exposure could be continued humanely, two samples of 0.5 grams of the test substance were then applied to separate skin-sites on the intact, clipped skin of the same animal, using an identical procedure and one sample per dressing. One of the dressings was removed after a 1-hour exposure. After similar considerations (i.e. no severe skin reactions, necrosis or corrosion), the other dressing was removed after a 4-hour exposure. Since signs of severe skin reactions (i.e. necrosis) were observed after 4 hours of exposure, the study was immediately terminated, and no further testing was performed.

Observation period:

up to 4 hours after the first application when the single treated animal was sacrificed for ethical reasons.

Number of animals:

1 (based on the severe skin reactions, no further animals were exposed to the test substance)

Details on study design:

TEST SITE
- Area of exposure: 2x3 cm
- Type of wrap if used: Coban elastic bandage

REMOVAL OF TEST SUBSTANCE
- Washing (if done): water and ethanol
- Time after start of exposure: immediately

SCORING SYSTEM:
The skin reactions of all visible treated sites were assessed immediately after removal of a dressing. The irritation scores and a description of all other (local) effects were recorded. Adjacent areas of untreated skin of the animal served as controls.

The irritation was assessed according to the following numerical scoring system. At each observation, the highest scores given were recorded:

Erythema and eschar formation:
No erythema 0
Very slight erythema (barely perceptible) 1
Well-defined erythema 2
Moderate to severe erythema 3
Severe erythema (beef redness) * 4
*. Where signs of necrosis or corrosion (injuries in depth) prevent erythema scoring, the
maximum grade for erythema (= 4) is given.

Oedema formation:
No oedema 0
Very slight oedema (barely perceptible) 1
Slight oedema (edges of area well-defined by definite raising) 2
Moderate oedema (raised approximately 1 millimeter) 3
Severe oedema (raised more than 1 millimeter and extending beyond the area of exposure) 4

Other observations:

Mortality/Viability Twice daily.

Toxicity At least once daily.

Body Weight Day of treatment (prior to application).

Necropsy No necropsy was performed.

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

other: Immediately after 4 hr exposure

Score:

4

Max. score:

4

Reversibility:

other: Dark-brown discolouration surrounded by grey discolouration at the edges of the application area, a sign of necrosis.

Remarks on result:

other: Considered corrosive. Study terminated.

Irritant / corrosive response data:

A 3-minute exposure to 0.5 g of Oleyl tripropylenetetramine resulted in very slight erythema at 1 and 4 hours after exposure.

A 1-hour exposure resulted in very slight erythema immediately after exposure and in well defined erythema at 3 hours after exposure.

A 4-hour exposure resulted in dark brown discolouration surrounded by grey discolouration at the edge of the application area (sign of necrosis) immediately after exposure.

Other effects:

Sticky or dry remnants of the test substance were present on the skin after exposure.

See attached table Individual irritation scores.

Interpretation of results:

Category 1C (corrosive) based on GHS criteria

Remarks:

Migrated information

Conclusions:

Oleyl tripropylenetetramine should be classified as : skin corrosive (Category 1C).

Executive summary:

One rabbit was exposed to three samples of 0.5 grams of Oleyl tripropylenetetramine applied to separate skin-sites on intact, clipped skin using a semi-occlusive dressing. The exposure periods were 3 minutes, 1 hour and 4 hours, respectively. Skin reactions were assessed up to 4 hours after the 3-minute exposure. Based on severe skin reactions, no further animals were exposed to the test substance.

A 3-minute exposure to 0.5 g of Oleyl tripropylenetetramine resulted in very slight erythema at 1 and 4 hours after exposure.

A 1-hour exposure resulted in very slight erythema immediately after exposure and in well defined erythema at 3 hours after exposure.

A 4-hour exposure resulted in dark brown discolouration surrounded by grey discolouration at the edge of the application area (sign of necrosis) immediately after exposure.

Sticky or dry remnants of the test substance were present on the skin after exposure.

The dark brown discolouration surrounded by grey discolouration at the edge of the application area are signs of necrosis. Following this observation, the animal was sacrificed for humane reasons. These severe skin reactions are expected to result in deep and thick scab formation with possible ruptures of the scab, or the scab may drop off exposing scar tissue. Overall, these skin reactions were considered evidence of full thickness destruction of the skin, and hence no further animals were tested.

Based on these results and according to the:

- Globally Harmonized System of Classification and Labeling of Chemicals (GHS) of the United Nations (2007), Oleyl tripropylenetetramine should be classified as : skin corrosive (Category 1C).

- Regulation (EC) No 1272/2008 on classification, labeling and packaging of substances and mixtures, Oleyl tripropylenetetramine should be classified as Corrosive (Category 1C) and labeled as H314: Causes severe skin burns and eye damage.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (corrosive)

Eye irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

There are two studies available that evaluated tallow tripropylenetetraamine for dermal irritation/corrosion in in vivo rabbit studies.

Tallow tripropylenetetraamine was evaluated for dermal corrosion in a standard OECD 404 study (SafePharm, 116/3 ,1987). A three minute, 1 hour and 4 hours, semi-occluded dermal application of the test material to the intact skin of three rabbits, resulted to maximum scores for erythema in all animals during first 3 days and in two animals accompanied by eschar formation even until day 7, with desquamation in all three animals. At end of observation period on day 14, all animals show pink and shiny skin. In two animals desquamation was still visible. Although the report indicates no visible necrosis, the seriousness of the effects, only partial recovery, and pink shiny colouration indicative of skin recovery after damage, makes it probably prudent to classify as corrosive. (Cat. 1C)

 

In a second study Tallow tripropylenetetraamine was also evaluated for dermal corrosion following standard guidelines (CIT, 1897 TAL, 1986): 3 rabbits were exposed for 3 minutes and a further three rabbits were exposed for 1 hour. After the exposure period, excess material was wiped off with moistened cloth.

Results: One hour after exposure are signs of dermal irritation very weak in the animals exposed for 3 minutes, and moderate in the others. After 24 hours were reactions increased in both groups.

The report concludes that the substance is corrosive following 1 hour application. However, the effects of corrosion are not conclusive. Specifically, no ulcers, bleeding or bloody scabs were observed in any of the animals. Only 'top necrosis' is mentioned for one animal with crusts visible until day 9, after which all effects had cleared.

Considering the serious skin effects observed after one hour exposure, for which classification as corrosive is disputable, it is prudent to certainly assume corrosion following a four times longer exposure of 4 hours. (Cat.1C)

For the evaluation of dermal corrosion/irritation for REACH substances of various categories of Fatty amines have recently been tested. Available data and practical experience indicated that these substances are corrosive to the skin. However, the information was generally incomplete, often inconsistent and of low validity. For support in the dossiers it was considered to perform the recommended in vitro dermal corrosion studies using human epidermal skin constructs to have adequate endpoint coverage. By comparing the more objective results from these studies, they were thought to be useful to demonstrate classification, in the support of the categories, and for inter- and extrapolation for borderline cases.

Unexpectedly, all the studies performed, including with the polyamine products, indicated that these substances are NOT corrosive in these in vitro test systems using human epidermis constructs, showing viability scores after 3 minutes and 1 hour not much different from controls (The study on Tallow tripropylenetetraamine itself was not possible as the substance could not be removed from the skin. Notox, 491242, 2009). Also for other fatty nitrile derivatives the same results were obtained.

To evaluate the validity of the in vitro test systems for these substance a few further studies were performed to validate the results with in vivo studies.

 

For the polyamines, the substance which was considered likely to have the least corrosive properties was selected for an in vivo confirmatory study. As experience (eg. from primary fatty amines, but also indicated by comparing cytotoxicity scores from genotoxicity studies with the various polyamines) indicate that corrosivity diminishes with increasing alkyl chain length, the substance oleyl tripropylene tetramine was selected, as this has the largest alkyl chain.

The structurally related Oleyl dipropylenetriamine was evaluated in an in vivo dermal irritation/corrosion study in rabbits (NOTOX, 491219, 2010). Exposure of the skin of one animal for 4 hours with oleyl dipropylenetriamine resulted to evidence of full thickness destruction of the skin, and hence no further animals were tested. It was concluded that Oleyl tripropylenetetramine should be classified as skin corrosive (Category 1C).

 

In the interest of animal welfare and to minimize any testing likely to produce severe responses in animals, it was decided not to perform further in vivo corrosion studies in rabbits to confirm their corrosive properties.

 

Overview available data on dermal corrosion for polyamines:

	dipropylene triamine			Tripropylene tetraamine		dipropylene triamine (branched)		Positive control
Based on FA:	Coco	Tallow	Oleyl	Tallow	Oleyl	C12	Tallow
Skin corrosion –viabilityin vitro:3 min 1 hour	Non-Cor. 58% 22%	Non-Cor. 98% 96%	Non-Cor. 95% 89%	not pos. (95%) -	Non-Cor. 91% 85%	Corrosive 43% 42%	-	Corrosive 8-9% 6-9%
Skin corrosion – in vivo	-	-	-	Corr.1C	Corr.1C	Corr. 1B (3 min)	Corr. 1B (3 min)

(In vitro dermal corrosion: Results considered corrosive when viability is below 50% following 3 minutes, or below 15% following 1 hour exposure)

 

None of the substances reached a viability indicating corrosion following 1 hour exposure, even in a case where in vivo results show corrosion following only 3 minutes exposure.Although in that case the 3 -minute exposure showed a viability below 50% thus indicating corrosion.

The mode of action follow from their structure, consisting of an apolar fatty acid chain and a polar end of a primary amine (linked to one or two secondary amine). The structure can disrupt the cytoplasmatic membrane, leading to lyses of the cell content and consequently the death of the cell.

The similar physicochemical properties among the group of polyamines, also suggest similar behavior and toxicological responses for these substances.

A study was performed to assess the effects of four different decontamination procedures on the irritancy potential of the test material to the skin of the New Zealand White rabbit (SafePharm, 116/10, 1987). These procedures consisted of gentle swabbing with cotton wool soaked in:

a) distilled water

b) distilled water & buttermilk soap followed by distilled water only

c) 3% (v/v) aqueous acetic acid followed by cotton wool soaked in distilled water only

d) acetone

A single, three minute, semi-occluded dermal application of the test material to the intact skin of three rabbits followed by these decontamination procedures produced different irritation scores.

It was concluded that distilled water is a suitable decontaminant for this type of product.

 

There is no information available regarding the threshold concentration for dermal irritation for Tallow dipropylene triamine. For a structurally related dodecane branched dipropylene triamine a threshold is indicated in a report of a Buehler test in Guinea pigs for dermal sensitisation [Huntington, 1996, Report No.: LZA 129/953059/SS, N-(3-aminopropyl)-Ndodecylpropane-1,3-diamine Skin sensitisation in the Guinea pig - study not included in this dossier]. A preliminary irritation study evaluated irritation from epidermal exposures to the substance at various concentrations in distilled water for 6 hrs under occlusion. The highest non-irritating concentration for epidermal exposures was established at 0.5%. Epidermal concentrations of 1% resulted to incidental irritation, and 5% resulted to necrotic patches in all animals. Considering that this substance is the most corrosive substance from the group of polyamines, this value can be used as worst case threshold concentration for the whole group of polyamines.

Corrosivity to eyes is assumed for substances for which dermal corrosion has been established.

Justification for classification or non-classification

There are two studies available that evaluated tallow tripropylenetetraamine for dermal irritation/corrosion in in vivo rabbit studies. Both studies show some indication of corrosive properties to the skin, but are not completely clear.

Additionally, for tallow tripropylenetetraamine read across is applied to the structural comparable Oleyl tripropylenetetraamine. As this substance is considered to represent the substance of the group of polyamines with probably the least corrosive properties, the positive corrosive results from the in vivo dermal irritation/corrosion study in rabbits with this substance indicates that all polyamines should be considered corrosive to the skin as well.

Based on the available information, it is concluded that tallow tripropylenetetraamine should be classified as corrosive (Cat.1C) under GHS.

 

Corrosive to eyes is assumed for substances for which dermal corrosion has been established.

 

There is no information is available following exposure via inhalation. However, with a vapour pressure less than 4.7 x 10-5 Pa at 20°C, 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.