Registration Dossier

Administrative data

Description of key information

Available information indicates that Oleyl tripropylenetetramine is corrosive to skin.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
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:
(See also Category polyamines in support of Oleyl dipropylenetriamine attached to 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:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.2500 (Acute Dermal Irritation)
Deviations:
no
Qualifier:
according to
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. certificate)
Species:
rabbit
Strain:
New Zealand White
Details on test animals 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

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, the in vitro data were thought to be useful in the support of the categories and to demonstrate appropriate classification, both for interpolation and extrapolation for borderline cases.

Unexpectedly, all the studies performed, including with the products of the polyamine category, 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. Also for other fatty nitrile derivatives the same results were obtained.

To evaluate the validity of the in vitro test systems for these substances 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 between 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.

Therefore, the structurally related Oleyl tripropylenetetramine 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 with polyamine products 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. Only for the C12 -alkyl branched dipropylene triamine product the 3 -minute exposure showed a viability below 50% thus indicating corrosion, whereas for the 1 hour exposure no corrosion level was reached. (Additionally, in repeat of all the experiments by MatTek itself, also for this substance the corrosion level was not reached.)

The mode of action follows 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 cytoplasmic 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 behaviour 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; Study not included in this dossier). 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-alkyl dipropylene triamine, branched, 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

As tallow tripropylenetetramine and oleyl tripropylenetetramine represent the substances with the highest number of propylene groups and longest alkyl chain-length in this group, they are expected within the group of polyamines to show the lowest corrosive properties. As in vivos kin corrosion studies indicate that these substances are corrosive, it is expected that all other substances in this group are corrosive to skin as well.

Consequently, it is concluded that Oleyl dipropylenetriamine should be classified as corrosive (Cat.1C) under GHS.

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.

 

Due to corrosive properties demonstrated in the dermal irritation/corrosion study with this substance, testing in eyes is not justified. 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 pressure of less than 4.7 x 10-5 Pa at 20°C (based on read-across from substance with shorter alkyl chain), 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.