Registration Dossier

Administrative data

Description of key information

Etherdiamine C13i/acetate was shown to cause corrosive effects to rabbit skin following 3 minutes exposure. Necrotic effects became visible 24 hour after exposure, but were not yet present 1 hour after exposure.

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:
10.02.10 to 26.05.10
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results.
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
GLP compliance:
yes (incl. certificate)
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
Animals: Young Adult New Zealand White Rabbits, SPF

Rationale: Recognized by international guidelines as a recommended test system.

Breeder: Charles River Deutschland GmbH, Stolzenseeweg 32-36, 88353 Kisslegg / Germany

Number of Animals per Test: 2 (Animals of both sexes were used)

Age (when treated): 14 weeks (male), 14 weeks (female)

Body Weight (when treated): 2760 g (male), 2565 g (female)

Identification: By unique cage number and corresponding ear, number.

Acclimatization: Under laboratory conditions after health examination. Only animals without any visual signs of illness were used for the study.

Randomization: Selected by hand at time of delivery. No computer generated randomization program.

Environnmental Conditions:
Standard Laboratory Conditions. Air-conditioned with 10-15 air changes per hour, and continuously monitored environment with a room temperature of 17-23 °C and a relative humidity between 30-70%, automatically controlled light cycle of 12 hours light and 12 hours dark and music played during the daytime light period.

Accommodation: Individually in stainless steel cages equipped with feed hoppers and drinking water bowls.

Diet:
Pelleted standard Kliba Nafag 3418 rodent maintenance diet (batch no. 65/09 provided by Provimi Kliba AG, 4303 Kaiseraugst / Switzerland) available ad libitum. Results of analyses for contaminants are archived at Harlan Laboratories Ltd. A piece of wood (imported by Indulab AG, Gams / Switzerland from ABEDD® - LAB & VET GmbH, 1160 Vienna / Austria) and a haystick 4642 (batch no. 0902401, Provimi Kliba AG, 4303 Kaiseraugst / Switzerland) were also provided for environmental enrichment.

Water:
Community tap water from Füllinsdorf ad libitum. Results of bacteriological, chemical and contaminant analyses are archived at Harlan Laboratories Ltd.
Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
0.5 mL
Duration of treatment / exposure:
One female: 4 hours
One male: 3 minutes
Observation period:
For the female: 24 hours
For the male: 48 hours
Number of animals:
2 (one male and one female)
Details on study design:
On the day of treatment, 0.5 mL of Alkoxypropandiamineacetate and alkoxypropandiamine was placed on a surgical gauze patch (ca. 2.5 cm x 2.5 cm) held in contact with the skin by means of an adhesive hypoallergenic aerated semi-occlusive dressing and a restrainer bandage wrapped around the abdomen.

The duration of treatment was 4 hours or 3 minutes. After remolval of the dressing, the skin was flushed with lukewarm tap water to clean the application site.

As it was suspected that the test item might produce irritancy, a single animal (female) was initially treated. In contradiction to the Study Plan, the first animal was treated for four hours by mistake (Amendment 1 to Study Plan). Due to the severe dermal signs observed, one further animal (male) was treated with a shortened application of 3 minutes. Since skin corrosion could be observed in both cases, no further exposure could be humanely allowed and the study was terminated.

No statistical analysis was performed.

Observations
Viability / Mortality: Daily from acclimatization of the animals to the termination of test.

Clinical Signs (systemic): Daily from acclimatization of the animals to the termination of test.

Body Weights: At start of acclimatization, on the day of application and at termination of observation.

Skin Reactions:Observation and Scoring

The skin reaction was assessed according to the numerical scoring system listed in the Commission Regulation (EC) No. 440/2008, B.4, at approximately 1, 24 or 48 hours after exposure.
Data were summarized in tabular form, showing for each animal the irritation scores for erythema and oedema at all measurement intervals. Any lesions were described, including the degree and nature of irritation, corrosion or any other toxic effects observed, and their reversibility.

The mean score could not be calculated across 3 relevant scoring times (24, 48 and 72 hours after patch removal, according to the guidelines) since the animals were killed due to ethical reasons either on test day 2 (female) or 3 (male).
Irritation parameter:
other: necrosis
Basis:
animal: male
Time point:
other: 3 minutes
Reversibility:
not reversible
Remarks on result:
other: The mean score could not be calculated across 3 relevant scoring times (24, 48 and 72 hours after patch removal, according to the guidelines) since the animals were killed due to ethical reasons either on test day 2 (female) or 3 (male).
Irritation parameter:
other: necrosis
Basis:
animal: female
Time point:
other: 4 hours
Reversibility:
not reversible
Remarks on result:
other: The mean score could not be calculated across 3 relevant scoring times (24, 48 and 72 hours after patch removal, according to the guidelines) since the animals were killed due to ethical reasons either on test day 2 (female) or 3 (male).
Irritant / corrosive response data:
The application of Alkoxypropandiamineacetate and alkoxypropandiamine to the skin resulted in severe erythema and oedema and depigmentation (blanching) of the treated skin one hour after the 4-hour application period (female). At the 24-hour observation point, the entire treated skin area was necrotic, severe edema persisted and the animal was killed for ethical reasons.
Then, the application period was shortened to 3 minutes (male). Well-defined erythema, slight oedema and blanching were noted one hour after removal of the dressing. However, at the 24-hour observation point, the treated skin area evolved a necrosis and moderate edema, which persisted until the 48-hour observation point when this animal was also killed for ethical reasons.
Other effects:
Viability / Mortality
No intercurrent deaths occurred during the course of the study.

Clinical Signs
No clinical signs were observed throughout the entire observation period.

Body Weights
The body weight of the animals was within the range commonly recorded for this strain and age.

Coloration
Staining of the treated skin produced by the test item was not observed. However, due to the substantial dermal signs, coloration may have been obscured.

Macroscopic Findings
No necropsy was performed at the end of the study.
Skin irritation scores:

Animal
#

Sex

Evaluation interval*

Erythema

Oedema

Necrosis

91

M

1 hour

2

2

present

92

F

4

4

present

91

M

24 hours

n.a.

3

present

92

F

n.a.

4

present

91

M

48 hours

n.a.

3

present

92

F

* Examinations were performed at the specified times after removal of the dressing.

n.a. = not assessable due to necrosis produced by the test item.

† = no observation point (animal was killed on test day 2)

Skin Irritation Scores - Mean Values after 24, 48 and 72 Hours

Not applicable. Since one animal was killed after the 24-hour observation point (female) and one

animal after the 48-hour observation point (male), mean scores could not be assessed.

Skin Irritation Scores - Assessment According to EC Classification Guidelines

Exposure (Animal)

Evaluated Invervals

Corrosion

Subcategory

3 min (91, M)

1h, 24h, 48h

classified

1B

4 hours (92, F)

1h, 24h

classified

not assessed

Body weights (g):

Animal #

Sex

Acclimatization

day 1

Treatment

day 1

2

4

91

M

2729

---

2760

2575

92

F

2550

2565

2520

---

Interpretation of results:
Category 1B (corrosive)
Remarks:
Migrated information Thus, the test item induced irreversible damage to the skin. Based upon the referred classification criteria (Regulation (EC) No 1272/2008 of the European Parliament and of the Council of 16 December 2008), Alkoxypropandiamineacetate and alkoxypropandiami Criteria used for interpretation of results: EU
Conclusions:
Based upon the referred classification criteria (Regulation (EC) No 1272/2008 of the European Parliament and of the Council of 16 December 2008), Alkoxypropandiamineacetate and alkoxypropandiamine is classified in Category 1: “Corrosive” and further in Subcategory 1B.
Executive summary:

The primary skin irritation potential of Alkoxypropandiamineacetate and alkoxypropandiamine was investigated according to OECD test guideline No. 404 and Commission Regulation (EC) No. 440/2008, B.4. The test item was applied by topical semi-occlusive application of 0.5 mL to the intact left flank of two adult New Zealand White rabbits. The duration of treatment was four hours (for one female, by mistake) or three minutes (for one male). The scoring of skin reactions was performed 1 and 24 hours (female) or 1, 24 and 48 hours after removal of the dressing.

The mean score could not be calculated across 3 relevant scoring times (24, 48 and 72 hours after patch removal, according to the guidelines) since the animals were killed due to ethical reasons either on test day 2 (female) or 3 (male).

The application of Alkoxypropandiamineacetate and alkoxypropandiamine to the skin resulted in severe erythema and oedema and depigmentation of the treated skin (blanching) one hour after the 4-hour application period (female). At the 24-hour observation point, the entire treated skin area was necrotic and the animal was killed for ethical reasons. Then, the application period was shortened to 3 minutes (male). Well-defined erythema, slight oedema and blanching were noted one hour after removal of the dressing. However, at the 24-hour observation point, the treated skin area evolved a necrosis, which persisted until the 48-hour observation point when this animal was also killed for ethical reasons. For both animals teated, no clinical signs were recorded throughout the observation period.

Thus, the test item induced irreversible damage to the skin.

Based upon the referred classification criteria (Regulation (EC) No 1272/2008 of the European Parliament and of the Council of 16 December 2008), Alkoxypropandiamineacetate and alkoxypropandiamine is classified in Category 1: “Corrosive” and further in Subcategory 1B.
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

Data is available from in vivo dermal corrosion/irritation study in rabbits with Etherdiamine C13i, the substance without acetate. This study indicated corrosive properties already after 3 minutes exposure.

It is possible that with the change to acetate salt its physico-chemical properties are changed that could influence the direct corrosive properties, and further studies to evaluate dermal irritation/corrosion by Etherdiamine C13i/acetate were initialised.

 

Etherdiamine C13i/acetate was non-corrosive in the in vitro skin irritation test applying a human skin construct model. However, this study model has shown not to provide reliable results for various fatty nitrile derivatives by largely underestimating corrosive/irritating properties for these compounds. Consequently, this study has been disregarded for the evaluation of Etherdiamine C13i/acetate for dermal irritation and an in vivo study was initiated.

Two rabbits were exposed to samples of 0.5 mL of Etherdiamine C13i/acetate applied to intact, clipped skin using a semi-occlusive dressing. The duration of treatment was four hours (for one female, by mistake) or three minutes (for one male). The scoring of skin reactions was performed 1 and 24 hours (female) or 1, 24 and 48 hours after removal of the dressing.

The application of Etherdiamine C13i/acetate to the skin resulted in severe erythema and oedema and depigmentation of the treated skin (blanching) one hour after the 4-hour application period (female). At the 24-hour observation point, the entire treated skin area was necrotic and the animal was killed for ethical reasons. Then, the application period was shortened to 3 minutes (male). Well-defined erythema, slight oedema and blanching were noted one hour after removal of the dressing. However, at the 24-hour observation point, the treated skin area evolved a necrosis, which persisted until the 48-hour observation point when this animal was also killed for ethical reasons.

Consequently it is concluded that the presence of acetate does not impact corrosive properties of the etherdiamine.

With results of highly corrosive for skin, similar results are expected for the eyes, and not further testing for eye irritation is indicated.

There is no information is available following exposure via inhalation. Likelihood of exposures via inhalation is low considering the high boiling point (> 300 °C) and low vapour pressure (0.005 Pa at 25°C). The substance is classified as severe corrosive and acute toxicity testing should normally not be conducted.


Justification for selection of skin irritation / corrosion endpoint:
Key study; with the highest quality and validity

Justification for selection of eye irritation endpoint:
Study is (highly) corrosive tio skin, therefore no studies for eye irritation are required.

Effects on skin irritation/corrosion: highly corrosive

Justification for classification or non-classification

The in vivo dermal corrosion study in rabbits, indicates that Etherdiamine C13i/acetate causes corrosive effects of the skin following 3 minutes exposure, which developed during the course of a day. Consequently, GHS classification 1B is appropriate, with hazard statement H314: Causes severe skin burns and eye damage and Corrosive with R35 “Causes severe burns” for DSD.

 

There is no information is available following exposure via inhalation. Inhalation may cause respiratory irritation due to the corrosive properties of the substance. However, with a vapour pressure of 0.005 Pa at 25 °C, potential for inhalation of vapours is limited.