Registration Dossier

Administrative data

Description of key information

The in vivo skin irritation test was conducted according to OECD 404 guideline and GLP principles. The test substance is not considered to be irritating  to skin in rabbits.
In an eye irritation study with rabbits, performed according to EPA OPP 81-4 (Acute eye irritation) guideline and without GLP principles, irritation was observed. The test substance is considered to be slightly irritating to eyes.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
26 March - 05 April 2013
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
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
Qualifier:
according to guideline
Guideline:
other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 12 Nohsan, Notification No 8147, April 2011, including the most recent partial revisions.
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
- Source: Charles River Deutschland, Kisslegg, Germany
- Age at study initiation: Animals used withihn the study were at least 6 weeks old.
- Weight at study initiation: Body weights were at least 1.0 kg .
- Housing: Animals were housed individually in cages with perforated floors.
- Diet: Free access to pelleted diet for rabbits (Global Diet 2030 from Harlan Teklad, Italy). Hay and wooden sticks were available during the study period.
- Water: Free access to tap water.
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
Environmental controls for the animal room were set to maintain 18 to 24°C, a relative humidity of 40 to 70%, approximately 15 room air changes/hour, and a 12-hour light/12-hour dark cycle. Any variations to these conditions were maintained in the raw data and had no effect on the outcome of the study.

IN-LIFE DATES: From: 26 March - 05 April 2013
Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
other: Adjacent areas of the untreated skin of each animal served as controls.
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 mL
Duration of treatment / exposure:
Single application.
Observation period:
14 days.
Number of animals:
3 males.
Details on study design:
STUDY DESIGN
The study was performed in a stepwise manner and was started by treatment of a single rabbit (sentinel). The two other animals were treated in a similar manner 7 days later, after considering the degree of skin irritation observed in the first animal.

TEST SUBSTANCE PREPARATION
The test substance was applied undiluted as delivered by the sponsor. No corrections were made for the purity/composition of the test substance, since the guidelines requires a fixed amount that has to be applied.

TEST SITE
Approximately 24 hours before treatment, the dorsal fur was clipped with electric clippers, exposing an area of approximately 150 square centimeters (10x15 cm). To facilitate scoring, treated skin areas were re-clipped at least 3 hours before the observations.

The test substance was applied to the skin of one flank, using a patch of 2x3 cm.

REMOVAL OF TEST SUBSTANCE
Four hours after the application, the dressing was removed and the skin cleaned of residual test substance using tap water and watery ethanol (50% v/v).

OBSERVATIONS
- Mortality/Viability: Twice daily.
- Toxicity: At least once daily.
- Body Weight: Day of treatment (prior to application) and after the final observation.
- Necropsy: No necropsy was performed according to protocol.
- Irritation: The skin reactions were assessed at approximately 1, 24, 48 and 72 hours after the removal of the dressings and test substance. The irritation scores and a description of all other (local) effects were recorded. Adjacent areas of the untreated skin of each animal served as controls.

SCORING SYSTEM:
The irritation was assessed according to the numerical scoring system according to OECD 404.
Irritation parameter:
erythema score
Basis:
mean
Time point:
24/48/72 h
Score:
0.2
Max. score:
4
Reversibility:
fully reversible within: 48 hours after exposure in two animals and within 24 hours in the remaining animal.
Irritation parameter:
edema score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritant / corrosive response data:
Irritation: Four hours exposure to 0.5 mL of m-(2,3-epoxypropoxy)-N,N-bis(2,3-epoxypropyl)aniline resulted in very slight erythema and very slight oedema in the treated skin areas of the three rabbits. The skin irritation resolved within 48 hours after exposure in two animals and within 24 hours in the remaining animal.
Corrosion: There was no evidence of a corrosive effect on the skin.
Other effects:
Coloration/remnants: No staining of the treated skin by the test substance was observed. Dry remnants of the test substance were present on the skin on Day 1.
Toxicity/mortality: No symptoms of systemic toxicity were observed in the animals during the test period and no mortality occurred.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not 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:
May 19 -may 26 1980
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study performed according draft of U.S. guideline and before GLP was in place. Reliable observations and reliable report.
Qualifier:
equivalent or similar to guideline
Guideline:
EPA OPP 81-4 (Acute Eye Irritation)
Deviations:
no
Principles of method if other than guideline:
Based on the draft guideline 163.81-4, FR 43, 163 of August 22, 1978. No difference to the final guideline identified.
GLP compliance:
no
Remarks:
study performed before GLP was in place.
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Ciba-Geigy Ltd, Sisseln, Switzerland
- Sex: male
- Weight at study initiation: 2-3 kg
- Housing: Individual housing in metal cages, numbered by ear tags
- Diet (e.g. ad libitum): ad libitum access to standard rabbit food, NAFAG No. 814
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 4 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22+/-2 deg C
- Humidity (%): 55 +/-10 %
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 10 hours light per day

IN-LIFE DATES: From: To: May 19, 1980 to May 26, 1980
Vehicle:
unchanged (no vehicle)
Controls:
other: The left eye was treated, the right eye was untreated and used as control.
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 ml inserted into the conjunctival sac of the left eye
- Concentration (if solution): 100%
Duration of treatment / exposure:
3 animals: unrinsed, 3 animals: eyes rinsed about 30 sec after instillation
Observation period (in vivo):
7 days, examinatinos on day 1, 2, 3, 4 and 7
Number of animals or in vitro replicates:
6
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): in 3 animals the eye was washed with physiological saline, in 3 animals the eye was not washed
- Time after start of exposure: 30 sec

TOOL USED TO ASSESS SCORE: hand-slit lamp
Irritation parameter:
other: Please refer to the table below in "Any other information on results incl. tables" field.
Basis:
other: See additional information
Remarks:
Any other information on results
Time point:
other: See additional information
Reversibility:
other: Please refer to the table below in "Any other information on results incl. tables" field.
Remarks on result:
other: Please refer to the table below in "Any other information on results incl. tables" field.
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24 h
Score:
1.7
Max. score:
80
Reversibility:
fully reversible
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
48 h
Score:
1.7
Max. score:
80
Reversibility:
fully reversible
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
72 h
Score:
0
Max. score:
80
Irritation parameter:
iris score
Basis:
mean
Time point:
24 h
Score:
0
Max. score:
10
Irritation parameter:
iris score
Basis:
mean
Time point:
48 h
Score:
0
Max. score:
10
Irritation parameter:
iris score
Basis:
mean
Time point:
72 h
Score:
0
Max. score:
10
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
24 h
Score:
7.3
Max. score:
20
Reversibility:
not fully reversible within: 7 days
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
48 h
Score:
6.7
Max. score:
20
Reversibility:
not fully reversible within: 7 days
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
72 h
Score:
4
Max. score:
20
Reversibility:
not fully reversible within: 7 days
Irritation parameter:
chemosis score
Basis:
mean
Time point:
24 h
Score:
1.3
Max. score:
4
Reversibility:
not fully reversible within: 7 days
Irritation parameter:
chemosis score
Basis:
mean
Time point:
48 h
Score:
1
Max. score:
4
Reversibility:
not fully reversible within: 7 days
Irritation parameter:
chemosis score
Basis:
mean
Time point:
72 h
Score:
0.667
Max. score:
4
Reversibility:
not fully reversible within: 7 days
Irritant / corrosive response data:
slightly irritant, see table
days after exposure mean reaction score (3 animals)
unrinsed eyes rinsed eyes
cornea iris conjunctiva cornea iris conjunctiva
Redness Chemosis Discharge Redness Chemosis Discharge
1 0.33 0 1.66 1.33 0.66 0 0 1 0.33 0.33
2 0.33 0 1.33 1 1 0 0 0.66 0.33 0.33
3 0 0 0.66 0.66 0.66 0 0 0 0 0
4 0 0 0.66 0.66 0.33 0 0 0 0 0
7 0 0 0.66 0.66 0 0 0 0 0 0
Interpretation of results:
slightly irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The test material is not an eye irritant according to Regulation (EC) No 1272/2008.
Executive summary:

The eye irritancy was investigated in rabbits. The effect on the left eye of each three rabbits was scored after instillation of 0.1 ml of test material, either rinsed after 30 seconds of exposure or unrinsed. The right eyes were left untreated and used as control. The observation period was 7 days. There were slight effects on the cornea and iris visible for 2 days or less. The conjunctiva of an unrinsed eye of one rabbit remained reddened until the end of the observation period, all other animals did not show an effect on day 3 and thereafter.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

In vivo skin irritation test:

The stuctural analogue m-(2,3-epoxypropoxy)-N,N-bis(2,3-epoxypropyl)aniline was tested in a skin irritation study with rabbits, performed according to OECD 404 guideline and GLP principles.

Four hours exposure to m-(2,3-epoxypropoxy)-N,N-bis(2,3-epoxypropyl)aniline resulted in very slight erythema and very slight oedema in the treated skin areas of the three rabbits. The skin irritation resolved within 48 hours after exposure in two animals and within 24 hours in the remaining animal. There was no evidence of a corrosive effect on the skin.

No symptoms of systemic toxicity were observed in the animals during the test period and no mortality occurred. The test substance is considered to be not irritating to skin.

In vivo eye irritation:

The eye irritancy was investigated in rabbits. The effect on the left eye of each three rabbits was scored after instillation of 0.1 ml of test material, either rinsed after 30 seconds of exposure or unrinsed. The right eyes were left untreated and used as control. The observation period was 7 days. There were slight effects on the cornea and iris visible for 2 days or less. The conjunctiva of an unrinsed eye of one rabbit remained reddened until the end of the observation period, all other animals did not show an effect on day 3 and thereafter.


Justification for selection of skin irritation / corrosion endpoint:
GLP and OECD conform study.

Justification for selection of eye irritation endpoint:
The substance is slightly eye irritating but not classified according to the Regulation (EC) No 1272/2008.

Effects on eye irritation: slightly irritating

Justification for classification or non-classification

Based on the above results p-(2,3-epoxypropoxy)-N,N-bis(2,3-epoxypropyl)aniline does not have to be classified and has no obligatory labelling requirement for skin and eye irritation according to Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures.