Registration Dossier

Administrative data

Description of key information

 Amines, polyethylenepoly-, triethylenetetramine fraction is corrosive to skin and 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:
August 4-19,1992
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
stability/purity not reported
GLP compliance:
yes (incl. certificate)
Specific details on test material used for the study:
- Amount received: 662.77 g (gross weight)
- pH: 8 (litmus paper)
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hazelton Research Products, Denver, PA
- Age at study initiation: 8-12 weeks
- Weight at study initiation: 2.325-2.607 kg
- Housing: Rabbits were housed individually in cages sized in accordance with the ''Guide for the Care and Use of Labolatory Animals'' of the Institute of National Research Council.
- Diet: Purina Lab Rabbit Chow (H.F.) ad libitum
- Water:fresh tap water, ad libitum
- Acclimation period: minimum 5d


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20°C ± 3 (63°-73°F)
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light):12h light, 12h dark


Type of coverage:
semiocclusive
Preparation of test site:
other: shaved and abraded
Vehicle:
unchanged (no vehicle)
Controls:
not specified
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5mL/site (6 cm²)

Duration of treatment / exposure:
The test article was administrated once per site:
3 min, 60 min, 4h, 24 h
Observation period:
14d
Number of animals:
Six (6) :3♂ and 3♀
Details on study design:
TEST SITE
- Area of exposure: 5 sites on the dorsal trunk
- Type of wrap if used: impervious material

REMOVAL OF TEST SUBSTANCE
- Washing (if done): by using water and a gauze
- Time after start of exposure: 3 min, 60 min, 4h, 24h

SCORING SYSTEM:
Draize Evaluation of Dermal Irritation, Primary Irritation Index
Irritation parameter:
primary dermal irritation index (PDII)
Basis:
mean
Remarks:
6 animals
Time point:
other: 4h exposure
Score:
8
Max. score:
8
Reversibility:
not reversible
Remarks on result:
other: necrosis at 24 hour reading time point in 5/6 animals
Irritation parameter:
erythema score
Remarks:
3-minute exposure
Basis:
mean
Remarks:
6 animals
Time point:
24/48/72 h
Score:
3.7
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: necrosis in all animals
Irritation parameter:
edema score
Remarks:
3-minute exposure
Basis:
mean
Remarks:
6 animals
Time point:
24/48/72 h
Score:
3.5
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: necrosis in all animals
Irritant / corrosive response data:
animals have been exposed for 60min, 4h, and 24h. All animals scored 4 (necrosis) for erythema and edema immediately after unwrapping.
Severe erythema and severe edema remained present in all animals at all observation periods during the study (up to 14 days).


 

 Animal No.  Sex  Body Weight Initial (kg)  Body weight Final (kg)
 1  M 2.405   2.752
 2  M  2.514  2.707
 3  M  2.387  2.673
 4  F  2.591  2.847
 5  F  2.607  2.903
 6  F  2.325  2.495

Table 1: 3-minute exposure

 

 

Rabbit/sex

sex

0 hours*

24 hours

48 hours

72 hours

Day 4 - 14

 

erythema

edema

erythema

edema

erythema

edema

erythema

edema

erythema

edema

1M

2

0

4N

4

4N

4

4N

4

4N

4

2M

1

0

4N

4

4N

4

4N

4

4N

4

3M

2

0

4N

4

4N

4

4N

4

4N

4

4F

1

0

4N

4

4N

4

4N

4

4N

4

5F

0

0

1

0

2

0

4N

4

4N

4

6F

2

0

4N

4

4N

4

4N

4

4N

4

mean

1.3

0

3.5

3.3

3.7

3.3

4

4

4

4

Mean erythema 24/48/72h

3.7

Mean edema 24/48/72h

3.5

*: immediately after unwrap

N = Necrosis

 

 

 

Table 2: 60-minute, 4-hour and 24-hour exposure

 

 

Rabbit/sex

sex

0 hours*

24 hours

48 hours

72 hours

Day 4 - 14

 

erythema

edema

erythema

edema

erythema

edema

erythema

edema

erythema

edema

1M

4N

4

4N

4

4N

4

4N

4

4N

4

2M

4N

4

4N

4

4N

4

4N

4

4N

4

3M

4N

4

4N

4

4N

4

4N

4

4N

4

4F

4N

4

4N

4

4N

4

4N

4

4N

4

5F

4N

4

4N

4

4N

4

4N

4

4N

4

6F

4N

4

4N

4

4N

4

4N

4

4N

4

mean

4

4

4

4

4

4

4

4

4

4

Mean erythema 24/48/72h

4.0

Mean edema 24/48/72h

4.0

*: immediately after unwrap

N = Necrosis

 

 

Interpretation of results:
other: CLP/EU GHS Category 1B (H314) according to Regulation (EC) No 1272/2008
Conclusions:
The test article was considered to be severe dermal irritant at both 4 and 24 hour exposures.
The Dermal Irritation Toxicity Category is Class I (corrosive).
The DOT Packing Group Classification is Class I (corrosive at less than 3 min).
Primary Dermal Irritation Index at 4h and 24h exposure=8.00 (according to Draize scoring system).
No reading time point at 1 hour after 3-minute exposure was available in order to definetly find a conclusion on subcategory 1A or 1B. Since after immediate observation after 3-minute exposure well-defined erythema (score 2) was found in 3 out of 6 animals it is not assumed that after on hour necrosis would have been formed. Therefore, a classification category 1B is considered.
Executive summary:

The test substance was examined undiluted for skin irritation in groups of 3 rabbits per sex. The test material was applied (semi-occlusive) directly on the intact and abraded skin sites. The skin was abraded using a burred needle, the abrasion penetrated the stratum corneum, but not the derma. The test article was administrated once per site for 3 min, 60 min, 4h, or 24 h. Necrosis was observed after 3 min exposure. The animals that had been exposed for 60 min, 4 h, or 24h scored 4 (necrosis) for erythema and edema immediately after unwrapping. Severe erythema and severe edema remained present in all animals at all observation periods during the study (up to 14 days).

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:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
yes
Remarks:
purity not reported
Qualifier:
according to
Guideline:
other: EPA FR Vol.50, No.188 (September 27, 1985)
GLP compliance:
yes (incl. certificate)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Hazleton Research Products, Denver, PA
- Age at study initiation: 8-12 weeks (adult)
- Weight at study initiation: 2.670kg
- Housing: individually in cages sized in accordance with the "Guide.for the Care and Use of Laboratory Animalsw of the Institute of Laboratory Animal Resources, National Research Council.
- Diet: Purina Lab Rabbit Chow H., ad libitum
- Water: Fresh tap water, ad libitum
- Acclimation period:min. 5d


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20±3
- Humidity (%): 50 ±20
- Photoperiod (hrs dark / hrs light):12h dark/12h light


IN-LIFE DATES: From: 17 Feb 1993 To: 17 Feb 1993
Vehicle:
unchanged (no vehicle)
Controls:
yes
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL/treated eye
Duration of treatment / exposure:
1 second
Observation period (in vivo):
1h
Number of animals or in vitro replicates:
One (1 ♀)
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): no

SCORING SYSTEM: observation
Draize and Ocular scores


TOOL USED TO ASSESS SCORE: hand-slit lamp / biomicroscope / fluorescein: Not applicable (NA)
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24/48/72 h
Reversibility:
not reversible
Remarks on result:
other: study was terminated after 1 hour due to severe effects (score 2)
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Reversibility:
not reversible
Remarks on result:
other: study was terminated after 1 hour due to severe effects (score 2)
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48/72 h
Reversibility:
not reversible
Remarks on result:
other: study was terminated after 1 hour due to severe effects (score 3)
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Reversibility:
not reversible
Remarks on result:
other: study was terminated after 1 hour due to severe effects (score 4)
Irritant / corrosive response data:
Vocalization occurred immediately after test article administration. Extreme positive ocular response for the cornea, iris and conjunctivae were observed at the 1 hour observation period. A red oculare discharge was also observed at this observation period.
Due to the extreme ocular scores observed, the study was terminated at the study director's discretion after the 1-hour observation period.
Interpretation of results:
other: CLP/EU GHS Category 1 (H318) according to Regulation (EC) No 1272/2008
Conclusions:
Based upon the observations made in the Primary Eye Irritation study, test article 6933-6-20, Project #92-014, was determined to be a severe irritant.
Executive summary:

Eye irritation of the test substance was tested in one female rabbit. The test substance was applied undiluted to the eye for 1 second. Vocalization occurred immediately after test article administration. Due to the extreme ocular scores observed, the study was terminated at the study director's discretion after the 1 -hour observation period.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irreversible damage)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation/corrosion:

An in vitro skin irritation study is available with Amines, polyethylenepoly-, triethylenetetraamine fraction (Gordon, 1994). This study was carried out for validation purposes of the OECD 435 testing guideline. The Corrositex ® test kit was used. Only a summary table is available. Amines, polyethylenepoly-, triethylenetetraamine fraction was tested as 60% solution. The test substance showed a full-thickness destruction of the biobarrier membrane after 49 minutes with a standard deviation of 1 minute and 19 seconds. Based on the definition given in the publication this would lead to a Corrosive Packing Group II which is equivalent to CLP/EU Category 1B.

A key study according to OECD guideline 404 with the registration substance is available (Pharmakon, 1992). Amines, polyethylenepoly-, triethylenetetramine fraction was examined at concentrations of 100%, 50%, 25%, and 5% in groups of 3 New Zealand White rabbits per sex. The test material was applied (semi-occlusive) directly on the intact and abraded skin sites. Only the results on intact sites are considered for hazard assessment. The test substance was administrated once per site for 3 min, 60 min, 4h, or 24 h.

Applying 100% of the registration substance to rabbit skin resulted in necrosis after 3 min of exposure. Necrosis was observed 24 hours after treatment. Immediately after unwrap very slight (score 1, 2/6 animals) or well-defined (score 2, 3/6 animals) erythema was observed. One animal showed no signs of irritation immediately after unwrap but developed necrosis at 72 hours after exposure. The animals that had been exposed for 60 min, 4 h, or 24h scored 4 (necrosis) for erythema and edema immediately after unwrapping. Severe erythema and severe edema remained present in all animals at all observation periods during the study (up to 14 days).

50% solution of the registration substance: Very slight erythema was observed in one animal after the 24 -hour observation period at the 3 -minute expsoure site. No other signs of erythema, edema or necrosis was observed during the study at this site. Immediately after unwrap at the 60 minute exposure site, very slight erythema was observed in three rabbits and necrosis, severe erythema and severe edema was observed in the three remaining rabbits. Necrosis, severe erythema and severe edema was observed in three rabbits at 24 hours through day 13 and continued in one rabbit to day 14. At the 4 -hour exposure site, very slight or well-defined erythema and no edema was observed in all six rabbits immediately after unwrap and continued in two rabbits to 48 hours. Necrosis, severe erytema and severe edema was observed in one rabbit at 24 hours and continued through day 14.

25% solution of the registration substance: No signs of erythema, edema or necrosis were observed at any observation period at the 3 -minute exposure site. Very slight to severe erythema and slight to severe edema were observed at the 60 -minute exposure site at the immediate and 24 hour observation periods. Necrosis, severe erythema and severe edema were observed in one rabbit at 24 hours and in two rabbits at 48 hours through day 11. All scores for the 60 -minute exposure returned to normal on day 12. At the 4 -hour exposure site, very slight or severe erythema and not edema were observed in four rabbits immediately after unwrap. Necrosis, severe erythema and severe edema were observed in one rabbit for the remainder of the study.

For the 5% test substance just one of 6 animals showed an erythema score of 1 at 24 hour observation time point after 4 hour exposure. All other scores for the 4 hour exposure was 0 for erythema and edema. No signs of erythema and edema were observed after 24h exposure on the intact site. No signs of necrosis were observed after 3 min, 60 min and 4 h and 24 h exposure time.

A supporting skin irritation study performed pre-GLP and pre-guideline according to an internal BASF test with the registration substance is available (BASF, 1966). The registration substance was examined undiluted for skin irritation. Two Vienna White rabbits were treated for 1, 5, 15 min and 20 hours using occlusive conditions. The application site was covered with the undiluted test substance. After the application time (1, 5, 15 min) the skin was washed with Lutrol. Effects were examined after 10 minutes, 1, 24, 48, 72 hours as well as after 8 days. After a 5 min exposure bleeding and at the end of the observation period after 8 days scale formation was observed. After a 15 min or 20 h exposure soft necrosis (24 h evaluation) was observed which turned into a leathery necrosis at the end of the observation period. It was concluded that the test substance caused necrosis after a 15 min exposure.

Two further skin irritation studies performed pre-GLP and pre-guideline with the registration substance are available (Meyers, 1976 and Oyen, 1953). Since no information on the study design and no detailed scores are reported, those studies cannot be used for hazard assessment and are thus disregarded.

Based on the observed results the registration substance is considered to be corrosive to skin (Cat. 1B).

Eye irritation

A key study according to OECD guideline 405 with Amines, polyethylenepoly-, triethylenetetramine fraction is available (Pharmakon, 1993). Eye irritation of Amines, polyethylenepoly-, triethylenetetramine fraction was tested in one female New Zealand White rabbit. The registration substance was applied undiluted to the eye for 1 second. Vocalization occurred immediately after test article administration. Due to the extreme ocular scores observed, the study was terminated at the study director's discretion after the 1 -hour observation period.

A supporting eye irritation study performed pre-GLP and pre-guideline according to an internal BASF test with the registration substance is available (BASF, 1966). 50 μL of the test substance was applied to the conjunctival sac of one eye in 2 Vienna White rabbits. The animals were observed after 10 min, 1 and 3 h on the day of treatment and up to 8 days afterwards. Findings were recorded daily. The eyes were not washed out after 24 hours as specified in OECD Guideline 405. A corneal opacity score of 3 was observed in both animals until the end of observation on day 8. 10 min after application corrosion of the nicktating and mucous membrane was noted. 24 h (animal 1) and 48 h (animal 2) post application suppuration was noted. In animal 2, 48 h post application iritis occurred. The application of the test substance caused corrosion to the exposed eyes, predominantly expressed by severe corneal opacity.

 

Two further eye irritation studies performed pre-GLP and pre-guideline with the registration substance are available (Meyers, 1976 and Oyen, 1953). Since no information on the study design and no detailed scores are reported, those studies cannot be used for hazard assessment and are thus disregarded.

Based on the observed results Amines, polyethylenepoly-, triethylenetetramine fraction is considered to be severe eye damaging (Cat. 1).

Justification for classification or non-classification

Reliable data with the registration substance on skin and eye irritation conclude that the registered substance meets the criteria for classification according to Regulation (EC) No. 1272/2008. The test substance is therefore classified as corrosive to skin Cat. 1B (H314) and damaging to eyes Cat. 1 (H318).