Registration Dossier

Administrative data

Description of key information

Ethanol, 2, 2’-iminobis-, N-coco alkyl derives CAS No 61791-31-9 will be registered for REACH as 2, 2’-(C12-18 evennumbered alkyl imino) diethanol CAS No 71786-60-2.

There are six studies available for skin corrosion/irritation on Ethanol, 2, 2’-iminobis-N-coco alkyl derives CAS No 61791-31-9, five in-vivo and one in-vitro.  There are three rabbit eye irritation studies available for Ethanol, 2,2’-iminobis-, N-coco alkyl derives CAS No 61791-31-9

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:
The study was performed between 15 April 2010 and 29 April 2010.
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
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. The study report was conclusive, done to a valid guideline and the study was conducted under GLP conditions.
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
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
One New Zealand White rabbit was supplied by Harlan Laboratories U.K. Ltd., Loughborough, UK. At the start of the study the animal weighed 2.79 kg and was twelve to twenty weeks old. After an acclimatisation period of at least five days the animal was given a number unique within the study which was written with a black indelible marker pen on the inner surface of the ear and on the cage label.

The animal was housed in a suspended cage. Free access to mains drinking water and food (2030 Teklad Global Rabbit diet supplied by Harlan Teklad, Blackthorn, Bicester, axon, UK) was allowed throughout the study. The diet and drinking water were considered not to contain any contaminant of a level that might have affected the purpose or integrity of the study.

The temperature and relative humidity were set to achieve limits of 17 to 23°C and 30 to 70% respectively. Any occasional deviations from these targets were considered not to have affected the purpose or integrity of the study. The rate of air exchange was at least fifteen changes per hour and the lighting was controlled by a time switch to give twelve hours continuous light (06:00 to 18:00) and twelve hours darkness.

The animal was provided with environmental enrichment items which were considered not to contain any contaminant of a level that might have affected the purpose or integrity of the study.

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 ml

- Concentration (if solution):
Not applicable.

VEHICLE
Not applicable.

- Concentration (if solution):
Not applicable.

- Lot/batch no. (if required):
Not given in study report.
Duration of treatment / exposure:
3-Minutes, 1-Hour and 4-Hours
Observation period:
14 days
Number of animals:
1
Details on study design:
TEST SITE
- Area of exposure:
On the day of the test three suitable sites were selected on the back of the rabbit

- % coverage:
Not given in study report.

- Type of wrap if used:
Test material was introduced under a 2.5 cm x 2.5 cm cotton gauze patch and placed in position on the shorn skin.


REMOVAL OF TEST SUBSTANCE
- Washing (if done):
Any residual test material removed by gentle swabbing with cotton wool soaked in distilled water.

- Time after start of exposure:
3 minutes, 1 hour and 4 hours.


SCORING SYSTEM:
Approximately one hour following the removal of the patches, and 24, 48 and 72 hours later, the test sites were examined for evidence of primary
irritation and scored according to the following scale (table below).
Additional observations were made on Days 7 and 14 to assess the reversibility of skin reactions.
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
>= 4
Max. score:
4
Reversibility:
not reversible
Remarks:
Corrosive effects noted
Remarks on result:
other: Max score not really applicable due to corrosive effects
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
> 4
Reversibility:
not reversible
Remarks:
Irreversible effetcs noted
Remarks on result:
other: Evaluation of oedema not possible due to adverse dermal reactions
Irritant / corrosive response data:
The individual scores for erythema/eschar and oedema are given in remarks on results including tables and figures.
3-Minute Exposure Period

The scores for erythema/eschar and oedema are given in Table 1.
Very slight erythema was noted at the treated skin site at the 24, 48 and 72 Hour observations.
The treated skin site appeared normal at the 7-Day observation.

1-Hour Exposure Period

The scores for erythema/eschar and oedema are given in Table 1.
Very slight erythema was noted at the treated skin site immediately and one hour after patch removal with well-defined erythema and slight oedema
noted at the 24, 48 and 72 Hour observations. The erythema extended approximately 2 cm beyond the test site at the 24, 48 and 72 Hour
observations. Very slight erythema, very slight oedema and severe desquamation were noted at the treated skin site at the 7 Day observation. Slight desquamation was noted at the treated skin site at the 14 Day observation.

4-Hour Exposure Period

The scores for erythema/eschar and oedema are given in Table 2.
Moderate to severe erythema and slight oedema were noted at the treated skin site immediately and one hour after patch removal. A hardened, dark
brown/black coloured scab, preventing accurate evaluation of erythema and oedema, was noted at the treated skin site at the 24, 48 and 72 Hour and 7 Day observations. Well-defined erythema surrounding the scab was noted at the 24, 48 and 72 Hour observations. Thickening of the skin was
noted at the treated skin site at the 14-Day observation.

The individual scores for erythema/eschar and oedema are given in the folowing table.

Table1              Individual Skin Reactions Following 3-Minute and 1-Hour Exposures

Skin Reaction

Observation Time
(following patch removal)

Individual Scores - Rabbit Number and Sex

69076

3-Minute Exposure

1-Hour Exposure

Erythema/Eschar Formation

Immediately

0

1

1 Hour

0

1

24 Hours

1

2R

48 Hours

1

2R

72 Hours

1

2R

7 Days

0

1D

14 Days

0

0D*

Oedema Formation

Immediately

0

0

1 Hour

0

0

24 Hours

0

2

48 Hours

0

2

72 Hours

0

2

7 Days

0

1

14 Days

0

0


R=      Erythema extends approximately 2 cm beyond the test site

D =      Severe desquamation

D* =     Slight desquamation

Table2          Skin Reactions Following 4-Hour Exposure

Skin Reaction

Observation Time
(following patch removal)

Individual Scores – Rabbit Number and Sex

69076Male

Erythema/Eschar Formation

Immediately

3

1 Hour

3

24 Hours

?eStWe

48 Hours

?eStWe

72 Hours

?eStWe

7 Days

?eSt

14 Days

0Th

Oedema Formation

Immediately

2

1 Hour

2

24 Hours

?od

48 Hours

?od

72 Hours

?od

7 Days

?od

14 Days

0


St=    Hardened dark brown/black coloured scab

Th =    Thickening of the skin

We =  Well-defined erythema surrounding other skin reactions

?e =    Adverse skin reactions prevent accurate evaluation of erythema

?od =  Adverse skin reactions prevent accurate evaluation of oedema


The test material was classified as CORROSIVE to rabbit skin.

The test material was also classified as corrosive to rabbit skin according to EU labelling regulations Commission Directive 2001/59/EC. The symbol “C”, the indication of danger “Corrosive” and the risk phrase R 34 “CAUSES BURNS” are therefore required.

Iirreversible alteration of the dermal tissue noted. Test material is classified as corrosive to rabbit skin. Classification according to Draize, therefore, not be applicable.


Interpretation of results:
Category 1C (corrosive) based on GHS criteria
Remarks:
Migrated information
Conclusions:
The test material was classified as CORROSIVE to rabbit skin.

The test material was also classified as corrosive to rabbit skin according to EU labelling regulations Commission Directive 2001/59/EC. The symbol “C”, the indication of danger “Corrosive” and the risk phrase R 34 “CAUSES BURNS” are therefore required.
Executive summary:

Introduction. 

The study was performed to assess the irritancy potential of the test material to the skin of the New Zealand White rabbit. The method was designed to meet the requirements of the following:

§        OECD Guidelines for the Testing of Chemicals No. 404 “Acute Dermal Irritation/Corrosion” (adopted 24 April 2002)

§        Method B4 Acute Toxicity (Skin Irritation) of Commission Regulation (EC) No. 440/2008

Results. 

3-minute and 1-hour semi-occluded applications of the test material to the intact skin of one rabbit produced no corrosive effects.

A single 4-hour, semi-occluded application of the test material to the intact skin of one rabbit produced moderate to severe erythema, slight oedema and a hardened, dark brown/black coloured scab which prevented accurate evaluation of erythema and oedema. Well-defined erythema surrounding the scab was also noted. Thickening of the skin was noted at the 14-Day observation.

Conclusion. 

The test material was classified as CORROSIVE to rabbit skin.

The test material was also classified as corrosive to rabbit skin according to EU labelling regulations Commission Directive 2001/59/EC. The symbol “C”, the indication of danger “Corrosive” and the risk phrase R 34 “CAUSES BURNS” are therefore required.

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
Study period:
ca. September-October 1967
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Basic study data given, according to standards/guidelines; Observation limited to 72 hrs, no information is available on reversibility.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
yes
Remarks:
6 animals instead of 3 animals; no observations at 60 min, or after 3 days
Principles of method if other than guideline:
According to FDA - Federal Register, 17 September 1964, par. 191.12
GLP compliance:
no
Remarks:
pre-GLP
Species:
rabbit
Strain:
other: albino
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: no data
- Age at study initiation: no data
- Weight at study initiation: no data
- Housing: no data
- Diet (e.g. ad libitum): no data
- Water (e.g. ad libitum): no data
- Acclimation period: no data


ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data


IN-LIFE DATES: somewhere between 26 September 1967 (receipt of test material) and 17 November 1967 (date of report).
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
0.1 ml
Duration of treatment / exposure:
single application in one eye
Observation period (in vivo):
3 days
Number of animals or in vitro replicates:
6
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): if done, after the 24-h reading (according to protocol)

SCORING SYSTEM (Fed. Reg. 17 SEptember 1964, Sec. 191.12):

1. CORNEA
No ulceration or opacity 0
Scattered or diffuse areas of opacity, details of iris clearly visible 1*
Easily discernible translucent areas, details of iris slightly obscured 2
Nacreous areas, no details of iris visible, size of pupil barely discernible 3
Complete corneal opacity, iris invisible 4

2. IRIS
Normal 0
Folds above normal, congestion, swelling, circumcorneal injection
(any or all of these or combination of any thereof), iris still reacting to light
(sluggish reaction is positive) 1*
No reaction to light, haemorrhage, gross destruction (any or all of these) 2

3. CONJUNCTIVAE
Redness (refers to palpebral and bulbar conjunctivae excluding cornea and iris)
Vessels normal 0
Some vessels definitely injected 1
Diffuse, crimson red, indiviual vessels not easily discernible 2*
Diffuse beefy red 3

Chemosis
No swelling 0
Any swelling above normal (includes nictitating membrane) 1
Obvious swelling with partial eversion of lids 2*
Swelling with lids about half closed 3
Swelling with lids more than half closed 4
* = considered positive

TOOL USED TO ASSESS SCORE: fluorescein (after the 24-h reading)
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24/48/72 h
Score:
2
Max. score:
2
Reversibility:
not specified
Remarks on result:
other: no observations after 3 days
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1
Max. score:
1
Reversibility:
not specified
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48/72 h
Score:
3
Max. score:
3
Reversibility:
not specified
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Score:
3
Max. score:
3
Reversibility:
not specified
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
24/48/72 h
Score:
2
Max. score:
2
Reversibility:
not specified
Remarks on result:
other: no observations after 3 days
Irritation parameter:
iris score
Basis:
animal #2
Time point:
24/48/72 h
Score:
1
Max. score:
1
Reversibility:
not specified
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
24/48/72 h
Score:
2.67
Max. score:
3
Reversibility:
not specified
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48/72 h
Score:
2.67
Max. score:
3
Reversibility:
not specified
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
24/48/72 h
Score:
2.67
Max. score:
3
Reversibility:
not specified
Remarks on result:
other: no observations after 3 days
Irritation parameter:
iris score
Basis:
animal #3
Time point:
24/48/72 h
Score:
1
Max. score:
1
Reversibility:
not specified
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
24/48/72 h
Score:
2.67
Max. score:
3
Reversibility:
not specified
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
24/48/72 h
Score:
3.33
Max. score:
4
Reversibility:
not specified
Irritation parameter:
cornea opacity score
Basis:
animal #4
Time point:
24/48/72 h
Score:
2
Max. score:
2
Reversibility:
not specified
Remarks on result:
other: no observations after 3 days
Irritation parameter:
iris score
Basis:
animal #4
Time point:
24/48/72 h
Score:
1
Max. score:
1
Reversibility:
not specified
Irritation parameter:
conjunctivae score
Basis:
animal #4
Time point:
24/48/72 h
Score:
2.33
Max. score:
3
Reversibility:
not specified
Irritation parameter:
chemosis score
Basis:
animal #4
Time point:
24/48/72 h
Score:
2.33
Max. score:
3
Reversibility:
not specified
Irritation parameter:
cornea opacity score
Basis:
animal #5
Time point:
24/48/72 h
Score:
2.67
Max. score:
3
Reversibility:
not specified
Remarks on result:
other: no observations after 3 days
Irritation parameter:
iris score
Basis:
animal #5
Time point:
24/48/72 h
Score:
1
Max. score:
1
Reversibility:
not specified
Irritation parameter:
conjunctivae score
Basis:
animal #5
Time point:
24/48/72 h
Score:
3
Max. score:
3
Reversibility:
not specified
Irritation parameter:
chemosis score
Basis:
animal #5
Time point:
24/48/72 h
Score:
4
Max. score:
4
Reversibility:
not specified
Irritation parameter:
cornea opacity score
Basis:
animal #6
Time point:
24/48/72 h
Score:
2
Max. score:
2
Reversibility:
not specified
Remarks on result:
other: no observations after 3 days
Irritation parameter:
iris score
Basis:
animal #6
Time point:
24/48/72 h
Score:
1
Max. score:
1
Reversibility:
not specified
Irritation parameter:
conjunctivae score
Basis:
animal #6
Time point:
24/48/72 h
Score:
3
Max. score:
3
Reversibility:
not specified
Irritation parameter:
chemosis score
Basis:
animal #6
Time point:
24/48/72 h
Score:
3.33
Max. score:
4
Reversibility:
not specified
Irritant / corrosive response data:
All 6 eyes showed a positive reaction consisting of corneal opacity, iritis, and severe conjunctivitis. The conjunctivae were
obviously swollen causing almost complete closure of the eyelids.
Other effects:
No data

Summary of ocular lesions

Anim.

No.

Effect

Hours

Days after application

Mean

score cornea

Days

1/2/3

Mean

score

iritis

Days

1/2/3

Mean score redness Days 1/2/3

Mean score chemosis Days 1/2/3

1

1

2

3

7

21

1

Cornea

Iris

Redness

Chemosis

-

-

-

-

2

1

3

3

2

1

3

3

2

1

3

3

-

-

-

-

-

-

-

-

2.0

1.0

3.0

3.0

2

Cornea

Iris

Redness

Chemosis

-

-

-

-

2

1

3

3

2

1

3

3

2

1

2

2

-

-

-

-

-

-

-

-

2.0

1.0

2.67

2.67

3

Cornea

Iris

Redness

Chemosis

-

-

-

-

2

1

3

4

3

1

3

3

3

1

2

3

-

-

-

-

-

-

-

-

2.67

1.0

2.67

3.33

4

Cornea

Iris

Redness

Chemosis

-

-

-

-

2

1

3

3

2

1

2

2

2

1

2

2

-

-

-

-

-

-

-

-

2.0

1.0

2.33

2.33

5

Cornea

Iris

Redness

Chemosis

-

-

-

-

2

1

3

4

3

1

3

4

3

1

3

4

-

-

-

-

-

-

-

-

2.67

1.0

3.0

4.0

6

Cornea

Iris

Redness

Chemosis

-

-

-

-

2

1

3

4

2

1

3

3

2

1

3

3

-

-

-

-

-

-

-

-

2.0

1.0

3.0

3.33

Mean all anim.

2.22

1.0

2.78

3.11

- = no observation done

Interpretation of results:
Category 1 (irreversible effects on the eye) based on GHS criteria
Remarks:
Migrated information
Conclusions:
The test compound was irritating to the rabbit eye. Because no information is available on reversibility within 21 days, based on the type and severity of the changes observed (corneal opacity, iritis, and severe conjunctivitis; the conjunctivae were obviously
swollen causing almost complete closure of the eyelids), it is expected that changes might still be present after 21 days. Therefore, the test compound was classified Category 1 according to OECD-GHS.
Executive summary:

A study was performed to assess the irritancy potential of the test material to the eye of albino rabbits. The method used generally followed that described in the OECD Guidelines for Testing of Chemicals No. 405 "Acute Eye Irritation/Corrosion". A single application of the test material to the non-irrigated eye of six rabbits produced clear corneal opacity, moderate iritis, and severe conjunctival irritation. The conjunctivae were obviously swollen causing almost complete closure of the eyelids. Observations were made up to 72 h after exposure; therefore no information is available on

reversibility.

The test compound was irritating to the rabbit eye. Because no information is available on reversibility within 21 days, based on the type and severity of the changes observed (corneal opacity, iritis, and severe conjunctivitis), it is expected that changes may still be present after 21 days. Therefore, the test compound was classified Category 1 according to OECD-GHS.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation /corrosion

There are six studies available for skin corrosion/irritation on Ethanol, 2, 2’-iminobis-N-coco alkyl derives CAS No 61791-31-9, five are in-vivo and one in-vitro. The first study is Klimisch validity 4 GLP OECD 404 rabbit study Liggett 1985, the report refers to a product name with no compositional details, but is for this substance. The results indicated an EU CLP (GHS) classification as skin corrosion category 1C. Then there is Klimisch validity 1 study Rose 2002, this was to OECD 404, however it was carried out on weanling pigs rather than on rabbits. It is claimed in the report that pigs are more predictive of the hazard to humans. The results in this study indicated EU CLP (GHS) skin irritation category 3. The third study is Klimisch validity 1 study, N, 2010, OECD431 Episkin study, using reconstructed human epidermis. This study showed no indication of corrosion as indicated by no significant reduction in the viability of the epidermal cells. Following this study an acute dermal irritation study in rabbits (OECD 404) was carried out, (Sanders 2010) which was also Klimisch validity 1. In this study initially on single animals, dark brown/ black coloured scabs were seen, only at the 4 hour exposure. After 14 days the scabs had fallen off to reveal thickened skin. This was interpreted as corrosion and classified under EU CLP (GHS) as category 1C for skin corrosion.

There were in addition two Hoechst studies on Hoechst (1982a) which was Klimisch 2 showed severe skin irritation and a second Hoechst (1982b) which showed corrosion supporting an EU CLP (GHS) classification of 1C.

When the five in-vivo studies are reviewed there is a discrepancy between the rabbit studies and the weanling pig study. However as rabbits are the normal species used for skin irritation/corrosion testing, therefore the result for the pig have not been used for classification purposes. The discrepancy between the in-vitro study and the subsequent in-vivo rabbit skin irritation study carried out in 2010, which at first surprising, however further investigation found it was consistent with the findings during the study validation. During the original validation tallow amines was not considered corrosive in the Episkin despite being classified as strongly corrosive when tested in rabbits. It appears that the in-vitro tests such as the Episkin are not predictive for skin corrosion for this amine based chemistry.

There are four rabbits studies for skin irritation/corrosion available for Ethanol, 2,2’-iminobis-, N-coco alkyl derives CAS No 61791-31-9, three show corrosive effects only after the 4 hour exposure, this corresponds based on a weight of evidence to an EU CLP(GHS) classification for skin corrosion of 1C.

Eye Irritation

There are three rabbits eye irritation studies available for Ethanol, 2,2’-iminobis-, N-coco alkyl derives CAS No 61791-31-9. The first study was pre-GLP, Davies, 1967, this is rated as Klimisch validity 2, as no observations were made after 3 days so any recovery could not be assess at day 21. However the severity of the effects seen at 3 days, of corneal opacity, iritis and severe conjunctivitis indicate that recovery was very unlikely. These results indicate that the EU CLP (GHS) classification is Category 1 for severe eye irritation. The second study Liggett, 1985, is Klimisch 4 for validity due to a lack of test substance batch number or composition; however the test substance was the substance being registered. In this study initially one rabbit had the test substance instilled in it eye. The severity of the effects on the eye was such that the rabbit was terminated after two days. There is a third study Hoechst (1983) in rabbit which showed severe eye irritation which, would be classified under GHS as 2A or 2 in EU CLP. The effects on a weight of evidence over the three available studies are considered to support classification as EU CLP (GHS) category 1 for severe eye irritation.

Respiratory Tract Irritation

There are no studies to assess the potential Ethanol, 2, 2’-iminobis- N-coco alkyl derives CAS No 61791-31-9 to cause respiratory irritation. The corrosive nature of the Ethanol, 2,2’-iminobis- N-coco alkyl derives would be anticipated to result in respiratory irritation but its physical form as a liquid with a low vapour pressure should make any significant inhalation exposure unlikely.

 

Justification for selection of skin irritation / corrosion endpoint:

This is a modern GLP Klimisch 1 study.

Justification for selection of eye irritation endpoint:

This study support the weight of evidence conclusion of Category 1 CLP (GHS) for irreversible eye damage.

Effects on skin irritation/corrosion: corrosive

Effects on eye irritation: corrosive

Justification for classification or non-classification

There are four rabbits studies for skin irritation/corrosion available for Ethanol, 2,2’-iminobis-, N-coco alkyl derives CAS No 61791-31-9, three show corrosive effects only after the 4 hour exposure, this corresponds based on a weight of evidence to an EU CLP(GHS) classification for skin corrosion of 1C.

There are three available studies for eye irritation in rabbits for the for Ethanol, 2,2’-iminobis-, N-coco alkyl derives CAS No 61791-31-9. Two indicate serious irreversible damage to the eyes, resulting in an EU CLP (GHS) classification of category 1 for severe eye irritation.

There are no studies to assess the potential Ethanol, 2, 2’-iminobis- N-coco alkyl derives CAS No 61791-31-9 to cause respiratory irritation. The corrosive nature of the Ethanol, 2,2’-iminobis- N-coco alkyl derives would be anticipated to result in respiratory irritation but its physical form as a liquid with a low vapour pressure should make any significant inhalation exposure unlikely.