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Description of key information

Based on the irritation parameters and the histopathological evaluation following 4-hour occlusive test item application in an in vivo skin irritation/corrosion study in male and female rabbits, 2,2,6,6-tetramethylpiperidinooxy was considered to be corrosive to the skin. In a supporting study according to a modified Draize protocol, the test item appeared to be slightly irritant to skin.

As a consequence of the instillation of 2,2,6,6-tetramethylpiperidinooxy into the rabbit eye, effects were noted on cornea, iris and conjunctiva in all animals. In half of the animals effects deteriorated after an initial improvement and became so severe that the animals needed to be sacrificed on day 7. Thus, the effects were not expected to reverse within the observation period of 21 days.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
20-May to 10-June 1986
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Remarks:
Study was not conducted in compliance with GLP, but is well documented and sufficient to cover this endpoint (conduction close to OECD 404). 3 male and 3 females animals were used, observation period was 21 days.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
3 male and 3 female amimals were used and observation period was 21 days after removal of patches.
GLP compliance:
no
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Species/Strain: Rabbit (New Zealand albino)
- Source: R and B Enterprise, Hamilton OH
- Body weigth: 2.7 to 3.1 kg
- Housing: single housing in stainless steel cages
- Diet: Purina Lab Rabbit Chow HF #5325, 150 g daily
- Water: Water supplied from a reverse-osmosis purifier, ad libitum
- Acclimation period: 14 days befor the first test-substance application

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C
- Humidity (%): 40 %
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
occlusive
Preparation of test site:
clipped
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
Approximateyl 24 hours prior to study initiation, fur was clipped from an area of approximateyl 240 cm2 on the back of each rabbit. A 0.5 g quantity of the test article was applied uniformly to each test side and was covered with a 2.5 x 2.3 cm adhesive dressing.
Duration of treatment / exposure:
4 hours, afterwards application sites were rinsed with 0.9% saline
Observation period:
21 days
Number of animals:
3F / 3M
Details on study design:
Application sites were examined for signs of dermal irritiation and corrosivity 50-60 min, 24, 48, and 72 hours, and 7, 14, and 21 days following removal of the wrappings.
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
2.67
Max. score:
4
Reversibility:
not fully reversible within: 21 days
Remarks on result:
positive indication of irritation
Irritation parameter:
edema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
2.67
Max. score:
4
Reversibility:
fully reversible within: 14 days
Remarks on result:
positive indication of irritation
Irritation parameter:
edema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
3
Max. score:
4
Reversibility:
not reversible
Remarks on result:
positive indication of irritation
Remarks:
Animal was sacrificed after 72 h.
Irritation parameter:
edema score
Basis:
animal #4
Time point:
24/48/72 h
Score:
2.33
Max. score:
4
Reversibility:
not fully reversible within: 21 days
Remarks on result:
positive indication of irritation
Irritation parameter:
edema score
Basis:
animal #5
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 21 days
Remarks on result:
positive indication of irritation
Irritation parameter:
edema score
Basis:
animal #6
Time point:
24/48/72 h
Score:
3
Max. score:
4
Reversibility:
not reversible
Remarks on result:
positive indication of irritation
Remarks:
Animal was sacrificed after 72 h.
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
4
Max. score:
4
Reversibility:
not fully reversible within: 21 days
Remarks on result:
positive indication of irritation
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
4
Max. score:
4
Reversibility:
not reversible
Remarks on result:
positive indication of irritation
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
4
Max. score:
4
Reversibility:
not reversible
Remarks on result:
positive indication of irritation
Remarks:
Animal was sacrificed after 72 h.
Irritation parameter:
erythema score
Basis:
animal #4
Time point:
24/48/72 h
Score:
4
Max. score:
4
Reversibility:
not fully reversible within: 21 days
Remarks on result:
positive indication of irritation
Irritation parameter:
erythema score
Basis:
animal #5
Time point:
24/48/72 h
Score:
4
Max. score:
4
Reversibility:
not fully reversible within: 21 days
Remarks on result:
positive indication of irritation
Irritation parameter:
erythema score
Basis:
animal #6
Time point:
24/48/72 h
Score:
4
Max. score:
4
Reversibility:
not reversible
Remarks on result:
positive indication of irritation
Remarks:
Animal was sacrificed after 72 h.
Irritant / corrosive response data:
Brown areas were seen within the test sites of all tested rabbits 30-60 minutes after removal of the wrappings and persisted through the 72-hour scoring interval. Eschar formation was apparent in five out of six rabbits at that time. Therefore, two rabbits exhibiting the strongest signs of dermal irritation (Nos 3 and 6) were sacrificed following the 72-hour scoring interval and most severely affected dermal sections were subjected to histopathological investigation and compared to untreated skin. As a result, severe necrosis of the epidermis and moderate necrosis of the dermis were observed in correlation with acute mild to moderate inflammation of the dermis. Deeper necrosis including adnexa was seen with foci distribution.
In the other four animals, eschar formation persisted through day 7 or day 14. Cracking and/or concavity of the test site was also seen during the study. New or repaired skin was evident within the test sites of three of the four remainign rabbits by day 21.
Interpretation of results:
Category 1C (corrosive) based on GHS criteria
Conclusions:
Based on the irritation parameters and the histopathological evaluation following 4-hour occlusive test item application in an in vivo irritation/corrosion study in male and female rabbits, 2,2,6,6-tetramethylpiperidinooxy is considered to be corrosive to the skin.
As a conclusion, the test substance is classified for this endpoint in accordance to the CLP Regulation (EC) No 1272/2008 as corrosive to the skin, category 1C.
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
documentation insufficient for assessment
Remarks:
Observation period too short, reversibility of effects cannot be assessed. Poor documentation of results.
Principles of method if other than guideline:
modified Draize protocol (Draize et al.1944, J. Pharmacol. Exp. Ther. 821, 377–390; Zisu 1995, Contact Dermatitis 32, 74–77)
GLP compliance:
no
Species:
guinea pig
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Species/Strain: Guinea pig
- Source: Charles River Wiga, Sulzfeld, Germany
- Body weigth: 300 to 400 g
- Housing: single housing in stainless steel cages
- Diet: Food pellets ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C
- Humidity (%): 60 %
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
occlusive
Preparation of test site:
other: One flank was shaved, the other scarified on the day before administration.
Vehicle:
other: petrolatum
Controls:
yes, concurrent vehicle
yes, concurrent positive control
Amount / concentration applied:
0.5 mL / 10mM or 100 mM
Duration of treatment / exposure:
24 h
Observation period:
72 h
Number of animals:
6
Details on study design:
The test substance (0.5 ml:10 mM, or 100 mM final concentration) in petrolatum was applied by an occlusive patch for 24 h on the flank carefully shaved the day before. The substances were also applied on the contralateral scarified flank. Petrolatum was used as a negative control and an aqueous solution of 5% sodium lauryl sulfate (SLS) as a positive control in each animal. Animals were observed for erythema and oedema. The scores 24 and 72 h after application of the substances were added (non-scarified and scarified zones). The primary irritation values are calculated by averaging values for erythema from all sites (abraded and non-abraded), averaging the values for edema from all sites and adding the average values. The total was divided by 4 corresponding to the sum of two scores (erythema and oedema) obtained after 24 and 72 h. The mean is termed the primary cutaneous irritation index and may be used to classify the test substance (Zisu, 1995).
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
other: 24 and 72h
Score:
1.7
Reversibility:
not specified
Remarks on result:
probability of mild irritation
Irritation parameter:
overall irritation score
Remarks:
positive control 5% SLS
Basis:
mean
Time point:
other: 24 and 72h
Score:
2.5
Reversibility:
not specified
Remarks on result:
probability of moderate irritation
Irritant / corrosive response data:
At a concentration of 100 mM, the test item was found to be slightly irritant (score 1.7), when compared with the moderate irritant 5% SLS (score 2.5). At a concentration of 10 mM no signs of skin irritation were observed.
Interpretation of results:
study cannot be used for classification
Conclusions:
As a result, this modified Draize test shows that the test item is slightly irritant to skin. However, there is too little information available for classification according to the CLP Regulation (EC) No 1272/2008.
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:
02 June to 24 June 1984
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Remarks:
Study was not conducted in compliance with GLP, but is well documented and sufficient to cover this endpoint (conduction close to OECD 405).
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
yes
Remarks:
6 animals (3M / 3F) were used.
GLP compliance:
no
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Species/Strain: Rabbit (New Zealand albino)
- Source: R and B Enterprise, Hamilton OH
- Body weigth: 2.9 to 3.2 kg
- Housing: single housing in stainless steel cages
- Diet: Purina Lab Rabbit Chow HF #5325, 150 g daily
- Water: Water supplied from a reverse-osmosis purifier, ad libitum
- Acclimation period: 14 days befor the first test-substance application

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C
- Humidity (%): 40 %
- Photoperiod (hrs dark / hrs light): 12/12
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
0.1 g undiluted test item
Duration of treatment / exposure:
Test substance was not removed.
Observation period (in vivo):
21 days
Number of animals or in vitro replicates:
3M / 3F
Details on study design:
Undiluted test substance (0.1 g) was placed in the conjunctival sac of one eye, the other served as control. Test substance was not removed. Evaluation of results 1, 2, 3, 4, 7, 14 and 21 days after instillation of the test substance.
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 7 days
Remarks on result:
positive indication of irritation
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
not reversible
Remarks on result:
positive indication of irritation
Remarks:
Animal was sacrificed after 7 days.
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
not reversible
Remarks on result:
positive indication of irritation
Remarks:
Animal was sacrificed after 7 days.
Irritation parameter:
cornea opacity score
Basis:
animal #4
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 7 days
Remarks on result:
positive indication of irritation
Irritation parameter:
cornea opacity score
Basis:
animal #5
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 14 days
Remarks on result:
positive indication of irritation
Irritation parameter:
cornea opacity score
Basis:
animal #6
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
not reversible
Remarks on result:
positive indication of irritation
Remarks:
Animal was sacrificed after 7 days.
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
2
Reversibility:
fully reversible
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Basis:
animal #2
Time point:
24/48/72 h
Score:
1
Max. score:
2
Reversibility:
not reversible
Remarks on result:
positive indication of irritation
Remarks:
Animal was sacrificed after 7 days.
Irritation parameter:
iris score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0.33
Max. score:
2
Reversibility:
not reversible
Remarks on result:
positive indication of irritation
Remarks:
Animal was sacrificed after 7 days.
Irritation parameter:
iris score
Basis:
animal #4
Time point:
24/48/72 h
Score:
1
Max. score:
2
Reversibility:
fully reversible within: 7 days
Remarks on result:
positive indication of irritation
Irritation parameter:
iris score
Basis:
animal #5
Time point:
24/48/72 h
Score:
1
Max. score:
2
Reversibility:
fully reversible within: 7 days
Remarks on result:
positive indication of irritation
Irritation parameter:
iris score
Basis:
animal #6
Time point:
24/48/72 h
Score:
1
Max. score:
2
Reversibility:
not reversible
Remarks on result:
positive indication of irritation
Remarks:
Animal was sacrificed after 7 days.
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48/72 h
Score:
2.33
Max. score:
3
Reversibility:
fully reversible within: 21 days
Remarks on result:
positive indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
24/48/72 h
Score:
3
Max. score:
3
Reversibility:
not reversible
Remarks on result:
positive indication of irritation
Remarks:
Animal was sacrificed after 7 days.
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
24/48/72 h
Score:
2
Max. score:
3
Reversibility:
not reversible
Remarks on result:
positive indication of irritation
Remarks:
Animal was sacrificed after 7 days.
Irritation parameter:
conjunctivae score
Basis:
animal #4
Time point:
24/48/72 h
Score:
3
Max. score:
3
Reversibility:
fully reversible within: 21 days
Remarks on result:
positive indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal #5
Time point:
24/48/72 h
Score:
3
Max. score:
3
Reversibility:
not fully reversible within: 21 days
Remarks on result:
positive indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal #6
Time point:
24/48/72 h
Score:
2.67
Max. score:
3
Reversibility:
not reversible
Remarks on result:
positive indication of irritation
Remarks:
Animal was sacrificed after 7 days.
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Score:
2.67
Max. score:
4
Reversibility:
fully reversible within: 21 days
Remarks on result:
positive indication of irritation
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48/72 h
Score:
4
Max. score:
4
Reversibility:
not reversible
Remarks on result:
positive indication of irritation
Remarks:
Animal was sacrificed after 7 days.
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
24/48/72 h
Score:
3
Max. score:
4
Reversibility:
not reversible
Remarks on result:
positive indication of irritation
Remarks:
Animal was sacrificed after 7 days.
Irritation parameter:
chemosis score
Basis:
animal #4
Time point:
24/48/72 h
Score:
3.33
Max. score:
4
Reversibility:
fully reversible within: 21 days
Remarks on result:
positive indication of irritation
Irritation parameter:
chemosis score
Basis:
animal #5
Time point:
24/48/72 h
Score:
4
Max. score:
4
Reversibility:
not fully reversible within: 21 days
Remarks on result:
positive indication of irritation
Irritation parameter:
chemosis score
Basis:
animal #6
Time point:
24/48/72 h
Score:
3.33
Max. score:
4
Reversibility:
not reversible
Remarks on result:
positive indication of irritation
Remarks:
Animal was sacrificed after 7 days.
Irritant / corrosive response data:
In treated eyes an inceased density of opacity was noted, in 3 out of 6 animals the finding was reversible, however, in the other 3 animals density was increasing again starting day 4 or 7. For the iris, the conjunctiva and chemosis scores, a comparable trend was observed. Due to the severity of those findings, the 3 rabbits with the deteriorating process were euthanized after the 7-day examination.

Interpretation of results:
Category 1 (irreversible effects on the eye) based on GHS criteria
Conclusions:
As a consequence of the instillation of 2,2,6,6-tetramethylpiperidinooxy into the rabbit eye, effects were noted on cornea, iris and conjunctiva in all animals. In half of the animals effects deteriorated after an initial improvement and became so severe that the animals needed to be sacrificed on day 7. Thus, the effects were not expected to reverse within the observation period of 21 days.
As a conclusion, the test substance is classified for this endpoint in accordance to the CLP Regulation (EC) No 1272/2008 in Category 1 (Irreversible Effects on the Eye).
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irreversible damage)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for classification or non-classification

In an in vivo skin irritation/corrosion study in male and female rabbits, 2,2,6,6-tetramethylpiperidinooxy was found to be corrosive to the skin. A supporting study according to a modified Draize protocol revealed the test item to be slightly irritant to skin. Further evidence for the corrosive effects to the skin resulted from an acute dermal toxicity study; the mean lethal dose (LD50) of the test substance was found to be lower than 2000 mg/kg bw in male and female rabbits in a limit test. Severe corrosive effects have been estimated to be the cause for mortality. As a conclusion, the test substance is classified for this endpoint in accordance to the CLP Regulation (EC) No 1272/2008 as corrosive to the skin, category 1C.

 

In an in vivo eye irritation study in rabbits, severe effects were noted on cornea, iris and conjunctiva in all animals that were considered not to be reversible. As a conclusion, the test substance is classified for this endpoint in accordance to the CLP Regulation (EC) No 1272/2008 in Category 1 (Irreversible Effects on the Eye).