Registration Dossier

Administrative data

Description of key information

- Skin corrosion /irritation (in vivo): not irritating (method similar to OECD 404)

- Eye irritation (in vivo): not irritating (method similar to OECD 405)

- Respiratory irritation: not irritating (based on the non-irritant properties of 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:
02-11-1976 - 13-12-1976
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
10 animals used; different scoring system; observation < 14 days (Reversibility check); positve and negative control substances used.
GLP compliance:
no
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 9-12 weeks
Type of coverage:
semiocclusive
Preparation of test site:
other: clipped
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 ml
- Concentration (if solution): 100%

Controls:
Positive control: Cyclamen Aldehyde
Negative control: Diethyl Phthalate
Duration of treatment / exposure:
4 hours
Observation period:
at 4, 24, 48 and 72 hours
Number of animals:
10
Details on study design:
TEST SITE
- Area of exposure: dorsal
- % coverage: no data
- Type of wrap if used: Patches are prepared by heat-sealing 1" x 1" 24 ply gauze pads on to 1 1/4" x 1 1/4" squares of polythene sheeting which is then attached to 3 1/2" x 1" strips of adhesive tape. Test solutions are applied to a dry patch. The patches are firmly attached to ensure good contact between the skin and test substance.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): wiped clean
- Time after start of exposure:4 hours

SCORING SYSTEM: The sites are scored for erythema, oedema, cracking and scaling and any other feature using an 8-point anchored ordinate scale ranging from “a” (very slight) to “h” (severe). At the end of the test the reaction grades are converted to corresponding numerical scores which are used to calculate the total irritation score per animal, an overall score per treatment group, a mean irritation score per site, and a mean irritation score per site per day for each treatment group. A mean irritation ranking for each treatment group is also given.
Reaction Grades and Scores of erythema, oedema, cracking and scaling:
a marginal/very slight = 1
b slight = 2
c fairly distinct =3
d quite distinct = 4
e becoming well developed = 6
f well developed = 8
g becoming severe = 10
h severe = 12

STATISTICS:
The Wilcoxon Matched-Pairs Signed Ranks Test, which considers the size and direction of differences between reactions is used to test the significance of differences between pairs of treatment groups.
Irritation parameter:
erythema score
Basis:
animal: 1, 2, 4, 5, 6, 7, 8, and 9
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
not fully reversible within: 72 hours
Remarks on result:
other: Animal 1, 2, 4, 5, 6, 7, 8, and 9
Irritation parameter:
erythema score
Basis:
animal: 3
Time point:
24/48/72 h
Score:
1.33
Max. score:
4
Reversibility:
not fully reversible within: 72 hours
Remarks on result:
other: Animal 3
Irritation parameter:
erythema score
Basis:
animal: 10
Time point:
24/48/72 h
Score:
1.67
Max. score:
4
Reversibility:
not fully reversible within: 72 hours
Remarks on result:
other: Animal 10
Irritation parameter:
edema score
Basis:
animal: 6 and 9
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
other: Animal 6 and 9
Irritation parameter:
edema score
Basis:
animal: 1 and 8
Time point:
24/48/72 h
Score:
0.33
Max. score:
4
Reversibility:
other: not fully reversible in 72 hours in 1/2 animals
Remarks on result:
other: Animal 1 and 8
Irritation parameter:
edema score
Basis:
animal: 2, 3, 4, 5, 7, and 10
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
other: not fully reversible in 72 hours in 5/6 animals
Remarks on result:
other: Animal 2, 3, 4, 5, 7, and 10
Irritant / corrosive response data:
Under the conditions of this test the test substance produced slight to moderate irritation consisting of marginal to slight erythema and oedema with variable cracking and scaling ranging from slight to distinct. The test substance was significantly more irritant than the negative control, diethyl phthalate, which produced only a marginal response. The test ingredient was significantly less irritant than the positive control, cyclamen aldehyde, which produced well-developed erythema fairly distinct cracking and slight scaling.

Table 1: Skin irritation scoring from test report

 

4 h

4 h

24 h

24 h

48 h

48 h

72 h

72 h

Animal

Er

Ed

Er

Ed

Er

Ed

Er

Ed

1

A

-

B

A

B

-

B

-

2

A

B

B

A

B

A

B

A

3

B

B

C

B

A

A

A

A

4

A

-

B

A

A

A

A

A

5

A

B

A

A

A

A

A

A

6

A

-

A

-

A

-

B

-

7

B

B

B

B

B

B

B

A

8

A

-

A

-

A

-

A

A

9

A

-

A

-

B

-

A

-

10

A

A

C

B

C

A

B

-

Er = Erythema; Ed = Edema

Table 2: Recalculated scoring system based on proposed conversion (see any other information on materials and methods).

 

4 h

4 h

24 h

24 h

48 h

48 h

72 h

72 h

Mean 24/48/72h

Mean 24/48/72h

Animal

Er

Ed

Er

Ed

Er

Ed

Er

Ed

Er

Ed

1

1

0

1

1

1

0

1

0

1

0.33

2

1

1

1

1

1

1

1

1

1

1

3

1

1

2

1

1

1

1

1

1.33

1

4

1

0

1

1

1

1

1

1

1

1

5

1

1

1

1

1

1

1

1

1

1

6

1

0

1

0

1

0

1

0

1

0

7

1

1

1

1

1

1

1

1

1

1

8

1

0

1

0

1

0

1

1

1

0.33

9

1

0

1

0

1

0

1

0

1

0

10

1

1

2

1

2

1

1

0

1.67

1

Er = Erythema; Ed = Edema 

Interpretation of results:
other: Not a skin irritant
Remarks:
according to EU CLP (EC 1272/2008 and its amendments)
Conclusions:
In the in vivo rabbit skin irritation test according to OECD TG 404, the substance is not a skin irritant.
Executive summary:

The skin irritation/corrosion potential of Cyclacet was investigated in a study similar to OECD Test Guideline 404 (Acute Dermal Irritation / Corrosion). In this Rabbit Covered Patch Skin Irritation Test, ten New Zealand White rabbits were exposed to the test substance for 4 hours under semi-occlusive conditions and reactions were scored after removal, and after 24, 48 and 72 hours. The test substance caused slight to moderate irritation, consisting of marginal to slight erythema and oedema with variable cracking and scaling ranging from slight to distinct. The mean erythema scores over the 24, 48 and 72 hour time period, were 1 (8 animals), 1.33 (1 animal) and 1.67 (1 animal). The mean edema scores over the 24, 48 and 72 hour time period, were 0 (2 animals), 0.33 (2 animals), and 1 (6 animals). As all animals had scorings below 2.3, the test substance is not considered to be a skin irritant.

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:
09-05-1977 - 31-05-1977
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
yes
Remarks:
different scoring system
Qualifier:
equivalent or similar to
Guideline:
other: Modified Federal Hazardous Substances Labelling Act Method
Deviations:
not specified
GLP compliance:
no
Species:
rabbit
Strain:
not specified
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Age at study initiation: 9 weeks
Vehicle:
unchanged (no vehicle)
Controls:
not specified
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 ml
- Concentration (if solution): 100%
Duration of treatment / exposure:
24 hours
Observation period (in vivo):
at 15 min., 1, 2, and 3 days
Number of animals or in vitro replicates:
3
Details on study design:



TOOL USED TO ASSESS SCORE: hand-slit lamp
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0.67
Max. score:
4
Reversibility:
fully reversible within: 3 days
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 2 days
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0.33
Max. score:
2
Reversibility:
fully reversible within: 2 days
Irritation parameter:
iris score
Basis:
animal: 2, 3
Time point:
24/48/72 h
Score:
0
Max. score:
2
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0.33
Max. score:
3
Reversibility:
fully reversible within: 2 days
Irritation parameter:
conjunctivae score
Basis:
animal: 2, 3
Time point:
24/48/72 h
Score:
0
Max. score:
3
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 2 days
Irritation parameter:
chemosis score
Basis:
animal: 2 and 3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritant / corrosive response data:
The test substance caused slight corneal lesions affecting up to half of the corneal surface in two animals. One of these lesions was associated with moderate corneal swelling, slight conjunctivitis and discharge. The lesions had healed within three days. The remaining animal was unaffected. One animal showed signs of discomfort when treated.
Interpretation of results:
other: Not an eye irritant
Remarks:
according to EU CLP (EC 1272/2008 and its amendments)
Conclusions:
The test substance is not eye irritating.
Executive summary:

The primary eye irritation potential of Cyclacet was investigated in a study similar to OECD Test Guideline 405 (Acute Eye Irritation / Corrosion). A single administration of Cyclacet in the eye of 3 rabbits caused slight corneal lesions affecting up to half of the corneal surface in two animals. One of these lesions was associated with moderate corneal swelling, slight conjunctivitis and discharge. The lesions had healed within three days. The remaining animal was unaffected. One animal showed signs of discomfort when treated. Mean chemosis, conjunctivae and iris scores at the 24, 48, and 72 hour time point were 0.33 in 1 animals and 0 in the other two animals. The effects seen in the one animal was reversible within one day. Corneal opacity scores were 0.67, 0.33, and 0 for the three animals respectively. The corneal opacity was absent within three days. It is concluded that Cyclacet is not an eye iritant.

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

Respiratory irritation

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

Additional information

Skin irritation: The skin irritation/corrosion potential of Cyclacet was investigated in a study similar to OECD Test Guideline 404 (Acute Dermal Irritation / Corrosion). In this Rabbit Covered Patch Skin Irritation Test, ten New Zealand White rabbits were exposed to the test substance for 4 hours under semi-occlusive conditions and reactions were scored after removal, and after 24, 48 and 72 hours. The test substance caused slight to moderate irritation, consisting of marginal to slight erythema and oedema with variable cracking and scaling ranging from slight to distinct. The mean erythema scores over the 24, 48 and 72 hour time period, were 1 (8 animals), 1.33 (1 animal) and 1.67 (1 animal). The mean edema scores over the 24, 48 and 72 hour time period, were 0 (2 animals), 0.33 (2 animals), and 1 (6 animals). As all animals had scorings below 2.3, the test substance is not considered to be a skin irritant.

Eye irritation: The primary eye irritation potential of Cyclacet was investigated in a study similar to OECD Test Guideline 405 (Acute Eye Irritation / Corrosion). A single administration of Cyclacet in the eye of 3 rabbits caused slight corneal lesions affecting up to half of the corneal surface in two animals. One of these lesions was associated with moderate corneal swelling, slight conjunctivitis and discharge. The lesions had healed within three days. The remaining animal was unaffected. One animal showed signs of discomfort when treated. Mean chemosis, conjunctivae and iris scores at the 24, 48, and 72 hour time point were 0.33 in 1 animals and 0 in the other two animals. The effects seen in the one animal was reversible within one day. Corneal opacity scores were 0.67, 0.33, and 0 for the three animals respectively. The corneal opacity was absent within three days. It is concluded that Cyclacet is not an eye irritant.

Respiratory irritation: For respiratory irritation mostly human data are used for the assessment because no suitable in vitro or in vivo tests are available that can identify respiratory irritation (ECHA guidance R.7.2.3 (2008) and ECHA guidance, 2017, page 240). There are no human data available that indicate respiratory reactions of the substance e.g. from consumer experience or occupational exposure. In addition the substance is not corrosive or severely irritating and therefore respiratory irritation is not considered a concern.

Justification for classification or non-classification

Based on the available corrosion and irritation information the substance does not need to be classified for skin, eye and irritation is not warranted according to EU CLP (EC 1272/2008 and its amendments).