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Diss Factsheets

Administrative data

Description of key information

Signs of irritation were observed in both a skin irritation and eye irritation assays performed in New-Zealand Whith rabbits.

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 March – 04 April 2006
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP study conducted in compliance with OECD Guideline 404 without any deviation.
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other 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
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Grimaud frères selection S.A.S., La Corbière, France
- Age at study initiation: 2-4 months
- Weight at study initiation: 2.5 ± 0.1 kg
- Housing: Individually housed in Pajon cages
- Diet: 110 pelleted diet (SAFE, Epinay-sur-Orge, France), ad libitum
- Water: Drinking water filtered by a FG Millipore membrane (0.22 µm), ad libitum
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 18 ± 3 °C
- Humidity: 30-70 %
- Air changes: Approximately 12 cycles/h of filtered, non-recycled air
- Photoperiod: 12 h dark / 12 h light
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 (weight with unit): 0.5 mL
- Concentration (if solution): Undiluted test item
Duration of treatment / exposure:
4 h
Observation period:
14 d
Number of animals:
3 males
Details on study design:
TEST SITE
- Area of exposure: Area of approximately 6 cm2 of the anterior left flank (application for 3 min), the anterior right flank (application for 1 h) or the posterior right flank (application for 4 h) of the animals.
- Type of wrap if used: Test item (0.5 mL) was applied to the clipped skin under a dry gauze pad. The gauze pad was held in contact with the skin by means of an adhesive hypoallergenic aerated semi-occlusive dressing and a restraining bandage.

REMOVAL OF TEST SUBSTANCE
- After removal of the dressing, any residual test item was wiped off by means of a dry cotton pad.

SCORING SYSTEM: According to OECD Guideline 404
Irritation parameter:
erythema score
Basis:
animal #1
Remarks:
mean individual score
Time point:
24/48/72 h
Score:
3
Max. score:
4
Reversibility:
not fully reversible within: 14 days
Irritation parameter:
edema score
Basis:
animal #1
Remarks:
mean individual score
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
erythema score
Basis:
animal #2
Remarks:
mean individual score
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 13 days
Irritation parameter:
edema score
Basis:
animal #2
Remarks:
mean individual score
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 5 days
Irritation parameter:
erythema score
Basis:
animal #3
Remarks:
mean individual score
Time point:
24/48/72 h
Score:
3
Max. score:
4
Reversibility:
not fully reversible within: 14 days
Irritation parameter:
edema score
Basis:
animal #3
Remarks:
mean individual score
Time point:
24/48/72 h
Score:
1.3
Max. score:
4
Reversibility:
fully reversible within: 5 days
Irritant / corrosive response data:
After a 3 min exposure period (one animal only):
- No cutaneous reactions were observed.

After a 1 h exposure period (one animal only):
- A very slight to moderate erythema (grades 1 to 3) was noted from Day 1 up to Day 15 (end of the observation period).
- A very slight edema (grade 1) was noted from Day 2 up to Day 5.
- A brownish area was observed from Day 4 up to Day 6.
- A dryness of the skin was noted from Day 6 up to Day 15 (end of the observation period).

After a 4 h exposure period (three animals):
- A very slight to moderate erythema (grades 1 to 3) was noted in all animals from Day 1 up to Day 13 in 1/3 animals or Day 15 in 2/3 animals (end of the observation period).
- A very slight or slight edema (grade 1 or 2) was observed in all animals from Day 2 up to Day 5 (2/3 animals) or Day 7 (1/3 animals).
- A brownish area was observed in 1/3 animals from Day 3 up to Day 6.
- A dryness of the skin was observed in 1/3 animals from Day 4, in 1/3 animals from Day 5 and 1/3 animals from Day 6, up to Day 15 (end of the observation period).
- Crusts were noted in 1/3 animals between Days 4 and 11.
Other effects:
None

Table 7.3.1/1: Individual skin reactions

 

Rabbits No.

Animal 1

Animal 2

Animal 3

Erythema

1 h

2

2

2

24 h

3

2

3

48 h

3

2

3

72 h

3

2

3

Mean (24, 48 and 72 h)

3

2

3

Oedema

1 h

0

0

0

24 h

2

1

2

48 h

2

1

1

72 h

2

1

1

Mean (24, 48 and 72 h)

2

1

1.3
Interpretation of results:
Category 2 (irritant)
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the test conditions, CHIMEXANE HB is classified as ‘R38 Irritating to skin’ according to the criteria of Annex VI to the Directive 67/548/EEC and ‘Category 2: Irritant’ according to CLP Regulation (EC) N° (1272-2008).
Executive summary:

In a primary dermal irritation study performed according to OECD Guideline 404 and in compliance with GLP, three male New Zealand White rabbits were dermally exposed to 0.5 mL of undiluted CHIMEXANE HB under a semi-occlusive dressing. The test item was first evaluated on a single animal and the duration of exposure was 3 min on the anterior left flank, 1 h on the anterior right flank and 4 h on the posterior right flank. Since the test item was not severely irritant on this first animal, it was then applied for 4 h to two other animals. After removal of the residual test item, irritation was scored as outlined in the OECD Guideline 404 at 1, 24, 48 and 72 h after removal of the dressing and then daily until the end of the observation period (Day 15).

 

After a 3 min exposure period, no cutaneous reactions were observed. After a 1 h exposure period, a very slight to moderate erythema was noted up to Day 15 and a very slight edema was noted up to Day 5. After a 4 h exposure period, a very slight to moderate erythema was noted in all animals up to Day 13 in 1/3 animals or Day 15 in 2/3 animals. A very slight or slight edema was observed in all animals up to Day 5 (2/3 animals) or Day 7 (1/3 animals). Mean individual scores for the 3 animals at 24, 48 and 72 h post patch removal were 3, 2, 3 for erythema and 2, 1, 1.3 for oedema score, respectively. In this study, CHIMEXANE HB is a skin irritant on male rabbits.

 

Under the test conditions, CHIMEXANE HB is classified as ‘R38 Irritating to skin’ according to the criteria of Annex VI to the Directive 67/548/EEC and ‘Category 2: Irritant’ according to CLP Regulation (EC) N° (1272-2008).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (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:
23 October - 13 November 1995
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: non-GLP study conducted in compliance with OECD Guideline 405 with deviations: age at study initiation and individual animal weights not reported; environmental conditions not reported.
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
yes
Remarks:
age at study initiation and individual animal weights not reported; environmental conditions not reported
Principles of method if other than guideline:
Not applicable
GLP compliance:
no
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: elevage BERTHO, Yffiniac, France
- Weight at study initiation: 2.4 kg (mean)
- Housing: Animals were housed individually on floor grid.
- Diet: Complete pelleted rabbit maintenance diet Energie H326 (COFNA, Tours, France), ad libitum
- Acclimation period: 5 days

Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL
- Concentration (if solution): Undiluted test item
Duration of treatment / exposure:
No washing was done.
Observation period (in vivo):
21 days
Number of animals or in vitro replicates:
3 males
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing: No

SCORING SYSTEM: According to OECD Guideline 405

TOOL USED TO ASSESS SCORE:
- Ocular reactions were performed with a U. V. and white magnification light. After recording the observations at 24 h, the eyes of all rabbits were examined with the aid of fluorescein.

Irritation parameter:
cornea opacity score
Basis:
animal #1
Remarks:
mean individual score
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
not reversible
Irritation parameter:
iris score
Basis:
animal #1
Remarks:
mean individual score
Time point:
24/48/72 h
Score:
1
Max. score:
2
Reversibility:
fully reversible within: 21 days
Irritation parameter:
conjunctivae score
Basis:
animal #1
Remarks:
mean individual score
Time point:
24/48/72 h
Score:
3
Max. score:
3
Reversibility:
not reversible
Irritation parameter:
chemosis score
Basis:
animal #1
Remarks:
mean individual score
Time point:
24/48/72 h
Score:
4
Max. score:
4
Reversibility:
not reversible
Irritation parameter:
cornea opacity score
Basis:
animal #2
Remarks:
mean individual score
Time point:
24/48/72 h
Score:
1.7
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
iris score
Basis:
animal #2
Remarks:
mean individual score
Time point:
24/48/72 h
Score:
1
Max. score:
2
Reversibility:
fully reversible within: 7 days
Irritation parameter:
conjunctivae score
Basis:
animal #2
Remarks:
mean individual score
Time point:
24/48/72 h
Score:
3
Max. score:
3
Reversibility:
fully reversible within: 7 days
Irritation parameter:
chemosis score
Basis:
animal #2
Remarks:
mean individual score
Time point:
24/48/72 h
Score:
3.3
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
cornea opacity score
Basis:
animal #3
Remarks:
mean individual score
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
iris score
Basis:
animal #3
Remarks:
mean individual score
Time point:
24/48/72 h
Score:
1
Max. score:
2
Reversibility:
fully reversible within: 7 days
Irritation parameter:
conjunctivae score
Basis:
animal #3
Remarks:
mean individual score
Time point:
24/48/72 h
Score:
3
Max. score:
3
Reversibility:
fully reversible within: 7 days
Irritation parameter:
chemosis score
Basis:
animal #3
Remarks:
mean individual score
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritant / corrosive response data:
- One hour after instillation of the substance, important irritation reactions were noticed in all animals, at the level of the conjunctivae (diffuse beefy red enanthemae, abundant discharge, chemosis with lids about half closed). Iris congestion was also observed.
- 24 h later, chemosis increased in two rabbits and a distinct corneal opacity was visible in three rabbits. All irritation phenomena regressed very slowly. Within about a week they disappeared in two animals.
- Irritation signs persisted in one animal at the end of the observation period (21 days)
Other effects:
No data

Table 7.3.2/1: Results of eye irritation

Animal no.

4615

4640

4641

 

Conjunctiva

Iris

Cornea

Conjunctiva

Iris

Cornea

Conjunctiva

Iris

Cornea

 

A

B

C

D

E

F

A

B

C

D

E

F

A

B

C

D

E

F

D1 (1 h)

3

3

3

1

0

0

3

3

3

1

0

0

3

3

3

1

0

0

24 h

4

3

3

1

2

4

4

3

3

1

2

3

3

2

3

1

2

2

48 h

4

3

3

1

2

2

3

2

3

1

2

2

2

1

3

1

2

1

72 h

4

2

3

1

2

2

3

2

3

1

1

1

1

1

3

1

2

1

M

4.0

2.7

3.0

1.0

2.0

2.7

3.3

2.3

3.0

1.0

1.7

2.0

2.0

1.3

3.0

1.0

2.0

1.3

D5

3

1

3

1

4

2

1

1

2

1

1

1

1

1

2

1

2

1

D6

2

1

2

1

3

2

1

1

1

1

1

1

1

1

1

1

1

1

D7

2

1

2

1

2

2

0

0

0

0

0

0

0

0

0

0

0

0

D8

1

1

2

1

2

1

-

-

-

-

-

-

-

-

-

-

-

-

D9

1

1

2

1

2

1

-

-

-

-

-

-

-

-

-

-

-

-

D10

1

1

2

1

2

1

-

-

-

-

-

-

-

-

-

-

-

-

D11

1

1

3

1

2

1

-

-

-

-

-

-

-

-

-

-

-

-

D12

3

1

3

1

2

1

-

-

-

-

-

-

-

-

-

-

-

-

D13

3

1

3

1

2

1

-

-

-

-

-

-

-

-

-

-

-

-

D14

3

1

3

1

2

1

-

-

-

-

-

-

-

-

-

-

-

-

D15

3

1

3

1

2

1

-

-

-

-

-

-

-

-

-

-

-

-

D16

3

1

3

1

2

1

-

-

-

-

-

-

-

-

-

-

-

-

D17

3

1

3

1

2

1

-

-

-

-

-

-

-

-

-

-

-

-

D18

3

1

3

1

2

1

-

-

-

-

-

-

-

-

-

-

-

-

D19

3

2

3

1

2

1

-

-

-

-

-

-

-

-

-

-

-

-

D20

3

1

3

1

2

1

-

-

-

-

-

-

-

-

-

-

-

-

D21

1

1

2

0

1

1

-

-

-

-

-

-

-

-

-

-

-

-

D22

1

1

2

0

1

1

-

-

-

-

-

-

-

-

-

-

-

-

 

A: Chemosis; B: Discharge; C: Redness; D: Iris lesion; E: Opacity; F: Opacity area; M: Mean

Interpretation of results:
irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the test conditions, Chimexane HB is classified as “R36 irritating to eyes”, according to the Annex VI of the Directive 67/548/EEC and ‘Category 1’ according to the Regulation (EC) N° 1272-2008 (CLP).
Executive summary:

In a non-GLP eye irritation study conducted according to the OECD Guideline 405, 3 healthy male rabbits of the New Zealand White strain were exposed to 0.1 mL of undiluted test item Chimexane HB in their right eye while the left eye remained untreated and served as control. The eyelids were then gently held together for about one second to avoid any loss of test item. At 24 h after treatment, fluorescein solution was instilled into the eyes and they were examined under UV-lamp to detect possible corneal damage. The eyes were examined and the changes were observed at 1, 24, 48 and 72 h and up to Day 22 after treatment and graded according to the method of OECD Guideline 405.

One hour after tiest item instillation, irritations of the palpebral and bulbar conjunctivae (enanthemae, discharge and chemosis) and iris congestion were noticed. 24 h later, chemosis increased in two rabbits and a distinct corneal opacity was visible in three rabbits. All irritation phenomena regressed very slowly. Within about a week they disappeared in 2 animals. Irritation signs persisted in one animal at the end of the observation period (21 days). Mean individual scores for the three animals at 24, 48 and 72 h post instillation were 2.0, 1.7, 2.0 for cornea score; 1.0, 1.0, 1.0 for iris score; 3.0, 3.0, 3.0 for conjunctivae score and 4.0, 3.3, 2.0 for chemosis score. In this study, Chimexane HB is an eye irritant on male rabbits.

Under the test conditions, Chimexane HB is classified as “R36 irritating to eyes”, according to the Annex VI of the Directive 67/548/EEC and ‘Category 1’ according to the Regulation (EC) N° 1272-2008 (CLP).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

In a GLP primary dermal irritation study performed according to OECD Guideline 404, three male New Zealand White rabbits exposed for 4 hours to 0.5 mL undiluted Chimexane HB (corresponding to the submission substance 55.9% in water) under a semi-occlusive dressing showed signs of irritation (well defined to sever erythema and slight edema) that were reversed within 13 -15 days. As these results were obtained with the submission substance at 55.9% in water, the submission substance at 100% is expected to be even more irritating, and should conservatively be considered corrosive.

In a non-GLP eye irritation study conducted according to the OECD Guideline 405, undiluted Chimexane HB induced reversible eye irritation in three male New Zealand White rabbits. Clinical signs consisted of irritationsof the palpebral and bulbar conjunctivae (enanthemae, discharge and chemosis) and of iris congestion. In one rabbit, some signs of slight irritation were still visible on D21. As these results were obtained with the submission substance at 55.9% in water, the submission substance at 100% is expected to be even more irritating and is expected to induce irreverible effects on the eyes.

 

Justification for selection of skin irritation / corrosion endpoint:

Only one study available

Justification for selection of eye irritation endpoint:

Only one study available

Effects on skin irritation/corrosion: irritating

Effects on eye irritation: irritating

Justification for classification or non-classification

As the submission substance is expected to be corrosive and to induce irreversible effects on the eyes, it is classified as "R35: Causes severe burns" and "R41: Risk of serious damage to eyes" according to the Annex VI of the Directive 67/548/EEC and "Skin corrosive - Category 1" and "Serious eye damage - Category 1" according to the Regulation (EC) N° 1272 -2008 (CLP).