Registration Dossier

Administrative data

Description of key information

Based on positive response in dermal testing with cetrimonium bromide at 2.5% classification with Skin Irrit 2 can be applied. The potential for dermal irritation is further supported by dermal testing on cetrimounium chloride in 24-29% aqueous solutions in two OECD 404 studies.

Only slight eye irritation was noted in experimental tests with cetrimonium bromide up to a concentration of 1.1%. However, severe eye irritation response corresponding to Eye Dam 1 was observed in two OECD 405 studies using cetrimonium chloride in water at concentrations of 24-30% . Using read-across to cetrimonium bromide this justifies classification with Eye Dam 1.

The substance should be considered as a respiratory irritant and should be classified as STOT SE3, H335. (see study section 7.2.2)

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:
September 1980
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study with no data on GLP compliance.
Qualifier:
according to
Guideline:
other: Appraisal of the Safety of Chemicals in Foods, Drugs, and Cosmetics
Deviations:
yes
Remarks:
Testing performed on three rabbits and for three preparations
Principles of method if other than guideline:
The method used for testing primary skin irritation was described by J.H. Draize in "Appraisal of the Safety of Chemicals in Foods, Drugs, and Cosmetics", The Association of Food and Drug Officials of the United States, 1975 (pp. 46-48).
GLP compliance:
no
Species:
rabbit
Strain:
other: SPF-Russian strain
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Versuchstierzuchtanstalt WIGA, D-8741 Sulzfeld
- Weight at study initiation: 1600-1750 G
- Housing: Single cages, 45x90 cm with a floor of wire netting
- Diet: free access to feed pellets (green rabbit KFK 7112)
- Water: free access to fresh water
- Acclimation period: one week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19±2
- Humidity (%): 50±10
Type of coverage:
other: 2 layers of gauze, rabbits hereafter wrapped in a plastic-coated cellulose material fastened by tape
Preparation of test site:
other: clipped, half of test sites were scratched by a 18G needle
Vehicle:
not specified
Controls:
not specified
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 g to each test field
- Concentration (if solution): 0.1, 0.5 and 2.5 % (w/w)
Duration of treatment / exposure:
24 hours, treated skin was washed with water and left uncovered 48 hours
Observation period:
24 and 72 hours
Number of animals:
9
Details on study design:
TEST SITE
- Area of exposure: 10x15 cm, divided into six fields (25 cm2 each)
- Type of wrap if used: 2 layers of gauze, rabbits hereafter wrapped in a plastic-coated cellulose material fastened by tape

REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes, after 24 hours of exposure
- Time after start of exposure: 24 hours

SCORING SYSTEM: Erythema and eschar; oedema
Irritation parameter:
erythema score
Basis:
animal: #1, #2, #3
Time point:
other: 24 hours
Score:
0
Max. score:
4
Remarks on result:
other: Intact and scratched, 0.1%
Irritation parameter:
erythema score
Basis:
animal: #4, #5, #6
Time point:
other: 24 hours
Score:
0
Max. score:
4
Remarks on result:
other: Intact and scratched, 0.5%
Irritation parameter:
erythema score
Basis:
animal: #7
Time point:
other: 24 hours
Score:
3
Max. score:
4
Remarks on result:
other: Intact and scratched, 2.5%
Irritation parameter:
erythema score
Basis:
animal: #8
Time point:
other: 24 hours
Score:
1
Max. score:
4
Remarks on result:
other: Intact and scratched, 2.5%
Irritation parameter:
erythema score
Basis:
animal: #9
Time point:
other: 24 hours
Score:
2
Max. score:
4
Remarks on result:
other: Intact and scratched, 2.5%
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
other: 72 hours
Score:
2
Max. score:
4
Remarks on result:
other: Intact and scratched, 0.1%
Irritation parameter:
erythema score
Basis:
animal: #2, #3
Time point:
other: 72 hours
Score:
0
Max. score:
4
Remarks on result:
other: Intact and scratched, 0.1%
Irritation parameter:
erythema score
Basis:
animal #4
Time point:
other: 72 hours
Score:
2
Max. score:
4
Remarks on result:
other: Scratched, 0.5%
Irritation parameter:
erythema score
Basis:
animal #5
Time point:
other: 72 hours
Score:
1
Max. score:
4
Remarks on result:
other: Scratched, 0.5%
Irritation parameter:
erythema score
Basis:
animal #6
Time point:
other: 72 hours
Score:
1
Max. score:
4
Remarks on result:
other: Intact and scratched, 0.5%
Irritation parameter:
erythema score
Basis:
animal: #7
Time point:
other: 72 hours
Score:
3
Max. score:
4
Remarks on result:
other: Intact and scratched, 2.5%
Irritation parameter:
erythema score
Basis:
animal: #8, #9
Time point:
other: 72 hours
Score:
2
Max. score:
4
Remarks on result:
other: Intact and scratched, 2.5%
Irritation parameter:
edema score
Basis:
animal: #1, #2, #3
Time point:
other: 24 and 72 hours
Score:
0
Max. score:
4
Remarks on result:
other: Intact and scratched, 0.1%
Irritation parameter:
edema score
Basis:
animal: #4, #5, #6
Time point:
other: 24 and 72 hours
Score:
0
Max. score:
4
Remarks on result:
other: Intact and scratched, 0.5%
Irritation parameter:
edema score
Basis:
animal: #7, #8, #9
Time point:
other: 24 hours
Score:
0
Max. score:
4
Remarks on result:
other: Intact and scratched, 2.5%
Irritation parameter:
edema score
Basis:
animal: #7
Time point:
other: 72 hours
Score:
2
Max. score:
4
Remarks on result:
other: Intact and scratched, 2.5%
Irritation parameter:
edema score
Basis:
animal: #8
Time point:
other: 72 hours
Score:
1
Max. score:
4
Remarks on result:
other: Intact and scratched, 2.5%
Irritation parameter:
edema score
Basis:
animal: #9
Time point:
other: 72 hours
Score:
0
Max. score:
4
Remarks on result:
other: Intact and scratched, 2.5%
Interpretation of results:
moderately irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The skin irritant effect of the test substance is investigated at different concentrations on nine albino male rabbits. Accordingly, at 0.1% (w/w) the substance was not a skin irritant, at 0.5% (w/w) the substance was non to mildly irritant, and at 2.5% (w/w) the susbtance was a moderate irritant giving a response complying with the CLP criteria for classification as Skin Irrit. 2.
The corresponding dermal loads were 20 µg/cm2, 100 µg/cm2 and 500 µg/cm2.
Executive summary:

The skin irritant effect of the test substance is investigated at different concentrations on nine albino male rabbits. Accordingly, at 0.1% (w/w) the substance was not a skin irritant, at 0.5% (w/w) the substance was non to mildly irritant, and at 2.5% (w/w) the substance was a moderate irritant almost complying with the CLP criteria for classification as Skin Irrit. 2. A specific concentration limit for classification of 2.5% would be appropriate.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
Jun-Jul 1984; Feb-Mar 1997
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Read-across to cetrimonium bromide from data on cetrimonium chloride (with data reliability value of 1). Read-across justifications are provided in the endpoint summary.
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
GLP compliance:
yes
Remarks:
Except study with 28-30% cetrimonium chloride, which was performed before EU GLP-guidelines
Species:
rabbit
Strain:
New Zealand White
Vehicle:
water
Remarks:
28-30% cetrimonium chloride in water; 24-26% cetrimonium chloride in wate
Controls:
other: The untreated eye served as control.
Amount / concentration applied:
0.1 ml of test substance
Observation period (in vivo):
Ocular reactions were evaluated 1, 24, 48, and 72 hours after instillation of the test article. When ocular reactions were noted at 72 hours, additional examinations were performed at 7, 14 and 21 days after the instillation.
Number of animals or in vitro replicates:
3
Details on study design:
A volume of 0.1 ml of the test substance was placed into the conjunctival sac of one eye of each animal. For 28-30% cetrimonium chloride treated eyes were rinsed thoroughly with physiological saline warmed to 37 °C after 24 hours. No informaiton on rinse of treated eyes was not given for the study with 24-26% cetrimonium chloride.
Irritation parameter:
cornea opacity score
Remarks:
opacity
Basis:
mean
Time point:
other: 24, 48, 72 hours
Score:
1.9
Remarks on result:
other: 28-30% cetrimonium chloride
Irritation parameter:
iris score
Basis:
mean
Time point:
other: 24, 48, 72 hours
Score:
1
Remarks on result:
other: 28-30% cetrimonium chloride
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
mean
Time point:
other: 24, 48, 72 hours
Score:
2.3
Remarks on result:
other: 28-30% cetrimonium chloride
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: 24, 48, 72 hours
Score:
3.7
Remarks on result:
other: 28-30% cetrimonium chloride
Irritation parameter:
cornea opacity score
Remarks:
opacity
Basis:
mean
Time point:
other: 24, 48, 72 hours
Score:
2.8
Remarks on result:
other: 24-26% cetrimonium chloride
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
mean
Time point:
other: 24, 48, 72 hours
Score:
2.4
Remarks on result:
other: 24-26% cetrimonium chloride
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: 24, 48, 72 hours
Score:
4
Remarks on result:
other: 24-26% cetrimonium chloride
Irritant / corrosive response data:
For 28-30% cetrimonium chloride: Grade 1-2 corneal opacity was found at time points between 1 and 72 hours. At 7, 14 and 21 days, grade 3 corneal opacity was noted. Grade 1 iritis was found at all time points between 1 hour and 7 days. No iritis was reported at 14 days and grade 1 iritis in 1/3
animals at 21 days. Conjunctival irritation was evident as grade 1-3 redness and grade 3-4 swelling at time points 24, 48 and 72 hours and still persisted as grade 1-2 redness and grade 2 swelling at 21 days.
For 24-26% cetrimonium chloride: The behaviour and physical condition of the rabbits were normal throughout the study. Grade 1 corneal opacity was observed at 1 hour and grade 3-4 opacity was found at all later time points including day 21. The iris could not be evaluated due to the corneal opacity. Conjunctival irritation was evident as grade 2-3 redness and grade 3-4 swelling at all time points including day 21.

Observation time

Observations

28-30% cetrimonium chloride

24-26% cetrimonium chloride

1 hour

Grade 1-2 corneal opacity

Grade 1 iritis

Grade 1 corneal opacity

Grade 2-3 redness

Grade 3-4 swelling

24 hours

Grade 1-2 corneal opacity

Grade 1 iritis

Grade 1-3 redness

Grade 3-4 swelling

Grade 3-4 corneal opacity

Grade 2-3 redness

Grade 3-4 swelling

48 hours

Grade 1-2 corneal opacity

Grade 1 iritis

Grade 1-3 redness

Grade 3-4 swelling

Grade 3-4 corneal opacity

Grade 2-3 redness

Grade 3-4 swelling

72 hours

Grade 1-2 corneal opacity

Grade 1 iritis

Grade 1-3 redness

Grade 3-4 swelling

Grade 3-4 corneal opacity

Grade 2-3 redness

Grade 3-4 swelling

7 days

Grade 3 corneal opacity

Grade 1 iritis

Grade 3-4 corneal opacity

Grade 2-3 redness

Grade 3-4 swelling

14 days

Grade 3 corneal opacity

Grade 3-4 corneal opacity

Grade 2-3 redness

Grade 3-4 swelling

21 days

Grade 3 corneal opacity

Grade 1 iritis 1/3

Grade 1-2 redness

Grade 2 swelling

Grade 3-4 corneal opacity

Grade 2-3 redness

Grade 3-4 swelling

Interpretation of results:
Category 1 (irreversible effects on the eye)
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Based on the observations in the two studies it is concluded that cetrimonium chloride in aquaous solutions in the cocentration range from 24-30% cause irreversible ocular damage, corneal opacity and conjunctival irritation which persisted throughout the test period until day 21.
Reading-across to cetrimonium bromide this imply classification with Eye Dam 1
Executive summary:

The SCCS opinion document refers to two studies with cetrimonium chloride: 28-30% cetrimonium chloride in water and 24-26% cetrimonium chloride in water. The studies were carried out according to OECD TG 405 with New Zealand white albino rabbits. A volume of 0.1 ml of the test substance was placed into the conjunctival sac of one eye of each animal. The untreatred eye served as control. Ocular reactions were evaluated 1, 24, 48, and 72 hours after instillation of the test article. When ocular reactions were noted at 72 hours, additional examinations were performed at 7, 14 and 21 days after the instillation.

For 28 -30% cetrimonium chloride, the mean score values of the 24, 48 and 72 hour readings were 1.9 for opacity, 1.0 for iritis, 2.3 for conjunctival redness and 3.7 for conjunctival chemosis. Corneal opacity persisted throughout the test period until day 21. Conjunctival irritation and swelling persisted as grade 1 -2 redness and grade 2 swelling at 21 days.

For 24 -26% cetrimonium chloride, the mean score values of the 24, 48 and 72 hour readings were 2.8 for opacity, 2.4 for conjunctival redness and 4.0 for conjunctival chemosis. Corneal opacity persisted throughout the test period until day 21. Conjunctival irritation was evident as redness and sweling at all time points including day 21.

Based on the observations in the two studies it is concluded that cetrimonium chloride causes irreversible ocular damage, corneal opacity and conjunctival irritation which persisted throughout the test period until day 21.

Reading-across to cetrimonium bromide this imply classification with Eye Dam 1

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Additional information

Justification for selection of skin irritation / corrosion endpoint:

Test performed with cetrimonium bromide applicable for classification as Skin Irrit. 2

Justification for selection of eye irritation endpoint:

OECD 405 guideline tests on cetrimonium chloride 24-30%

Effects on skin irritation/corrosion: moderately irritating

Effects on eye irritation: corrosive

Effects on respiratory irritation: irritating

Justification for classification or non-classification

Based on positive response in dermal testing with cetrimonium bromide classification with Skin Irrit 2 with a SCL of 2.5% can be applied. The potential for dermal irritation is further supported by dermal testing on cetrimonium chloride in 24-29% aqueous solutions in two OECD 404 studies.

Only slight eye irritation was noted in experimental tests with cetrimonium bromide up to a concentration of 1.1%. However, severe eye irritation response corresponding to Eye Dam 1 was observed in two OECD 405 studies using cetrimonium chloride in water at concentrations of 24-30%. Using read-across to cetrimonium bromide this justifies classification with Eye Dam 1.

The substance should be considered as a respiratory irritant and should be classified as STOT SE3, H335. (see study section 7.2.2)