Registration Dossier

Administrative data

Description of key information

Benzoyl peroxide is slightly irritating to skin, not irritating to the eyes of rabbits if washed out within 5 minutes after instillation, but slightly irritating at a 78 % concentration if not washed out until 24 hours. 

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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study was conducted in accordance with a recognized scientific procedure for analyzing the primary dermal irritation of a test material in experimental animals, but the animals were observed for only three day.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
Observation period: 3 days versus 14 days.
Principles of method if other than guideline:
Method: other
GLP compliance:
not specified
Species:
rabbit
Strain:
other: New zealand, albino
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Weight at study initiation: male/female weighting 2643 - 2952 grams
Type of coverage:
semiocclusive
Preparation of test site:
other: abraded and intact skin
Vehicle:
other: none used
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount applied : 500 mg of benzoyl peroxide
Duration of treatment / exposure:
4 hour(s)
Observation period:
72 hours after the begining of the exposure
Number of animals:
6
Details on study design:
TEST SITE
- Type of wrap: gauze bandage

REMOVAL OF TEST SUBSTANCE
- Washing : with lukewarm water
- Time after start of exposure: 4 hours

SCORING SYSTEM: Draize scale
Irritation parameter:
erythema score
Basis:
animal: all rabbits
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
animal: all rabbits
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritant / corrosive response data:
The skin on the six rabbits appeared unaffected.
Interpretation of results:
GHS criteria not met
Conclusions:
Benzoyl peroxide (concentration at 78%) is neither a primary skin irritant nor a corrosive substance.
Executive summary:

ln a rabbit study in which 78 % granular benzoyl peroxide was applied to the back of 3 males and 3 females, the substance was held in place for 4 hours with a gauze bandage. After 4 hours, the bandages were removed and the exposed areas washed with lukewarm water. The skin was examined for any injury or irritation according to Draize scale at 4, 24 and 72 hours. No signs of skin irritation were observed at 1, 3 days after 4 hr exposure.

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:
1973
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions.
Qualifier:
according to guideline
Guideline:
other: US FDA, 21 CFR, Part 191, Hazardous substances test for eye irritants
Deviations:
yes
Remarks:
Few data on experimental conditions and no individual animal data reported
GLP compliance:
not specified
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 2563-3217 grams
- Diet and Water: ad libitum
Vehicle:
unchanged (no vehicle)
Controls:
other: the left eye served as the untreated control for each rabbit.
Amount / concentration applied:
Dosed used : 0.1 ml of test material was instilled into the everted lower eye lid of one eye of each rabbit.
The average weight of the test material was 111.4 (group I, 5 minute wash) and 120.7 mg (group II, 24 hours wash).
Duration of treatment / exposure:
Rinced after 5 min (Group I) and not rinced (Group II)
Observation period (in vivo):
Observation period : Eyes were examined at 1, 24, 48, 72 hours and 7 days after washing. 14 and 21 day examination were precluded by the absence of ulceration or opacity at 7 days.
Number of animals or in vitro replicates:
5 rabbits in Group I (5-min exposure) and 3 rabbits in Group II (24-hour exposure).
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing: yes, following the exposur period, with a continuous stream of water over a 2 minute period.
- Time after start of exposure: 5 min ou 24 hours

SCORING SYSTEM: OECD grading
Examination were perfored 1 hour following was, then at 24 hours, 48 hours, 72 hours, 7 days, 14 days and 21 days.

TOOL USED TO ASSESS SCORE: fluorescein. The fluorescein was not used in the group 1 for examination at 48 hours and in the group 2 for scoring 1 hour and 48 hours after exposure.
Irritation parameter:
cornea opacity score
Basis:
animal: #1, 2 and 3
Time point:
24/48/72 h
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: 48 hours
Remarks on result:
other: not rinced
Irritation parameter:
iris score
Basis:
animal: #1, 2 and 3
Time point:
24/48/72 h
Score:
0
Max. score:
2
Remarks on result:
other: not rinced
Irritation parameter:
conjunctivae score
Basis:
mean
Remarks:
for the 3 animals together
Time point:
24/48/72 h
Score:
1
Max. score:
3
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: not rinced
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
for the 3 animals together
Time point:
24/48/72 h
Score:
1.22
Max. score:
4
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: not rinced
Irritant / corrosive response data:
Group I : benzoyl peroxide produced very minor redness (conjunctivitis) and swelling (chemosis) in 1/5 and 2/5 rabbits, respectively, but it was clear in 24 hours. No corneal opacity was observed.
Group II : there was grade 1 opacity in 3/3 at 24 hours but it was clear at 48 hours. No iritis. There was grade 2 redness in 2/3 at 48 hours, degrading to grade 1 in 1/3 at 72 hours ; clear by day 7.

GROUP 1 (5 min wash):

-Cornea: no ulceration or opacity: at 1, 24, 48, 72 hours and 7 days for all the animals (5/5)

-Normal iris: at 1, 24, 48, 72 hours and 7 days: 5/5

-Conjunctivae: vessels normal at 1 and 24 hours: 4/5 (grade 1 for 1/5); and at 48, 72 hours and 7 days: normal for 5/5

-Chemosis: at 1 hour: 2/5 with no swelling, 2/5 with grade 1 and 1/5 with grade 2; at 24, 48,72 hours, and 7 days: no swelling for 5/5

GROUP 2 (24 hours wash):

-Cornea: no ulceration or no opacity for 3/3 at 1, 48 and 72 hours, grade 1 at 24 hours for 3/3 animals

- Iris: normal for all animals for all time observation

-Conjunctivae : redness

-         at 1 hour and 24 hours: grade 1 for 1/3 and grade 2 for 2/3

-         at 48 hours: grade 1 for 2/3 and grade 2 for 1/3

-         at 72 hours: vessels normal for 2/3 and grade 1 for 1/3

-         at 7 days: vessels normal for 3/3

-Chemosis: 

-         at 1 hour: grade 1 for 1/3 and grade 2 for 2/3

-         at 24 hours: grade 1 for 1/3, grade 2 for 1/3 and grade 3 for 1/3

-         at 48 hours: no swelling for 1/3, grade 1 for 1/3 and grade 1 for 1/3

-         at 72 hours: grade 1 for for 1/3 and grade 2 for 2/3

- at 7 days: no swelling for 3/3 Fluorescein examination: 3/3 positive damage at 24 hours, 1/3 at 48 hours and 0/3 after 7 days Blanching of the conjunctival tissue was observed for one animal only after one hour.

Interpretation of results:
GHS criteria not met
Conclusions:
Benzoyl peroxide was neither irritating not corrosive to the eyes of albino rabbits if it was washed out within 5 minutes, but if 78 % benzoyl peroxide was not washed out until 24 hours later, it proved to be moderately irritating to rabbit eyes. It was not considered corrosive because corneal opacity lasted less than 6 days. Moreover, all the signs were reversible for 7 days.
Executive summary:

The potential of dibenzoyl peroxide to induce ocular irritation was evaluated in rabbits according to a method similar to OECD (No. 405, 24th April 2002) guideline.

A single dose of 0.1 mL of dibenzoyl peroxide (purity, 78 %) was instilled into the right conjunctival sac. The left eye was not treated and served as control.The substance was administered to 5 New Zealand White rabbits for 5 minutes, then the eye was washed. Moreover, the substance was adminstered to 3 New Zealand White rabbits for 24 hours, the eye was not washed.

Ocular reactions were observed approximately 1 hour, 24, 48 and 72 hours and 7 days after the administration of the substance. The mean values of the scores for chemosis, redness of the conjunctiva, iris lesions and corneal opacity were not calculated for each animal, but global scores for these effects were reported.

In group 1 (duration exposure: 5 minutes), benzoyl peroxide produced very minor redness (conjunctivitis) and swelling (chemosis) in 1/5 and 2/5 rabbits, respectively, but it was clear in 24 hours. No corneal opacity was observed.

In group 2 (duration exposure: 24 hours), there was grade 1 opacity in 3/3 rabbits at 24 hours ; clear in 3/3 at 48 hours. No iritis was observed. There was grade 2 redness in 2/3 at 48 hours, degrading to grade 1 in 1/3 at 72 hours ; clear by day 7. Even a clear irritative response was observed, all the signs were reversible within 7 days.

At fluorescein examination, corneal damage was observed in all animals after 24 hours, in one animal after 72 hours, and in no animal after 7 days.

Under these experimental conditions, the test item was moderately irritant when administered by ocular route to rabbits.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

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

Additional information

Skin irritation

In a rabbit study in which 78 % granular benzoyl peroxide was applied to the back of 3 males and 3 females, the substance was held in place for 4 hours with a gauze bandage. After 4 hours, the bandages were removed and the exposed areas washed with lukewarm water. The skin was examined for any injury or irritation according to Draize scale at 4, 24 and 72 hours. No signs of skin irritation were observed at 1, 3 days after 4 hr exposure (Wazeter and Goldenthal, 1973).

Different concentrations (0.1 to 30%) of benzoyl peroxide in yellow soft paraffin were applied under occlusion to shaved areas on the back of rabbits for 24 hours or repeated once daily for a maximum of 10 days (Haustein et al., 1985). The application was stopped when erythematous reactions occurred. The concentration which causes an irritant reaction in 50 % of the animals (IC50) after a 24-hour application was 2.52% (1.36%-4.04%). The number of days necessary to produce an irritant reaction in 50 % of the animals (IT50) after daily application were 8.35 (7.06 - 10.40) days, 4.34 (3.44 - 5.16) days and 2.31 (1.75 - 2.80) days at the concentrations of 0.1 %, 1 % and 5 % benzoyl peroxide, respectively.

Eye irritation

In a key eye irritation test, 8 male and female rabbits were divided into 2 groups. The 5 rabbits in group 1 were exposed to 111.4 mg benzoyl peroxide for 5 minutes. The rabbits in group 2 were exposed to 120.7 mg of the substance for 24 hrs. The study concluded that benzoyl peroxide was not irritating to the eyes of albino rabbits if it was washed out within 5 minutes after being placed in the conjunctival sac, however, if 78 % benzoyl peroxide was not washed out until 24 hr later, it proved to be slightly irritating (Wazeter and Goldenthal, 1973).

In a supporting study on eye irritation in rabbits, 70 % granular benzoyl peroxide was not irritating to the eye of 3 rabbits when immediately washed after instillation, whereas one rabbit in which benzoyl peroxide was not washed out immediately showed eye irritation until 72 hrs after application of 100 mg benzoyl peroxide. Corrosiveness was not observed in all animals (NIER, Korea, 2002).

Justification for classification or non-classification

According to EU Regulation (EC) N0. 1272/2008 (CLP), benzoyl peroxide is not classified for the skin irritation and is classified as eye irritant category 2 (Annex VI, Table 3.1)