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Administrative data

Description of key information

The primary skin irritation study by Hoff (1991) was done with a single dose of Di-(4 -Methy1benzoy1)-peroxid (INTEROX PMBP) placed (semi-occlusive) on the skin of NZW rabbits. Local signs (mean values from 1 hour to 72 hours) consisted of grade 0.58 erythema and grade 0.42 edema. No corrosive effect occurred on the treated skin of any animal at each measuring interval. Under the conditions of this GLP study, Di-(4-Methylbenzoyl)-peroxid (INTEROX PMBP) was found to cause a primary irritation score of 0.44. Mean value of the scores for each type of lesion, calculated for each animal separately was done according to EEC Council Directive, 83/467/EEC, July 1983 and 67/548/EEC, May 1987, Brussels, Belgium. Based on these results, the test article Di-(4 -Methy1benzoy1)-peroxid (INTEROX PMBP) is classified as not irritant to the skin of NZW rabbits. 
The primary eye irritation study by Hoff (1991) was done with a single dose of Di-(4-Methylbenzoy1)-peroxid (INTEROX-PMBP) placed in the conjunctival sac of NZW rabbit eyes. The mean value of the scores for each type of lesion, calculated for each animal separately, was done according to EEC Council Directive, 83/467/EEC, July 1983 and 67/548/EEC, May 1987, Brussels, Belgium. Under the conditions of this GLP-certified experiment, Di-(4-Methylbenzoyl)-peroxid was found to cause a primary irritation score of: 0.58 (mean of 24, 48, and 72 hr scores). No staining of the cornea and conjunctivae of the treated eyes by pigment or coloring of the test article was observed. Body weight gain of all rabbits was similar. Due to the results described above, the test article (Di-(4-Methy1benzoyl)-peroxid (INTEROX-PMBP) had to be classified as not irritant to the rabbit eye.

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:
4 days of treatment and observation ( September 9, 1991 to September 12, 1991)
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: A reliability rating of K2 was given due to minor deficiencies such as the lack of inclusion of CAS number and the Certificate of Analysis of the test material in the Study report.
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
GLP compliance:
yes (incl. QA statement)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
IN-LIFE DATES:
Acclimatization: September 5 to 8, 1991
Treatment/Observation: September 9 to 12, 1991
Completion: September 12, 1991
Reported: October 16, 1991

Test System: Rabbit, ChbbIbm: NZW (SPF)
Rationale: Recognized by the international guidelines as the recommended test system (e.g. OECD, EEC).
Source: BRL, Biological Research Laboratories Ltd., Wolferstrasse 4, CH-4414, Fullinsdorf
Number of animals: 1 male, 2 females
Age at start of treatment: male: 15 weeks; females: 16 weeks
Body weight at start of treatment: male: 2.8 kg; females: 2.8 kg
Identification: By unique cage number and corresponding ear tags.
Acclimatization: Four days under test conditions after veterinary examination.
Allocation: Animal Numbers, Male no. 34, and Female nos. 35 – 36


Standard Laboratory Conditions.
Air-conditioned with 10-15 air changes per hour and hourly monitored environment with a temperature of 20±3 degrees centigrade, a relative humidity between 40-70% (values above 70% during cleaning process possible), 12 hours artificial fluorescent light (approx. 100 Lux) / 12 hours dark, music during the light period.

Accommodation
Individually, in stainless steel cages (size: 35.5 x 55.5 x 45 cm) equipped with an automatic cleaning and drinking system (Dipl. Ing. W. Ehret GmbH, 0-7830 Emmendingen).

Diet
Pelleted standard Kliba 341, Batch 63/91 rabbit maintenance diet ("Kliba", Klingentalmuehle AG, CH-4303 Kaiseraugst), ad libitum. Results of analysis for contaminants are included in the original study report.

Water
Community tap water from Itingen, ad libitum. Results of bacteriological, chemical and contaminant analyses are included in the original Study report.
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
water
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
0.5 g of the test article was applied to approx. 6 sq. cm of the intact skin.

VEHICLE
The test article was applied moistened with bi-distilled water. The vehicle used, was found to be the most qualified to assure an optimum
technical application procedure of the test article.
Duration of treatment / exposure:
4 hrs
Number of animals:
three
Details on study design:
Rationale: Skin contact is one of the probable routes of human exposure.

Approximately 24 hours before treatment, the dorsal fur was clipped with an electric clipper, exposing an area of approximately 100 square centimeters (10 cm x 10 cm). The skin of the animals was examined once, 1 day prior to test article administration. Only those animals with no signs of skin injury or irritation were used in the test.

On test day 1, 0.5 g of the test article was applied to approx. 6 cm2 of the intact skin of the clipped area. It was covered with a 3.0 cm x 3.0 cm patch of surgical gauze. The gauze was covered with a semi-occlusive dressing. The dressing was wrapped around the abdomen and anchored with an elastic bandage. The duration of treatment was 4 hours. Then the dressing was removed and the skin was flushed with lukewarm-tap water.

Viability/Mortality and Clinical Signs : Observed dail y.
(Viability/mortality was recorded together with clinical signs on-line at the same time intervals. It is not specifically indicated in the computer system.)

Body Weights: At the start of acclimatization, day 1 of test (application day) and at termination of observation.

Irritation Scores: Four hours after the application, the dressing was removed and the skin was flushed with lukewarm tap water. The skin reaction was assessed according to the following numerical scoring system. (See under "other information on materials and methods" Section.) The skin reaction was assessed at 1, 24, 48 and 72 hours after the removal of the dressing, gauze patch and test article. The corrosive properties of the test article and the staining of the treated skin area related to the test article were described and recorded.
Irritation parameter:
erythema score
Basis:
animal #1
Remarks:
(#34, male)
Time point:
other: 1 hr
Score:
2
Max. score:
4
Remarks on result:
other: Well defined erythema and slight edema, whole area
Irritation parameter:
edema score
Basis:
animal #1
Remarks:
(#34, male)
Time point:
other: 1 hr
Score:
2
Max. score:
4
Irritation parameter:
erythema score
Basis:
animal #2
Remarks:
(#35, female)
Time point:
other: 1 hr
Score:
1
Max. score:
4
Remarks on result:
other: Very slight erythema, edema, whole area
Irritation parameter:
edema score
Basis:
animal #2
Remarks:
(#35, female)
Time point:
other: 1 hr
Score:
1
Max. score:
4
Irritation parameter:
erythema score
Basis:
animal #3
Remarks:
(#36, female)
Time point:
other: 1 hr
Score:
1
Max. score:
4
Remarks on result:
other: Very slight erythema, edema, whole area
Irritation parameter:
edema score
Basis:
animal #3
Remarks:
(#36, female)
Time point:
other: 1 hr
Score:
1
Max. score:
4
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24 h
Score:
1
Max. score:
4
Remarks on result:
other: Very slight erythema, maculated
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24 h
Score:
0
Max. score:
4
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24 h
Score:
0
Max. score:
4
Remarks on result:
other: No abnormalities visible
Irritation parameter:
edema score
Basis:
animal #2
Time point:
24 h
Score:
0
Max. score:
4
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24 h
Score:
1
Max. score:
4
Remarks on result:
other: Very slight erythema, edema, maculated
Irritation parameter:
edema score
Basis:
animal #3
Time point:
24 h
Score:
1
Max. score:
4
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
48 h
Score:
0
Max. score:
4
Remarks on result:
other: No abnormalities visible.
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
48 h
Score:
0
Max. score:
4
Remarks on result:
other: No abnormalities visible
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
48 h
Score:
1
Max. score:
4
Remarks on result:
other: Very slight erythema, maculated
Irritation parameter:
edema score
Basis:
other: All 3 animals
Time point:
48 h
Score:
0
Max. score:
4
Remarks on result:
other: Zero score for all 3 animals at 48 hrs
Irritation parameter:
erythema score
Basis:
animal #1
Remarks:
(#34, male)
Time point:
72 h
Score:
0
Max. score:
4
Remarks on result:
other: No abnormalities visible
Irritation parameter:
erythema score
Basis:
animal #2
Remarks:
(#35, female)
Time point:
72 h
Score:
0
Max. score:
4
Remarks on result:
other: No abnormalities visible
Irritation parameter:
erythema score
Basis:
animal #3
Remarks:
(#36, female)
Time point:
72 h
Score:
0
Max. score:
4
Remarks on result:
other: No abnormalities visible
Irritation parameter:
edema score
Basis:
other: All 3 animals
Time point:
72 h
Score:
0
Max. score:
4
Remarks on result:
other: Zero score for all 3 animals at 72 hrs
Irritant / corrosive response data:
RESULTS

IRRITATION: Di-(4-Methylbenzoyl)-peroxid (INTEROX PMBP) showed a primary irritation score of 0.44 when applied to healthy intact rabbit skin. Local signs (mean values from 1 hour to 72 hours) consisted of grade 0.58 erythema and grade 0.42 edema.

COLORATION: In the area of application no staining of the treated skin by pigment or coloring of the test article was observed.

CORROSION: No destructions or irreversible alterations of the treated skin were observed. No corrosive effect was evident on the skin.


Other effects:
CLINICAL SIGNS AND VIABILITY I MORTALITY: No acute clinical symptoms were observed in the animals during the test and observation period, and no mortality occurred.

BODY WEIGHTS: The body weight gain of all rabbits was similar.

The individual skin irritation scores at 1, 24, 48 and 72 hrs as well as the calculated mean scores for each animal based on 24, 48 and 72 hour observations are provided as two tables under "overall remarks, attachments" (see illustration).

Interpretation of results:
GHS criteria not met
Conclusions:
The test article Di-(4 -Methy1benzoy1)-peroxid (INTEROX PMBP) is classified as not irritant to the skin of rabbits based on the EEC Council Directive,83/467/EEC,July 1983 and67/548/EEC, May 1987, Brussels, Belgium.
Executive summary:

The purpose of this primary skin irritation study was to assess the possible irritation potential when single doses of Di-(4 -Methy1benzoy1)-peroxid (INTEROX PMBP) were placed (semi-occlusive) on the skin of NZW rabbits. This study should provide a rational basis for risk assessment in man. The GLP study was conducted according to OECD 404 and EEC B4 test guidelines. A reliability rating of K2 was given due to minor deficiencies such as the lack of inclusion of CAS number and the Certificate of Analysis of the test material in the Study report. 

Local signs (mean values from 1 hour to 72 hours) consisted of grade 0.58 erythema and grade 0.42 edema. In the area of application, no staining of the treated skin by pigment or coloring of the test article was observed. No corrosive effect occurred on the treated skin of any animal at each measuring interval. Under the conditions of this experiment, Di-(4-Methylbenzoyl)-peroxid (INTEROX PMBP) was found to cause a primary irritation score of 0.44 when applied to healthy intact rabbit skin.  

According to EEC Council Directive, 83/467/EEC, July 1983 and 67/548/EEC, May 1987, Brussels, Belgium, the mean value of the scores for each type of lesion, calculated for each animal separately, is the following:  

AnimalNo. / Sex   Mean 24 - 72 hours                                                                                           

Erythema       Edema 

34 M                          0.33                0.00     

35 F                           0.00                0.00     

36 F                           0.67                0.33      

Conclusion: Based on the results described above, the test article Di-(4 -Methy1benzoy1)-peroxid (INTEROX PMBP) is classified as not irritant to the skin of NZW rabbits.

Endpoint:
skin irritation: in vitro / ex vivo
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
an in vitro skin irritation study does not need to be conducted because adequate data from an in vivo skin irritation study are available
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Referenceopen allclose all

Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
72 hours (treatment/observation: October 1, 1991 to October 4, 1991).
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: A reliability rating of K2 was given due to minor deficiencies e.g., non-inclusion of CAS number and the Certificate of Analysis of the test material in the Study Report.
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
IN-LIFE DATES:
Acclimatization: September 27 to 30, 1991
Treatment/Observation: October 1 to 4, 1991
Termination: October 4, 1991
Reported: October 24, 1991

Test System: Rabbit, ChbbIbm: NZW (SPF)
Rationale: Recognized by the international guidelines as the recommended test system (e.g. OECD, EEC).
Source: BRL, Biological Research Laboratories Ltd., Wolferstrasse 4, CH-4414, Fullinsdorf
Number of animals: 1 male, 2 females
Age at start of treatment: male: 15 weeks; females: 16 weeks
Body weight at start of treatment: male: 2.9 kg; females: 2.9 - 3.0 kg
Identification: By unique cage number and corresponding ear tags.
Acclimatization: Four days under test conditions after veterinary examination.
Allocation: Animal Numbers, Male no. 34, and Female nos. 35 – 36

Standard Laboratory Conditions.
Air-conditioned with 10-15 air changes per hour and hourly monitored environment with a temperature of 20±3 degrees centigrade, a relative humidity between 40-70% (values above 70% during cleaning process possible), 12 hours artificial fluorescent light (approx. 100 Lux) / 12 hours dark, music during the light period.

Accommodation
Individually, in stainless steel cages (size: 35.5 x 55.5 x 45 cm) equipped with an automatic cleaning and drinking system (Dipl. Ing. W. Ehret GmbH, 0-7830 Emmendingen).

Diet
Pelleted standard Kliba 341, Batch 63/91 rabbit maintenance diet ("Kliba", Klingentalmuehle AG, CH-4303 Kaiseraugst), ad libitum. Results of analysisfor contaminants are included in the original study report.

Water
Community tap water from Itingen, ad libitum. Results of bacteriological, chemical and contaminant analyses are included in the original Study report.
Vehicle:
unchanged (no vehicle)
Controls:
other: The right eye of each animal remained untreated and served as the reference control
Amount / concentration applied:
0.1 g of the test article (undiluted)
Duration of treatment / exposure:
Single application
Observation period (in vivo):
72 hours
Number of animals or in vitro replicates:
Three
Details on study design:
Rationale: Ocular contact is one of the probable routes of human exposure.

TREATMENT: The eyes of the animals were examined once, one day prior to test article administration. Only those animals with no signs of ocular injury or irritation were used on the test. On test day 1, 0.1 g of the test article (undiluted) was placed in the conjunctival sac of the left eye of each animal after gently pulling the lower lid away from the eyeball. The lids were then gently held together for about one second to prevent loss of the test article. The right eye remained untreated and served as the reference control. In cases of equivocal results when comparing the treated and untreated eyes, the illustrated guide from the Consumer Product Safety Commission Washington, D.C. 20207 was used for additional control purposes.

Viability/Mortality and Clinical Signs**: Daily.

Body Weights: At the start of acclimatization, at day 1 of test (application day) and at termination of observation.

** Viability/mortality was recorded together with clinical signs on-line at the
same time intervals. It is not specifically indicated in the computer system.
Irritation parameter:
overall irritation score
Remarks:
(Mean)
Basis:
mean
Remarks:
of animals # 34M, 35F & 36F
Time point:
other: 1 hr
Score:
1.67
Irritation parameter:
overall irritation score
Remarks:
(Mean)
Basis:
mean
Remarks:
of animals # 34M, 35F & 36F
Time point:
other: 24 hrs
Score:
0.67
Irritation parameter:
overall irritation score
Remarks:
(Mean)
Basis:
mean
Remarks:
of animals # 34M, 35F & 36F
Time point:
other: 48 hrs
Score:
0
Irritation parameter:
overall irritation score
Remarks:
(Mean)
Basis:
mean
Remarks:
of animals # 34M, 35F & 36F
Time point:
other: 72 hrs
Score:
0

RESULTS

 

VIABILITY / MORTALITY AND CLINICAL SIGNS:

No acute clinical symptoms were observed in the animals during the test and observation period, and no mortality occurred.

 

IRRITATION:

Di-(4-Methylbenzoyl)-peroxid (INTEROX-PMBP) showed a primary irritation score

of 0.58, when applied to the conjunctival sac of the rabbit eye.

 

COLORATION:

In the area of application no staining of the cornea and conjunctivae by pigment or coloring of the test article was observed.

 

CORROSION:

Generally slightly diffuse corneal opacity was observed in one animal (female

no. 36) in the first hour after test article application.

 

BODY WEIGHTS:

The body weight gain of all rabbits was similar.

Interpretation of results:
GHS criteria not met
Conclusions:
The test article, Di-(4-Methy1benzoyl)-peroxid (INTEROX-PMBP), had to be classified as not irritant to the rabbit eye.
Executive summary:

SUMMARY

The purpose of this primary eye irritation study was to assess the possible irritation potential when a single dose of Di-(4-Methylbenzoy1)-peroxid (INTEROX-PMBP) was placed in the conjunctival sac of NZW rabbit eyes. This study should provide a rational basis for risk assessment in man. This GLP study was conducted according to OECD 405 and EEC B5 test guidelines. A reliability rating of K2 was given due to minor deficiencies such as the lack of inclusion of CAS number and the Certificate of Analysis of the test material in the study report.

 

According to EEC Council Directive, 83/467/EEC, July 1983 and 67/548/EEC, May 1987, Brussels, Belgium, the mean value of the scores for each type of lesion, calculated for each animal separately, is the following:

 

Animal                              Mean values 24 - 72 hours         

No.                  Cornea            Iris                                   Conjunctivae

opacity                                             Redness         Chemosis        

34 M               0.00                0.00                             0.33                      0.00     

35 F                0.00                0.00                             0.00                      0.00     

36 F                0.00                0.00                             0.33                      0.00    

 

Mean cumulative score: 0.22; Primary irritation score: 0.58 (mean of 24, 48, and 72 hr scores)

Under the conditions of this GLP-certified experiment, Di-(4-Methylbenzoyl)-peroxid was found to cause a primary irritation score of: 0.58 when applied to the conjunctival sac of the rabbit eye. No staining of the cornea and conjunctivae of the treated eyes by pigment or coloring of the test article was observed. Generally slightly diffuse corneal opacity was observed in one animal (female animal No. 36) in the first hour after test article application. Body weight gain of all rabbits was similar.

Conclusion: Due to the results described above, the test article (Di-(4-Methy1benzoyl)-peroxid (INTEROX-PMBP) had to be classified as not irritant to the rabbit eye.

Endpoint:
eye irritation: in vitro / ex vivo
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
an in vitro eye irritation study does not need to be conducted because adequate data from an in vivo eye irritation study are available
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for classification or non-classification

Based on the results of the rat primary skin irritation / corrosion test and the rat eye irritation test in vivo, it was concluded that the data are conclusive but not sufficient for classification.