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Administrative data

Description of key information

The acute ORAL study by Hoff (1991) assessed the toxicological profile of Di-(4 -Methylbenzoyl)-peroxid (INTEROX-PMBP) when administered by a single dose with an observation period of 15 days. The test article was administered to 8 -10 week old rats [(HanIbm: WIST (SPF)] of both sexes (five each) by oral gavage, at 2000 mg/kg, prepared in PEG 400. The death rate was: 0 % at 2000 mg/kg. The LOGIT-Model could not be applied to these data. It was concluded that the acute oral toxicity of Di-(4-Methylbenzoyl)-peroxid (INTEROX-PMBP) in rats of both sexes was estimated to be greater than 2000 mg/kg. An acute DERMAL toxicity study by Hoff (1991) assessed the toxicological profile of Di-(4-Methylbenzoyl)-peroxid (INTEROX-PMBP) when administered to rats by a single semiocclusive dermal application to 10-12 week old rats [(HanIbm: WIST (SPF)] of both sexes (five each) for 24 hours at 2000 mg/kg, prepared in PEG 400. Rats were observed for 15 days. The death rate was 0 % at 2000 mg/kg. Based on these observations, the LOGIT-Model could not be applied to the observed rate of death. Therefore, the toxicity of Di-(4-Methylbenzoyl)-peroxid (INTEROX-PMBP) was estimated to be greater than 2000 mg/kg.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Single treatment followed by an observation period of 15 days (September 3, 1991 to September 17, 1991)
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: A reliability rating of K2 was assigned due to the following minor deficiencies: lack of inclusion of CAS number and the Certificate of Analysis of the test material.
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: BRl, Biological Research laboratories Ltd. Wolferstrasse 4, CH-4414 Fullinsdorf
- Age at study initiation: males: 8 weeks; females: 10 weeks
- Weight at study initiation: males: 189 - 212 g; females: 175 - 182 g
- Fasting period before study: yes, overnight, but had access to water

- Housing:
Groups of five in Makrolon type-3 cages (size: 22 x 37.5 x 15 cm) with standard softwood bedding ("Lignocel", Schill AG, CH-4132 Muttenz).

Diet: Pelleted standard Kliba 343, Batches 85/91 and 86/91 rat maintenance diet ("Kliba", Klingentalmuehle AG, CH-4303 Kaiseraugst) available ad libitum. Results of analysis for contaminants are included in this report (see appendix).

Water: Community tap water from Fullinsdorf, available ad libitum. Results of bacteriological, chemical and contaminant analyses are included in this report.

- Acclimation period: August 27, 1991 to September 2, 1991

ENVIRONMENTAL CONDITIONS: Room No.: 103; standard Laboratory Conditions.
Air-conditioned with 10-15 air changes per hour, and continuously monitored environment with a temperature of 22 +/- 3 degrees centigrade
Relative Humidity between 40-70%.
Photoperiod (hrs dark / hrs light): 12 hours artificial fluorescent light (approx. 100 Lux) / 12 hours dark, music during the light period.

IN-LIFE DATES: From: To: August 27, 1991 to September 17, 1991.
Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Details on oral exposure:
VEHICLE: Polyethylene glycol. The lot/batch no. and purity were not mentioned.

MAXIMUM DOSE VOLUME APPLIED: Application Volume/ kg body weight: 10 ml at 2000 mg/kg

Semiocclusive

The animals received a single dose of the test article on a mg/kg body weight base by oral gavage after being fasted overnight (access to water was not interrupted). Food was again presented approximately 3 hours after dosing.

DOSAGE PREPARATION (if unusual): The test article was placed into a glass beaker on a tared Mettler PM 480 balance, and the vehicle, (Polyethylene glycol, PEG 400) was added. A weight by volume dilution was prepared using a homogenizer. Homogeneity of the test article in the vehicle was maintained during treatment using a magnetic stirrer. The preparation was made immediately prior to dosing.
Doses:
2000 mg/kg body weight
No. of animals per sex per dose:
Five
Control animals:
no
Details on study design:
Rationale: The oral administration was used because this is one possible route of human exposure during manufacture, handling and use of the test article.

OBSERVATIONS

Mortality / Viability: Four times during test day 1, and daily during days 2 - 15.

Body Weights Test days 1 (pre-administration), 8 and 15.

Clinical Signs
Each animal was examined for changes in appearance and behaviour four times during day 1, and daily during days 2-15. All abnormalities were recorded. The animals were checked for the clinical signs listed below. Positive findings are indicated under Appendix B.

GENERAL BEHAVIOUR
Aggressiveness, vocalization, restlessness / excitation, nervousness, fear / sedation, somnolence, sleep and coma.

RESPIRATION
Apnea, dyspnea, and rales.

EYE
Chromodacryorrhea, exophthalmos, miosis, mydriasis, whitish discharge, lid adhesion, lacrimation, and negative corneal reflex.

NOSE
Rhinorrhea, epistaxis

MOTILITY
Akinesia, Ataxia, dropped head, hyperkinesia, hypokinesia, paralysis (flaccid), paralysis (spastic), paddling movements, stiff gait and rolling movements.

BODY POSTURE
ventral body position, lateral-abdominal position and hunched posture.

MOTOR SUSCEPTIBILITY
spasms, tonic muscle spasms, clonic muscle spasms, opisthotonus, saltatory spasms, trismus, tremor, muscle-twitching, and muscle-twitching generalized

SKIN
erythema, edema, and necrosis

VARIOUS
loss of weight, emaciation, diarrhea, ruffled fur, salivation, pallor, or cyanosis

DATA' COMPILATION
The following data were recorded on-line: mortality/viability, clinical signs, body weights, macroscopical findings.

Pathology
Necropsies were performed by experienced prosectors. All animals were necropsied. All animals were euthanized by intraperitoneal injection of sodium pentobarbitone.
Statistics:
The LOGIT-Model could not be applied to the observed rates of death. The toxicity was estimated without use of a statistical model.
Preliminary study:
None reported.
Sex:
male/female
Dose descriptor:
discriminating dose
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
The test article Di-(4-Methylbenzoyl)-peroxid (INTEROX-PMBP) was administered to rats of both sexes by oral gavage, at a single dose of 2000 mg/kg. The following death rate was observed: 0 % at 2000 mg/kg. The LOGIT-Model could not be applied to these data.

The acute oral toxicity of Di-(4-Methylbenzoyl)-peroxid (INTEROX-PMBP) in rats of both sexes, observed over a period of 15 days, was estimated to be greater than 2000 mg/kg.
Clinical signs:
other: The following clinical signs were observed: 2000 mg/kg: males/females - no systemic clinical signs noted (9); males - sedated (1). ( ) = number of positive animals. Local clinical effects: General erythema in 3 out of 5 males, and 4 out of 5 females was
Gross pathology:
The following macroscopical organ findings were observed: 2000 mg/kg: males/females - sacrificed - no macroscopical organ findings noted (10).

( ) = number of positive animals

The original study report has individual animal data tables: Appendix A (mortality), Appendix B (clinical signs), Appendix C (Body weights), and Appendix D (macroscopical findings). These agree with the findings already reported above. Additionally, Appendix E contained water and feed analyses as required.

Interpretation of results:
GHS criteria not met
Conclusions:
The acute oral toxicity of Di-(4-Methylbenzoyl)-peroxid (INTEROX-PMBP) in rats of both sexes, observed over a period of 15 days, was estimated to be greater than 2000 mg/kg.
Executive summary:

The purpose of this acute oral study was to assess the toxicological profile of Di-(4 -Methylbenzoyl)-peroxid (INTEROX-PMBP)

when administered orally by a single dose followed by an observation period of 15 days. The test article Di-(4-Methylbenzoyl)-peroxid (INTEROX-PMBP) was administered to 8 -10 week old rats [(HanIbm: WIST (SPF)] of both sexes (five each) by oral gavage, at 2000 mg/kg, prepared in PEG 400. This GLP study by N. Hoff, 1991 was done according to OECD 401 and EU B.1 guidelines.

A reliability rating of K2 was given due to minor deficiencies: lack of inclusion of CAS number and the Certificate of Analysis of the test material.

The death rate was: 0 % at 2000 mg/kg. The LOGIT-Model could not be applied to these data.

 

The following clinical signs were observed: 2000 mg/kg: males/females - no clinical signs noted (9); males - sedated(1). The body weight gain of the animals was not affected by the test article treatment throughout the entire study period. All dosed males/females with 2000 mg/kg were sacrificed and macroscopic organ findings were not noted in any animal.

 

Conclusion: The acute oral toxicity of Di-(4-Methylbenzoyl)-peroxid (INTEROX-PMBP) in rats of both sexes, observed over a period of 15 days, was estimated to be greater than 2000 mg/kg. 

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 mg/kg bw
Quality of whole database:
The study had a reliability rating of K2.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
Due to its low vapor pressure (0.0000152 Pa at 25 degress Celcius) exposure to the test material by inhalation is not expected.

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
September 2, 1991 to September 16, 1991 (treatment and obserrvation)
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: A reliability rating of K2 was given due to minor deficiencies in the study report such as the lack of inclusion of CAS number and the Certificate of Analysis of the test material.
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: The HanIbm: WIST (SPF) rats were from BRl, Biological Research laboratories Ltd. Wolferstrasse 4, CH-4414 Fullinsdorf
- Age at study initiation: males: 10 weeks; females: 12 weeks
- Weight at study initiation: males: 212 - 233 g; females: 199 - 213 g
- Identification: By unique cage number and corresponding spots on the tail.
- Randomization: Randomly selected at the time of delivery
- Housing: Individually in Makrolon type-2 cages (size: 16.5 x 22 x 14 cm) with standard softwood bedding ("Lignocel", Schill AG, CH-4132 Muttenz).
-Diet: Pelleted standard Kliba 343, Batches 85/91 and 86/91 rat maintenance diet ("Kliba", Klingentalmuehle AG, CH-4303 Kaiseraugst) available ad li bitum. Results of analysis for contaminants are included in this report (see appendix).
-Water: Community tap water from Fullinsdorf, available ad libitum. Results of bacteriological, chemical and contaminant analyses are included in this report.
- Acclimation: One week (August 26, 1991 to September 1, 1991) under laboratory conditions after veterinary examination

ENVIRONMENTAL CONDITIONS: Room No.: 103; standard Laboratory Conditions.
-Air-conditioned with 10-15 air changes per hour, and continuously monitored environment with a temperature of 22 +/- 3 degrees centigrade
-Relative Humidity between 40-70%.
-Photoperiod (hrs dark / hrs light): 12 hours artificial fluorescent light (approx. 100 Lux) / 12 hours dark, music during the light period.
-Acclimation: August 26, 1991 to September 1, 1991.
Type of coverage:
semiocclusive
Vehicle:
polyethylene glycol
Details on dermal exposure:
TEST MATERIAL; Application Volumel/kg body weight was 4 ml at 2000 mg/kg

VEHICLE: Polyethylene glycol was used to prepare the dosing suspension. No control animals were dosed with the vehicle.

Approximately 24 hours before treatment, the backs of the animals were clipped with an electric clipper, exposing an area of approximately 10 % of the total body surface. Only those animals with no injury or irritation on the skin were used in the test.

On test day 1, the test article was applied evenly on the intact skin with a syringe and covered with a semi-occlusive dressing. The dressing was wrapped around the abdomen and fixed with an elastic adhesive bandage.

Twenty-four hours after the application, the dressing was removed. The treated skin was washed with lukewarm tap water, dried with disposable paper towels and the skin reaction was assessed according to the method of Noakes and Sanderson (Noakes, D.N. and Sanderson, D.M. "A Method for Determining the Dermal Toxicity of Pesticides". Brit. J. Industr. Med., 26, 59-64, 1969).
Duration of exposure:
24 hours
Doses:
2000 mg/kg, single application
No. of animals per sex per dose:
Five
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 15 days
- Frequency of observations and weighing:
- Necropsy of survivors performed: yes/no
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other:

OBSERVATIONS

Mortality / Viability * : Four times during test day 1, and daily during days 2 -15. Mortality/viability was recorded together with clinical signs on-line at the same time intervals. It is not specifically indicated in the computer system.

Body Weights: Test days 1 (pre-administration), 8 and 15.

Clinical Signs: Each animal had an examination for changes in appearance and behaviour 4 times during day 1, and daily during days 2-15. All abnormalities were recorded. Due to the 24 hour semi-occlusive treatment, the local findings were observed starting with day 2 of test. The animals werechecked for the signs listed below. Positive findings are indicated under Appendix B.

GENERAL BEHAVIOUR
aggressiveness
vocalization
restlessness / excitation
nervousness, fear
sedation
somnolence
sleep
coma

RESPIRATION
apnea
dyspnea
rales

EYE
chromodacryorrhea
exophthalmos
miosis
mydriasis
whitish discharge
lid adhesion
negative corneal reflex

NOSE
rhinorrhea
epistaxis

MOTILITY
akinesia
ataxia
dropped head
hyperkinesia
hypokinesia
paralysis, flaccid
paralysis, spastic
paddling movements
stiff gait
rolling movements

BODY POSITION
ventral body position
latero-abdominal position
hunched posture

MOTOR SUSCEPTIBILITY
spasms
tonic muscle spasms
clonic muscle spasms
opisthotonus
saltatory spasms
trismus
tremor
muscle-twitching
muscle-twitching, generalized

SKIN
erythema
edema
necrosis
crusts
scale formations

VARIOUS
loss of weight
emaciation
diarrhea
ruffled fur
necrosis of tissue of application area
salivation
pallor
cyanosis

PATHOLOGY: Necropsies were performed by experienced prosectors. All animals were necropsied. All animals surviving to the end of the observation period were euthanized by intraperitoneal injection of sodium pentobarbitone.
Statistics:
The LOGIT-Model could not be applied to the observed rates of death. The toxicity was estimated without use of a statistical model.


Preliminary study:
None.
Sex:
male/female
Dose descriptor:
discriminating dose
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
The test article Di-(4-Methylbenzoyl)-peroxid (INTEROX-PMBP) was applied to the skin of rats of both sexes for 24 hours at a single dose of 2000 mg/kg.

The following death rate was observed: 0 % at 2000 mg/kg. Based on these observations, the LOGIT-Model could not be applied to the observed rate of death. Therefore, the toxicity of Di-(4-Methylbenzoyl)-peroxid (INTEROX-PMBP) was estimated to be: greater than 2000 mg/kg.
Clinical signs:
other: The following local signs were observed: 2000 mg/kg: males - skin: general erythema (3); no clinical signs noted (2); females - skin: general erythema (4); scales (1); no clinical signs noted (1). The animals had recovered from local signs within 5 to 8
Gross pathology:
MACROSCOPICAL FINDINGS
No macroscopical organ findings were observed in any of the 2000 mg/kg: males/females sacrificed.

Information on results, including the individual animal data tables were provided in the Appendix A (mortality), Appendix B (individual and summary of clinical signs), Appendix C (Body weights, individual animals), and Appendix D (macroscopical findings, individual animals) of the study report. These findings are already described above. Appendix E of the report containeds water and feed analyses.

Interpretation of results:
GHS criteria not met
Conclusions:
The acute dermal toxicity of Di-(4-Methylbenzoyl)-peroxid (INTEROX-PMBP) in rats of both sexes, observed over a period of 15 days, was estimated to be greater than 2000 mg/kg.
Executive summary:

The purpose of this acute dermal toxicity study was to assess the toxicological profile of Di-(4-Methylbenzoyl)-peroxid (INTEROX-PMBP) when administered to rats by a single occlusive dermal application, with an observation period of 15 days. This study should provide a rational basis for risk assessment in man. The dermal administration was used because this is one possible route of humanexposure during manufacture, handling and use of the test article.

The test article, Di-(4 -Methylbenzoyl)-peroxid (INTEROX-PMBP), was applied to the skin of 10-12 week old rats [(HanIbm: WIST (SPF)] of both sexes (five each) for 24 hours at a single dose of 2000 mg/kg, prepared in PEG 400. This GLP study by N. Hoff, 1991 was done according to OECD 402 and EU B.3 guidelines.

A rating of K2 was given due to minor deficiencies in the study report (lack of inclusion of the CAS number and the Certificate of Analysis of the test material).

The death rate was 0 % at 2000 mg/kg. Based on these observations, the LOGIT-Model could not be applied to the observed rate of death. Therefore, the toxicity of Di-(4-Methylbenzoyl)-peroxid (INTEROX-PMBP) was estimated to be greater than 2000 mg/kg.

Conclusion: The acute dermal toxicity of Di-(4-Methylbenzoyl)-peroxid (INTEROX-PMBP) in rats of both sexes, observed over a period of 15 days, was estimated to be greater than 2000 mg/kg.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 mg/kg bw
Quality of whole database:
The study had a reliability rating of K2.

Additional information

The test item did not meet the criteria for classification according to the Regulation (EC) No. 1272/2008, relating to the Classification, Labekling and Packaging of the Dangerous Substances.


Justification for selection of acute toxicity – oral endpoint
A well-conducted GLP study based on OECD test guideline 401.

Justification for selection of acute toxicity – dermal endpoint
A well-conducted GLP study based on OECD test guideline 402.

Justification for classification or non-classification

Based on the results of the acute oral and dermal toxicity studies in rats, it was concluded that the data are conclusive but not sufficient for classification.