Bis(4-methylbenzoyl)peroxide

Acute Toxicity: dermal

Administrative data

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.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1991

Report date:

1991

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Test guideline 2

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

Test material

Test material information

Constituent 1

Reference substance name:

Bis(4-methylbenzoyl)peroxide

EC Number:

407-950-9

EC Name:

Bis(4-methylbenzoyl)peroxide

Cas Number:

895-85-2

Molecular formula:

C16H14O4

IUPAC Name:

4-methylbenzoyl 4-methylbenzene-1-carboperoxoate

Test material form:

solid - liquid: suspension

Details on test material:

- Name of test material (as cited in study report): Di-(4-Methylbenzoyl)-peroxid (INTEROX-PMBP)
- Physical state: solid, white
- Analytical purity:water damped powder 72% PMBP
- Purity test date: Not provided
- Batch No.: IR 240001
- Expiration date of the batch: Stable, November, 1991
- Stability under test conditions: Stable for at least 48 hours
- Storage condition of test material: In the original container; protected from light at room temperature (approx. 20 degrees C)

Test animals

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.

Administration / exposure

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.

Results and discussion

Preliminary study:

None.

Effect levels

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.

Any other information on results incl. tables

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.

Applicant's summary and conclusion

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.