Bis(4-methylbenzoyl)peroxide

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / developmental toxicity

Remarks:

based on test type

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Experimental start date: July 2nd 2014 Experimental completion date: 19th January 2015

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2015

Report date:

2015

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

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:

other: granular solid

Details on test material:

Identification : bis(4-methylbenzoyl)peroxide, 75% in water
CAS Number : 895-85-2
Physical State/Appearance :White granular solid
Chemical Name :bis(4-methylbenzoyl)peroxide, 75% in water
Chemical Formula :C16H14O4
Purity : 75.3%
Batch Number : BDT 13-003
Label : Perkadox PM-W75 Batchnr BDT 13-003
Date Received : 13 June 2014
Storage Conditions :Approximately 4 °C in the dark, in original container.
Expiry Date : 01 May 2016

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

A sufficient number of male and female Wistar Han™:RccHan™:WIST strain rats were obtained from Harlan Laboratories U.K. Ltd., Blackthorn, Bicester, Oxon, UK. On receipt the animals were examined for signs of ill-health or injury. The animals were acclimatized for five days during which time their health status was assessed. A total of ninety six animals (forty eight males and forty eight females) were accepted into the study. At the start of treatment the males weighed 301 to 340g, the females weighed 198 to 239g, and were approximately twelve weeks old.

Initially, all animals were housed in groups of four in solid floor polypropylene cages with stainless steel mesh lids and softwood flake bedding (Datesand Ltd., Cheshire, UK). During the pairing phase, the animals were transferred to polypropylene grid floor cages suspended over trays lined with absorbent paper on a one male: one female basis. Following evidence of successful mating, the males were returned to their original cages. Mated females were housed individually during gestation and lactation in solid floor polypropylene cages with stainless steel mesh lids and softwood flakes.

The animals were allowed free access to food and water. A pelleted diet (Rodent 2018C Teklad Global Certified Diet, Harlan Laboratories U.K. Ltd., Oxon, UK.) was used. Certificates of analysis of the batches of diet used are given in Appendix 22. Mains drinking water was supplied from polycarbonate bottles attached to the cage. Environmental enrichment was provided in the form of wooden chew blocks and cardboard fun tunnels (Datesand Ltd., Cheshire, UK) except for paired animals and mated females during final week of gestation and lactation. Mated females were also given softwood flakes, as bedding, throughout gestation and lactation. The diet, drinking water, bedding and environmental enrichment were considered not to contain any contaminant at a level that might have affected the purpose or integrity of the study.

The animals were housed in a single air-conditioned room within the Harlan Laboratories Ltd., Shardlow, UK Barrier Maintained Rodent Facility. The rate of air exchange was at least fifteen air changes per hour (see deviations from Study Plan) and the low intensity fluorescent lighting was controlled to give twelve hours continuous light and twelve hours darkness. Environmental conditions were continuously monitored by a computerized system, and print-outs of hourly temperatures and humidities are included in the study records. The Study Plan target ranges for temperature and relative humidity were 22 ± 3 °C and 50 ± 20% respectively. Short term deviations from these targets were considered not to have affected the purpose or integrity of the study; see deviations from Study Plan.

The animals were randomly allocated to treatment groups using a stratified body weight randomization procedure and the group mean body weights were then determined to ensure similarity between the treatment groups. The cage distribution within the holding rack was also randomized. The animals were uniquely identified within the study by an ear punching system routinely used in these laboratories.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

polyethylene glycol

Details on exposure:

For the purpose of this study the test item was prepared at the appropriate concentrations as a suspension in Polyethylene glycol 400. The stability and homogeneity of the test item formulations were determined by Harlan Laboratories Ltd., Shardlow, UK, Analytical Services. Results show the formulations to be stable for at least nineteen days. Formulations were initially prepared daily for the first week, weekly for the second and final week and fortnighlty for the remaining weeks. All formulations were stored at approximately 4 °C in the dark.

Samples of the test item formulation were taken and analyzed for concentration of bis(4-methylbenzoyl)peroxide, 75% CAS No. 895-85-2 in water at Harlan Laboratories Ltd., Shardlow, UK, Analytical Services. The results indicate that the prepared formulations were within ± 6% of the nominal concentration.

Details on mating procedure:

i. Groups of twelve male and twelve female animals were treated daily at the appropriate dose level throughout the study (except for females during parturition where applicable). The first day of dosing was designated as Day 1 of the study.
ii. On Day 15, animals were paired on a 1 male: 1 female basis within each dose group for a maximum of fourteen days.
iii. Following evidence of mating (designated as Day 0 post coitum) the males were returned to their original cages and females were transferred to individual cages.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The test item concentration in the test samples was determined by high performance liquid chromatography with UV detection (HPLC/UV) using an external standard technique. The test item gave a chromatographic profile of a single peak.

Instrumental Setup

HPLC: Agilent Technologies 1200, incorprating autosampler and workstation
Column: Zorbax Eclipse XDB C18 (150 x 4.6 mm id)
Column temp: 40°C
Mobile phase: Acetonotrile:water (90:10 v/v)
Flow-rate: 1 mL/min
UV detector wavelength: 252 nm
Injection volume: 5 microL
Retention time: ~3 mins

Study samples and storage
Representative samples were dispatched to the analytical laboratories internally (under vambient conditions) and stored at room temperature until analysis.

Discussion
The detection system was found to have acceptable linearity. The analytical procedure ahd acceptable recoveries of test item in the vehicle. The method of analysis was validated and proved to be suitable for use.

Duration of treatment / exposure:

Females: Until Day 5 post-partum
Males: 42 days

Frequency of treatment:

The test item was administered daily by gavage using a stainless steel cannula attached to a disposable plastic syringe. Control animals were treated in an identical manner with 4 mL/kg of Polyethylene glycol 400.

Details on study schedule:

Chronological Sequence of Study
i. Groups of twelve male and twelve female animals were treated daily at the appropriate dose level throughout the study (except for females during parturition where applicable). The first day of dosing was designated as Day 1 of the study.
ii. On Day 15, animals were paired on a 1 male: 1 female basis within each dose group for a maximum of fourteen days.
iii. Following evidence of mating (designated as Day 0 post coitum) the males were returned to their original cages and females were transferred to individual cages.
iv. Pregnant females were allowed to give birth and maintain their offspring until Day 5 post partum. Litter size, offspring weight and sex, surface righting and clinical signs were also recorded during this period.
v. The male dose groups were euthanized and examined macroscopically on Day 43.
vi. At Day 5 post partum, all surviving females and offspring were euthanized and examined macroscopically.

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0 mg/kg bw/day
Basis:
actual ingested
Control.

Doses / concentrations 2

Remarks:

Doses / Concentrations:
50 mg/kg bw/day
Basis:
actual ingested
Concentration: 12.5 mg/mL

Doses / concentrations 3

Remarks:

Doses / Concentrations:
200 mg/kg bw/day
Basis:
actual ingested
Concentration: 50 g/mL

Doses / concentrations 4

Remarks:

Doses / Concentrations:
1000mg/kg bw/day
Basis:
actual ingested
Concentration: 250 mg/mL

No. of animals per sex per dose:

12 males, 12 females per dose group (including Control)

Control animals:

yes, concurrent vehicle

Details on study design:

The animals were randomly allocated to treatment groups using a stratified body weight randomization procedure and the group mean body weights were then determined to ensure similarity between the treatment groups. The cage distribution within the holding rack was also randomized. The animals were uniquely identified within the study by an ear punching system routinely used in these laboratories.

Positive control:

Not applicable

Examinations

Parental animals: Observations and examinations:

Clinical Observations
All animals were examined for overt signs of toxicity, ill-health and behavioral change immediately before dosing, soon after dosing, and one hour after dosing (except for females during parturition where applicable). All observations were recorded.

Body Weight
Individual body weights were recorded on Day 1 (prior to dosing) and then weekly for males until termination and weekly for females until pairing. During the pairing phase females were weighed daily until mating was confirmed. Body weights were then recorded for females on Days 0, 7, 14 and 20 post coitum, and on Days 1 and 4 post partum.

Food Consumption
During the pre-pairing period, weekly food consumption was recorded for each cage of adults until pairing. This was continued for males after the mating phase. For females showing evidence of mating, food consumption was recorded for the periods covering post coitum Days 0-7, 7-14 and 14-20. For females with live litters, food consumption was recorded during the lactation period (Days 1-4).

Weekly food efficiency (body weight gain/food intake) was calculated retrospectively for males and for females during the pre-pairing phase. Due to offspring growth and milk production for lactation, food efficiency for females could not be accurately calculated during gestation and lactation.

Water Consumption
Water intake was observed daily by visual inspection of water bottles for any overt changes.

Reproductive Performance
Mating
Animals were paired on a 1 male: 1 female basis within each dose group, for a period of up to fourteen days. Cage tray-liners were checked each morning for the presence of ejected copulation plugs and each female was examined for the presence of a copulation plug in the vagina. A vaginal smear was prepared for each female and the stage of oestrus or the presence of sperm was recorded. The presence of sperm within the vaginal smear and/or vaginal plug in situ was taken as positive evidence of mating (Day 0 of gestation) and the males were subsequently returned to their original holding cages. Mated females were housed individually during the period of gestation and lactation.

Oestrous cyclicity (parental animals):

Pregnancy and Parturition
Each pregnant female was observed at approximately 0830, 1230 and 1630 hours and around the period of expected parturition. Observations were carried out at approximately 0830 and 1230 hours at weekends and public holidays. The following was recorded for each female:

i. Date of pairing
ii. Date of mating
iii. Date and time of observed start of parturition
iv. Date and time of observed completion of parturition

Sperm parameters (parental animals):

The epididymides and testes were removed from terminal kill adult males dissected free from fat and weighed before fixation.

Litter observations:

On completion of parturition (Day 0 post partum), the number of live and dead offspring was recorded. Offspring were individually identified within each litter by tattoo on Day 1 post partum.

For each litter the following was recorded:

i. Number of offspring born
ii. Number of offspring alive recorded daily and reported on Days 1 and 4 post partum
iii. Sex of offspring on Days 1 and 4 post partum
iv. Clinical condition of offspring from birth to Day 5 post partum
v. Individual offspring weights on Days 1 and 4 post partum (litter weights were calculated retrospectively from this data)

Physical Development
All live offspring were assessed for surface righting reflex on Day 1 post partum

Postmortem examinations (parental animals):

Adult males were euthanized by intravenous overdose of a suitable barbiturate agent followed by exsanguination on Day 43. Surviving adult females were euthanized by intravenous overdose of a suitable barbiturate agent followed by exsanguination on Day 5 post partum. Surviving offspring were euthanized via intracardiac overdose of a suitable barbiturate agent. Any females which failed to achieve pregnancy or produce a litter were euthanized on or after Day 25 post coitum.

For all females, the uterus was examined for signs of implantation and the number of uterine implantations in each horn was recorded. This procedure was enhanced; as necessary, by staining the uteri with a 0.5% ammonium polysulphide solution (Salewski 1964). The corpora lutea were also counted.

All adult animals and offspring, including those dying during the study, were subjected to a full external and internal examination, and any macroscopic abnormalities were recorded.

Histopathology
Samples of the following tissues were preserved from all animals from each dose group, in buffered 10% formalin, except where stated:

Coagulating gland, Prostate, Epididymides ♦, Seminal vesicles, Ovaries, Testes ♦, Mammary gland (females only), Uterus/Cervix, Pituitary, Vagina

All tissues were dispatched to the histology processing Test Site (Propath UK Ltd, Willow Court, Netherwood Road, Rotherwas, Hereford, HR2 6JU) for processing. The tissues from control and 1000 mg/kg bw/day dose group animals, and any animals which did not achieve a pregnancy were prepared as paraffin blocks, sectioned at a nominal thickness of 5 μm and stained with Hematoxylin and Eosin for subsequent microscopic examination. In addition, sections of testes from all control and 1000 mg/kg bw/day males were also stained with Periodic Acid-Schiff (PAS) stain and examined.

Detailed qualitative examination of the testes was undertaken, taking into account the tubular stages of the spermatogenic cycle. The examination was conducted in order to identify treatment-related effects such as missing germ cell layers or types, retained spermatids, multinucleated or apoptotic germ cells and sloughing of spermatogenic cells into the lumen. Any cell or stage specificity of testicular findings was noted.

Microscopic examination was conducted by the Study Pathologist (Roger Alison Ltd, Caerfyrddin Fach, Cilcennin, Lampeter, SA48 8RN, United Kingdom).

Postmortem examinations (offspring):

All adult animals and offspring, including those dying during the study, were subjected to a full external and internal examination, and any macroscopic abnormalities were recorded.

Statistics:

Please refer to the section below, "Any other information on materials and methods)

Reproductive indices:

Mating Performance and Fertility

The following parameters were calculated from the individual data during the mating period of the parental generation:

i. Pre-coital Interval - Calculated as the time elapsing between initial pairing and the observation of positive evidence of mating.

ii. Fertility Indices - For each group the following were calculated:

Mating Index (%) = (Number of animals mated / Number of animals paired) x 100

Pregnancy Index (%) = (Number of pregnant females / number of animals mated) x 100

Gestation and Parturition Data

The following parameters were calculated from individual data during the gestation and parturition period of the parental generation:

i. Gestation Length

Calculated as the number of days of gestation including the day for observation of mating and the start of parturition.

ii. Parturition Index

The following was calculated for each group:

Parturition Index (%) = (Number of females delivering live offspring / Number of pregnant females) x 100

Offspring viability indices:

Litter Responses
The standard unit of assessment was considered to be the litter, therefore values were first calculated for each litter and the group mean was calculated using their individual litter values. Group mean values included all litters reared to termination (Day 5 of age).

i. Implantation Losses (%)

Group mean percentile pre-implantation and post-implantation loss were calculated for each female/litter as follows:

Pre–implantation loss (%) = ((Number of corpora lutea - Number of implantation sites) / Number of corpora lutea) x100

Post–implantation loss (%) = ((Number of implantation sites - Total number of offspring born) / Number of implantation sites) x 100

ii. Live Birth and Viability Indices

The following indices were calculated for each litter as follows:

Live Birth Index (%) = (Number of offspring alive on Day 1 / Number of offpsring born) x 100

Viability Index (%) = (Number of offsoring alive on Day 4 / Number of offspring alive on Day 1) x 100

iii. Sex Ratio (% males)

Sex ratio was calculated for each litter value on Days 1 and 4 post partum, using the following formula:

(Number of male offspring / Total number if offspring) x 100

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

no effects observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Other effects:

not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

Details on results (P0)

Adult Reponses
Mortality
There were no deaths that were considered to be related to treatment.

One female treated with 1000 mg/kg bw/day was found dead shortly after smearing on Day 21. This female had not shown any clinical signs prior to Day 21, no effect on body weight gain and no macroscopic or microscopic abnormalities were evident. This death was therefore considered to be incidental and not related to treatment.

Clinical Observations
There were no toxicologically significant clinical signs evident in treated animals.

Two males treated with 1000 mg/kg bw/day and one male treated with 50 mg/kg bw/day showed isolated incidents of increased salivation on Day 29 and 30 (respectively). One female treated with 1000 mg/kg bw/day had noisy respiration on Day 36 and one female treated with 200 mg/kg bw/day had generalised fur loss between Days 21 and 44.

Body Weight
There were no treatment-related effects on body weight development.

Females treated with 1000 and 50 mg/kg bw/day showed a statistically significant increase in body weight on Day 4 of lactation. An increase in body weight or body weight gain is not considered to represent an adverse effect of treatment therefore the intergroup differences were considered not to be toxicologically important.

Food Consumption
No adverse effects on dietary intake were noted for males during the study or for females during the pre-pairing, gestation or lactation phases of the study.

Statistical analysis of the data for females during gestation and lactation did not reveal any significant intergroup differences.

Water Consumption
No adverse effect on water consumption was evident in treated animals when compared to controls.

Reproductive Performance
Mating
No treatment-related effects were detected in mating performance.

One control female showed positive evidence of mating but was non pregnant. No histopathological abnormalities were observed to explain the failure of this animal to breed successfully.

Fertility
There were no treatment-related differences in fertility.

One female treated with 50 mg/kg bw/day showed positive evidence of mating but failed to give birth to any live offspring. No histopathological abnormalities were observed to explain the failure of this animal to breed successfully and in the absence of a similar effect at 1000 mg/kg bw/day this was considered incidental and unrelated to treatment.

Gestation Length
Gestation lengths were between 22 and 23½ days and the distribution of gestation lengths for treated females was essentially similar to control.

No macroscopic abnormalities were detected.

Organ Weights
No treatment-related changes were evident in the organ weights measured.

Statistical analysis of the data did not reveal any significant intergroup differences.

Histopathology
No treatment-related microscopic abnormalities were detected.

Effect levels (P0)

Dose descriptor:

NOEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: The oral administration of bis(4-methylbenzoyl)peroxide, 75% in water CAS No. 895-85-2 to rats by gavage, at dose levels of 50, 200 and 1000 mg/kg bw/day, did not result in any treatment-related effects.

Results: F1 generation

General toxicity (F1)

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Histopathological findings:

not examined

Details on results (F1)

Litter Responses
In total eleven females from the control, 50 and 1000 mg/kg bw/day dose groups and twelve females from the 200 mg/kg bw/day dose group gave birth to a live litter and successfully reared young to Day 5 of age. The following assessment of litter response is based on all litters reared to termination on Day 5 of lactation/age.

Offspring Litter Size, Sex Ratio and Viability
No significant differences were detected for corpora lutea, implantation counts, implantation losses, litter size or litter viability for treated animals when compared to controls. Statistical analysis of the data did not reveal any significant intergroup differences.

There were no intergroup differences in sex ratio (percentage male offspring) for litters from treated groups compared to controls. Statistical analysis of the data did not reveal any significant intergroup differences.

Offspring Growth and Development
There were no toxicologically significant effects detected.

Statistical analysis of the litter, offspring weights or surface righting reflex data did not reveal any significant intergroup differences.

No obvious clinical signs of toxicity were detected for offspring from treated females when compared to controls. The incidental clinical signs detected throughout the control and treated groups, consisting of small size, cold, physical injury, bruising or scab formation were considered to be low incidence findings observed in offspring in studies of this type and were considered unrelated to test item toxicity.

No treatment-related macroscopic abnormalities were detected for offspring. The incidental findings observed were those occasionally observed in reproductive studies of this type and were considered to be unrelated to toxicity of the test item.

Effect levels (F1)

Dose descriptor:

NOEL

Generation:

F1

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: The oral administration of bis(4-methylbenzoyl)peroxide, 75% in water CAS No. 895-85-2 to rats by gavage, at dose levels of 50, 200 and 1000 mg/kg bw/day, did not result in any treatment-related effects.

Overall reproductive toxicity

Reproductive effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The oral administration of bis(4-methylbenzoyl)peroxide, 75% in water CAS No. 895-85-2 to rats by gavage, at dose levels of 50, 200 and 1000 mg/kg bw/day, did not result in any treatment-related effects.

The ‘No Observed Effect Level’ (NOEL) for reproductive and developmental toxicity was considered to be 1000 mg/kg bw/day.

Executive summary:

Introduction

The study was performed to screen for potential adverse effects of the test item on reproduction, including offspring development, and provides an initial hazard assessment for effect on reproduction. The study is compatible with the requirements of the recommendations of the OECD Guidelines for Testing of Chemicals No. 421 “Reproduction/Developmental Toxicity Screening Test” (adopted 27 July 1995).

 

This study was also designed to be compatible with Commission Regulation (EC) No 440/2008 of 30 May 2008 test methods pursuant to Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH).

 

 

Methods…….

The test item was administered by gavage to three groups, each of twelve male and twelve female Wistar Han™:RccHan™:WIST strain rats, for up to eight weeks (including a two week pre-pairing phase, pairing, gestation and early lactation for females), at dose levels of 50, 200 and 1000 mg/kg bw/day. A control group of twelve males and twelve females was dosed with vehicle alone (Polyethylene glycol 400).

 

Clinical signs, body weight change, dietary intake and water consumption were monitored during the study. 

 

Pairing of animals within each dose group was undertaken on a one male: one female basis within each treatment group on Day 15 of the study, with females subsequently being allowed to litter and rear their offspring to Day 5 of lactation.

 

During the lactation phase, daily clinical observations were performed on all surviving offspring, together with litter size and offspring weights and assessment of surface righting reflex.

 

Adult males were euthanized on Day 43, followed by the euthanization of all surviving females and offspring on Day 5post partum. Any female which did not produce a pregnancy was euthanized on or after Day 25post coitum. All animals were subjected to a gross necropsy examination and histopathological evaluation of reproductive tissues was performed.

 

 

Results…….

 

Adult Responses

Mortality

There were no deaths that were considered to be related to treatment.

 

 

Clinical Observations

No toxicologically significant clinical signs were detected in treated animals.

 

 

Body Weight

There were no treatment-related effects on body weight development.

 

 

Food Consumption

No adverse effects on dietary intake were noted for males during the study or for females during the pre-pairing, gestation or lactation phases of the study.

 

 

Water Consumption

No adverse effect on water consumption was evident in treated animals when compared to controls.

 

 

Reproductive Performance

Mating

No treatment-related effects were detected in mating performance. One control female showed positive evidence of mating but was non pregnant.

 

 

Fertility

There were no treatment-related differences in fertility.

 

 

Gestation Length

Gestation lengths were between 22 and 23½ days and the distribution of gestation lengths for treated females was essentially similar to control.

 

 

Litter Responses

Offspring Litter Size, Sex Ratio and Viability

Of the litters born, litter size at birth and subsequently on Days 1 and 4post partumwere comparable to controls. Sex ratio in treated litters was comparable to controls.

 

 

Offspring Growth and Development

Offspring body weight gain and litter weights at birth and subsequently on Days 1 and 4 post partum were comparable to controls. Surface righting in treated litters was comparable to controls.

 

 

Offspring Observations

The clinical signs and necropsy findings apparent for offspring on the study were typical for the age observed. Neither the incidence nor distribution of these observations indicated any adverse effect of maternal treatment on offspring development at 50, 200 or 1000 mg/kg bw/day.

 

 

Pathology

Necropsy

No macroscopic abnormalities were detected.

 

 

Organ Weights

No treatment-related changes were evident in the organ weights measured.

 

 

Histopathology

No treatment-related microscopic abnormalities were detected.

 

 

Conclusion

The oral administration of bis(4-methylbenzoyl)peroxide, 75% in water CAS No. 895-85-2 to rats by gavage, at dose levels of 50, 200 and 1000 mg/kg bw/day, did not result in any treatment-related effects.

 

The ‘No Observed Effect Level’ (NOEL) for reproductive and developmental toxicity was considered to be 1000 mg/kg bw/day.