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EC number: 201-279-3 | CAS number: 80-43-3
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2013-11-18 to 2014-06-20
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Referenceopen allclose all
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 014
- Report date:
- 2014
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 015
- Report date:
- 2015
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- Bis(α,α-dimethylbenzyl) peroxide
- EC Number:
- 201-279-3
- EC Name:
- Bis(α,α-dimethylbenzyl) peroxide
- Cas Number:
- 80-43-3
- Molecular formula:
- C18H22O2
- IUPAC Name:
- 1,1'-(dioxydipropane-2,2-diyl)dibenzene
- Test material form:
- not specified
- Details on test material:
- - Name of test material (as cited in study report): Dicumyl Peroxide; Chemical name: bis(α, α-dimethylbenzyl) peroxide
- Physical state: Crystalline, white
- Analytical purity: technically pure
- Composition of test material, percentage of components: bis(α, α-dimethylbenzyl) peroxide , technically pure
- Lot/batch No.: 113040311
- Expiration date of the lot/batch: August 20, 2014
- Storage condition of test material: Store in original package at room temperature (max.: 30 °C)
- Assay (peroxide content): 99.00%
- Active oxygen content: 5.86%
Constituent 1
- Specific details on test material used for the study:
- - Name of test material (as cited in study report): Dicumyl Peroxide; Chemical name: bis(α, α-dimethylbenzyl) peroxide
- Physical state: Crystalline, white
- Analytical purity: technically pure
TREATMENT OF TEST MATERIAL PRIOR TO TESTING
Preparation of the test item formulation was made in the vehicle from daily up to every five days using magnetic stirrer in the formulation laboratory of the test facility.
Test animals
- Species:
- rat
- Strain:
- Wistar
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Strain: Hsd. Brl.Han: WIST
- Source: TOXI-COOP ZRT. 1103 Budapest, Cserkesz u. 90.
- Age at study initiation: Females 6-9 weeks; males 9-10 weeks
- Weight at study initiation: Females 100-160 g; males 250-310 g
- Fasting period before study: not specified
- Housing: 2-3 males or females per cage, Type II polypropylene/polycarbonate with stainless steel covers equipped by self-feeding baskets, certified laboratory wood bedding changed twice a week.
- Diet : ad libitum ,ssniff® SM R/M-Z+H complete diet (ssniff Spezialdiäten GmbH, D-59494 Soest Germany)
- Water : tap water, ad libitum
- Acclimation period: 64 days for females, 82 days for males
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-22
- Humidity (%): 30-59
- Air changes (per hr): 10-15 air exchanges/hour by central air-conditioning system.
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: until 3 weeks after mating
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: sunflower oil
- Details on exposure:
- VEHICLE
- Justification for use and choice of vehicle (if other than water): Dicumyl Peroxide was proved to be stable in sunflower oil in formulations at room temperature for up to 24 hours and at 5 ± 3 ºC for up to five days
- Amount of vehicle (if gavage): 2 ml/kg bw
- Lot/batch no. (if required): 1305-4630 - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Preparation of the test item formulation was made in the vehicle from daily up to every five days using magnetic stirrer in the formulation laboratory of the test facility. A sufficient stability and homogeneity in the chosen vehicle were verified over the range of relevant concentrations at the appropriate frequency of preparation.
- Details on mating procedure:
- - Impregnation procedure: cohoused
- M/F ratio per cage: 1 male/1-3 females
- Length of cohabitation: 2-3 hours until the number of sperm positive females/group were achieved
- Proof of pregnancy: vaginal plug and/or sperm in the vaginal smear referred to as day 0 / day 1 of pregnancy - Duration of treatment / exposure:
- Days 5-19 of gestation
- Frequency of treatment:
- Daily
- Duration of test:
- Necropsy on gestation day 20
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Dose / conc.:
- 50 mg/kg bw/day (nominal)
- Remarks:
- concentration 25 mg/mL
- Dose / conc.:
- 150 mg/kg bw/day (nominal)
- Remarks:
- concentration 75 mg/mL
- Dose / conc.:
- 450 mg/kg bw/day (nominal)
- Remarks:
- concentration 225 mg/mL
- No. of animals per sex per dose:
- 24 sperm positive females/group
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The dose levels were selected with agreement of the sponsor based on the results of a dose range finding study by oral administration and literature data presented by the sponsor
- Rationale for animal assignment (if not random): The sperm positive females were allocated if possible to each experimental group on each mating day in such a way that the group averages of the body weight were as similar as possible on the first day of gestation. If possible, females paired with the same male were allocated to different groups on the same mating day.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations checked: mortality and morbidity
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at least once a day
BODY WEIGHT: Yes (females only)
- Time schedule for examinations: once during pre-mating period, gestation days 0, 3, 5, 8, 11, 14, 17 and 20, corrected body weight was calculated for the 20th day of pregnancy
FOOD CONSUMPTION: Yes
- The food consumption was measured between gestation days 0 to 3, 3 to 5, 5 to 8, 8 to 11, 11 to 14, 14 to 17 and 17 to 20
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: uterus with cervix and the left ovary, viscera - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: No
- Number of late resorptions: No
- Other: live fetuses, early and late embryonic death, foetal death - Blood sampling:
- not reported
- Fetal examinations:
- - External examinations: Yes: all live foetuses per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: all per litter
- viability, weight, gender, half subject to visceral examination - Statistics:
- - Statistical analysis was performed with SPSS PC+ software.
- The heterogeneity of variance between groups was checked by Bartlett's homogeneity of variance test. Where no significant heterogeneity was detected, a one-way ANOVA was carried out. If the obtained result was positive, Duncan's multiple range test was used to assess the significance of inter-group differences. Where significant heterogeneity was found, the normal distribution of data was examined by Kolmogorov-Smirnov test. In case of a none-normal distribution, the non-parametric method of Kruskal-Wallis one-way ANOVA was used. If there is a positive result, the intergroup comparisons are performed using the Mann-Whitney U-test. The chi²-test was performed where appropriate and feasible. - Indices:
- Maternal: Pre-implantation loss, post-implantation loss
Fetus: Sex distribution, fetal body weight external abnormalities/litter, visceral abnormalities/litter, skeletal abnormalities/litter - Historical control data:
- Historical control data was provided to allow comparison with current controls. Historical control data was taken from "Background pregnancy and fetal data from developmental toxicity studies in teh Hsd. Brl. Han: WIST Rat" from January 2014.
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Piloerection, reduced activity, paleness, vaginal bleeding, hypotonicity and coldness were noted for females in the 450 mg/kg bw/day dose group which was attributed to an effect of the test item. Salivation was recorded for dams in the 450 and in the 150 mg/kg bw/day group which was judged to be in association with the treatment however as non adverse. No clinical observations were noted for the dams in the 50 mg/kg bw/day dose group
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- One dam died before scheduled necropsy in the 450 mg/kg bw/day dose group which was considered to be due to an effect of the test item.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- A lower mean body weight and corrected body weight of the pregnant females as well as a weight loss and a moderately to markedly lower body weight gain and corrected body weight gain of the pregnant females was observed in the 150 and 450 mg/kg bw/day groups which was attributed to the treatment, however these changes were judged not to reach an adverse degree in case of the animals in the 150 mg/kg bw/day dose group considering the reversibility of the body weight gain reduction and the slight degree of the body weight and corrected body weight A reduced body weight gain of the females was calculated in the
50 mg/kg bw/day dose group just for the first three days of the treatment. This was judged to be likely incidental concerning the small difference and that thereafter the body weight development of the females was at the control level and there was no difference relative to the control in the body weight and corrected body weight of the females during the whole in-life phase. - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- There was a moderate to marked dose related decrease in the food consumption of pregnant females to see in the 150 and 450 mg/kg bw/day groups respectively in the whole treatment period which was ascribed to the treatment. The food consumption reduction in the 150 mg/kg bw/day dose group was judged to be below an adverse level and biologically non relevant.
A slight reduction in the food consumption was indicated in the 50 mg/kg bw/day dose group during the treatment period, however this statistically significant but toxicologically irrelevant change was considered to be within the biological variation and not proven to be due to the test item. - Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Endocrine findings:
- not examined
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Macroscopic findings at necropsy such as enlarged spleen and adrenals as well as bloody orifice and bloody uterine content in the 450 mg/kg bw/day dose group were found to be a result of the treatment with Dicumyl Peroxide. There were no macroscopic findings observed in the dams in the 50 and 150 mg/kg bw/day dose groups.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
Maternal developmental toxicity
- Number of abortions:
- not specified
- Pre- and post-implantation loss:
- effects observed, treatment-related
- Description (incidence and severity):
- Postimplantation loss (due to late embryonic and fetal death) increased, the number of viable fetuses decreased significantly in the 450 mg/kg bw/day group which was considered to be an adverse effect due to the treatment with the test item.
Preimplantation loss was statistically significantly higher in the 450 mg/kg bw/day group than in the control, however without a clear dose response. - Total litter losses by resorption:
- not specified
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- effects observed, treatment-related
- Description (incidence and severity):
- The number of viable fetuses decreased significantly in the 450 mg/kg bw/day group which was attributed to an effect of the test item.
- Changes in pregnancy duration:
- not specified
- Changes in number of pregnant:
- no effects observed
- Other effects:
- not specified
- Details on maternal toxic effects:
- Maternal toxic effects:yes
Details on maternal toxic effects:
450 mg/kg bw/day caused death, piloerection, reduced activity, coldness, paleness, vaginal bleeding and hypotonicity, enlarged adrenals and spleen and blood in the uterus, markedly reduced food consumption, lower body weight, markedly reduced body weight gain and weight loss as well as markedly reduced corrected body weight and body weight gain in the maternal animals.
Effect levels (maternal animals)
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 150 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
- Key result
- Dose descriptor:
- LOAEL
- Effect level:
- 450 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
- Dose descriptor:
- NOEL
- Effect level:
- 50 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
Results (fetuses)
- Fetal body weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- The body weight of the male and female fetuses was statistically significantly lower in the 450 mg/kg bw/day dose group if compared to the control and this was attributed to an effect to the test item. The mean weight of the fetuses in the control, 50 and 150 mg/kg bw/day groups was identical.
- Reduction in number of live offspring:
- effects observed, treatment-related
- Description (incidence and severity):
- Postimplantation loss (due to late embryonic and fetal death) increased, the number of viable fetuses decreased significantly in the 450 mg/kg bw/day group which was attributed to an effect of the test item
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- not specified
- Anogenital distance of all rodent fetuses:
- not specified
- Changes in postnatal survival:
- not examined
- External malformations:
- effects observed, treatment-related
- Description (incidence and severity):
- Body weight retardation (below 2.84 g for males and 2.54 g for females) was categorized as an external variation. The incidence of body weight retarded fetuses increased markedly in the 450 mg/kg bw/day dose group which was attributed to an effect due to the treatment of the dams. There were no significant differences in the incidence of body weight retardation of fetuses in the 50 and 150 mg/kg dose group.
External malformations malrotated fore and/or hindlimbs in 6 fetuses (mainly associated with skeletal findings) were found in the 450 mg/kg bw/day group which was judged to be in association with the treatment of the dams with the test item.
No fetal malformations found at external examination in the control, 50 and 150 mg/kg bw/day dose groups.
Placental findings as dark brownish discoloration of the margin of the placentas were found in 44 and fibrinoid degeneration was recorded in 11 cases in the 450 mg/kg bw/day group which was attributed to an effect of the test item. There were no placental findings observed in the control, 50 and 150 mg/kg bw/day dose group. - Skeletal malformations:
- effects observed, treatment-related
- Description (incidence and severity):
- There was a significant increase in the incidence of fetuses with skeletal malformations and variations in the 450 mg/kg bw/day group.
Malformations:
Malformations such as short and/or bent scapula, clavicula, humerus, radius, ulna, femur, tibia and fibula occurred only in the 450 mg/kg bw/day group.
Short and/or bent scapula, humerus and radius occurred with a higher incidence than recorded in the historical control database. The incidence of short and/or bent femur, tibia and fibula was within the historical control range. Malformations of the pectoral girdle and extremities in the 450 mg/kg bw/day dose groups were considered to be in association with the treatment of the dams with the test item.
Variations:
Significanty increased the occurrence of incomplete ossification of skull bones (markedly incomplete ossification of one or more bone), the incompletely ossified sternum, metacarpal/metatarsal and wavy and markedly wavy ribs in the 450 mg/kg bw/day dose group which was considered to be in association with the treatment, possibly due to maternal toxicity.
In a re-evaluation of the findings, it was suggested that these findings might not only be reversible but also of short duration and not harmful to the animal in the longer term. With this in mind, it can be argued that the critical girdle and limb findings in this study could all be classified as variations and, in the absence of other major foetal abnormalities at this dose level, it could be suggested that the NOAEL for developmental toxicity could be raised to 450 mg/kg. - Visceral malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The visceral variation hydroureter (bilateral) was found in the 50 and mg/kg bw/day and 450 mg/kg bw/day groups with a low incidence (2 in both groups) without a dose response.
This variation was considered to be without a relationship to the treatment. - Other effects:
- not specified
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:yes
Details on embryotoxic / teratogenic effects:
450 mg/kg bw/day resulted in increased postimplantation loss (and lower number of viable fetuses), a decreased foetal weight, an increased percentage of foetuses with body weight retardation, malrotated fore-and hindlimbs as well as skeletal malformations of the pectoral girdle and extremities, increase of skeletal variations and placentas with dark brownish discoloration or fibrinoid degeneration possibly due to the marked maternal toxicity.
Effect levels (fetuses)
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 150 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: developmental toxicity
- Key result
- Dose descriptor:
- LOAEL
- Effect level:
- 450 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- reduction in number of live offspring
- fetal/pup body weight changes
- external malformations
- skeletal malformations
- other: placentas with dark brownish discoloration or fibrinoid degeneration possibly due to the marked maternal toxicity
Fetal abnormalities
- Key result
- Abnormalities:
- effects observed, treatment-related
- Localisation:
- skeletal: clavicle
- skeletal: scapule
- other: humerus, radius and ulna
- Description (incidence and severity):
- Skeletal malformations such as short and/or bent scapula, clavicula, humerus, radius and ulna occurred in the 450 mg/kg bw/day group with a higher incidence than recorded in the historical control database. This change was considered to be due to an effect of the test item.
Overall developmental toxicity
- Key result
- Developmental effects observed:
- yes
- Lowest effective dose / conc.:
- 450 mg/kg bw/day (nominal)
- Treatment related:
- yes
- Relation to maternal toxicity:
- developmental effects as a secondary non-specific consequence of maternal toxicity effects
- Relevant for humans:
- not specified
Any other information on results incl. tables
Pregnancy data of females, mortality
Dose groups | Control | 50 mg/kg bw/day | 150 mg/kg bw/day | 450 mg/kg bw/day |
Number of sperm positive females | 24 | 24 | 24 | 24 |
Number of females with no implantation but corpora lutea | 0 | 0 | 0 | 0 |
Number of females with no implantation and no corpora lutea | 1 | 4 | 3 | 6 |
Number and percent of pregnant females (females with implantation) | 23 | 20 | 21 | 18 |
Number of evaluated dams | 23 | 20 | 21 | 18 |
Number of pregnant females died (due to toxicity) | 0 | 0 | 0 | 1 |
Number of dams with total intrauterine death | 0 | 0 | 0 | 0 |
Number of evaluated litters | 23 | 20 | 21 | 17 |
Number and percent of evaluated litters with malformed fetuses | 4 | 0 | 3 | 10 |
SUMMARY OF CLINICAL SIGNS AND NECROPSY FINDINGS OF DAMS (sum, %) | |||||||||||||||||||
DESCRIPTIONDOSES: No. of animals: |
control 23 |
50 mg/kg bw/day 20 |
150 mg/kg bw/day 21 |
450 mg/kg bw/day 18 |
|||||||||||||||
MORTALITY | |||||||||||||||||||
- died due to an unclear reason | N | 0 | 0 | 0 | 1 | ||||||||||||||
% | 0 | 0 | 0 | 6 | |||||||||||||||
CLINICAL SYMPTOMS | |||||||||||||||||||
- none | N | 22 | 20 | 17 | 7 | ||||||||||||||
% | 96 | 100 | 81 | 39 | |||||||||||||||
- alopecia | N | 1 | 0 | 0 | 3 | ||||||||||||||
% | 4 | 0 | 0 | 17 | |||||||||||||||
- salivation | N | 0 | 0 | 4 | 8 | ||||||||||||||
% | 0 | 0 | 19 | 44 | |||||||||||||||
- piloerection | N | 0 | 0 | 0 | 4 | ||||||||||||||
% | 0 | 0 | 0 | 22 | |||||||||||||||
- reduced activity | N | 0 | 0 | 0 | 2 | ||||||||||||||
% | 0 | 0 | 0 | 11 | |||||||||||||||
- red coloration around red eye | N | 0 | 0 | 0 | 1 | ||||||||||||||
% | 0 | 0 | 0 | 6 | |||||||||||||||
- pale | N | 0 | 0 | 0 | 2 | ||||||||||||||
% | 0 | 0 | 0 | 11 | |||||||||||||||
- vaginal bleeding | N | 0 | 0 | 0 | 2 | ||||||||||||||
% | 0 | 0 | 0 | 11 | |||||||||||||||
- hypotonicity | N | 0 | 0 | 0 | 2 | ||||||||||||||
% | 0 | 0 | 0 | 11 | |||||||||||||||
- cold | N | 0 | 0 | 0 | 2 | ||||||||||||||
% | 0 | 0 | 0 | 11 | |||||||||||||||
NECROPSY FINDINGS | |||||||||||||||||||
- no macroscopic alterations | N | 23 | 20 | 21 | 11 | ||||||||||||||
% | 100 | 100 | 100 | 61 | |||||||||||||||
- enlarged adrenals | N | 0 | 0 | 0 | 5 | ||||||||||||||
% | 0 | 0 | 0 | 28 | |||||||||||||||
- enlarged spleen | N | 0 | 0 | 0 | 2 | ||||||||||||||
% | 0 | 0 | 0 | 11 | |||||||||||||||
- uterus filled up with blood | N | 0 | 0 | 0 | 1 | ||||||||||||||
% | 0 | 0 | 0 | 6 | |||||||||||||||
- bloody vaginal orifice | N | 0 | 0 | 0 | 1 | ||||||||||||||
% | 0 | 0 | 0 | 6 | |||||||||||||||
- blood in uterus | N | 0 | 0 | 0 | 3 | ||||||||||||||
% | 0 | 0 | 0 | 17 | |||||||||||||||
- pale liver | N | 0 | 0 | 0 | 1 | ||||||||||||||
% | 0 | 0 | 0 | 6 | |||||||||||||||
- pale kidneys | N | 0 | 0 | 0 | 1 | ||||||||||||||
% | 0 | 0 | 0 | 6 | |||||||||||||||
- stomach distended, | N | 0 | 0 | 0 | 1 | ||||||||||||||
filled up with darker content | % | 0 | 0 | 0 | 6 |
Body weight (g) of Dams (mean, SD) | |||||
TIME Gestational days | DOSE GROUPS (mg/kg bw/day) | ||||
Control | 50 | 150 | 450 | ||
0 | |||||
MEAN | 236 | 236.8 | 233.1 | 234.9 | |
SD | 20.67 | 14.86 | 10.65 | 10.96 | |
N | 23 | 20 | 21 | 18 | NS |
5 | |||||
MEAN | 248.6 | 251 | 248.9 | 251.2 | |
SD | 20.56 | 15.05 | 12.48 | 13.86 | |
N | 23 | 20 | 21 | 18 | NS |
8 | |||||
MEAN | 254.4 | 253.9 | 246.7 | 245.2 | |
SD | 21.21 | 15.2 | 12.65 | 14.98 | |
N | 23 | 20 | 21 | 18 | |
11 | |||||
MEAN | 267.3 | 265.3 | 254.8 | 246.3 | |
SD | 21.51 | 16.3 | 13.08 | 15.2 | |
N | 23 | 20 | 21 * | 18 ** | DN |
14 | |||||
MEAN | 278.8 | 275.8 | 265.5 | 255.5 | |
SD | 21.89 | 15.53 | 11.47 | 17.66 | |
N | 23 | 20 | 21 * | 18 ** | U |
17 | |||||
MEAN | 301.1 | 297.8 | 286.4 | 274.2 | |
SD | 22.36 | 16.74 | 12.06 | 18.76 | |
N | 23 | 20 | 21 * | 18 ** | DN |
20 | |||||
MEAN | 338.7 | 335.8 | 321.2 | 283.6 | |
SD | 27.59 | 20.72 | 14.54 | 24.5 | |
N | 23 | 20 | 21 ** | 17 ** | U |
SUMMARY OF BODY WEIGHT GAIN OF DAMS | |||||
Body weight gain (g) (mean, SD) | |||||
TIME Gestational days | DOSE GROUPS (mg/kg bw/day) | ||||
Control | 50 | 150 | 450 | ||
0-5 | MEAN | 12.6 | 14.2 | 15.8 | 16.2 |
SD | 3.95 | 4.46 | 4.43 | 5.24 | |
n | 23 | 20 | 21 * | 18 * DN | |
5-8 | MEAN | 5.8 | 2.9 | -2.2 | -5.9 |
SD | 3.42 | 3.48 | 3.80 | 5.61 | |
n | 23 | O * | 21 ** | 18 ** DN | |
8-11 | MEAN | 12.8 | 11.5 | 8.1 | 1.1 |
SD | 3.60 | 3.61 | 5.32 | 7.77 | |
n | 23 | 20 | 21 ** | 18 ** U | |
11-14 | MEAN | 11.6 | 10.5 | 10.7 | 9.2 |
SD | 4.02 | 3.69 | 4.30 | 8.51 | |
n | 23 | 20 | 21 | 18 NS | |
14-17 | MEAN | 22.3 | 22.1 | 20.9 | 18.7 |
SD | 3.99 | 3.93 | 3.79 | 7.75 | |
n | 23 | 20 | 21 | 18 NS | |
17-20 | MEAN | 37.7 | 38.0 | 34.8 | 11.5 |
SD | 8.40 | 7.59 | 6.86 | 16.49 | |
n | 23 | 20 | 21 | 17 ** U | |
0-20 | MEAN | 102.7 | 99.0 | 88.0 | 49.5 |
SD | 14.70 | 13.11 | 12.77 | 19.96 | |
n | 23 | 20 | 21 ** | 17 ** DN |
SUMMARY OF FOOD CONSUMPTION DATA OF DAMS | ||||||
(mean, SD) | ||||||
TIME Gestational days | DOSE GROUPS (mg/kg bw/day) | |||||
Control | 50 | 150 | 450 | |||
0-3 | MEAN | 17.2 | 17.3 | 17.7 | 18.1 | |
SD | 1.84 | 2.18 | 1.41 | 1.56 | ||
n | 23 | 20 | 21 | 18 | NS | |
3-5 | MEAN | 19.8 | 20.5 | 20.7 | 21.5 | |
SD | 1.19 | 2.27 | 1.15 | 2.33 | ||
n | 23 | 20 | 21 ** | 18 ** | U | |
5-8 | MEAN | 19.4 | 17.2 | 14.0 | 10.9 | |
SD | 1.37 | 2.16 | 1.53 | 1.43 | ||
n | 23 | 20 ** | 21 ** | 18 ** | DN | |
8-11 | MEAN | 19.4 | 17.7 | 14.5 | 11.5 | |
SD | 1.11 | 2.49 | 2.47 | 2.24 | ||
n | 23 | 20 ** | 21 ** | 18 ** | U | |
11-14 | MEAN | 20.5 | 19.1 | 16.6 | 13.9 | |
SD | 1.41 | 1.52 | 1.37 | 2.38 | ||
n | 23 | 20 ** | 21 ** | 18 ** | U | |
14-17 | MEAN | 20.9 | 19.7 | 17.6 | 16.7 | |
SD | 1.29 | 2.57 | 1.58 | 2.08 | ||
n | 23 | O * | 21 ** | 18 ** | U | |
17-20 | MEAN | 22.0 | 21.8 | 18.9 | 13.9 | |
SD | 1.77 | 2.33 | 1.58 | 2.67 | ||
n | 23 | 20 | 21 ** | 18 ** | DN |
INTRAUTERINE MORTALITY, VIABLE FETUSES, SEX DISTRIBUTION (mean, SD) | ||||||
GROUPS (mg/kg bw/day): | Control | 50 | 150 | 450 | ||
NUMBER OF DAMS: | 23 | 20 | 21 | 18 | ||
Corpora Lutea | Mean: | 13.5 | 12.9 | 12.4 | 12.8 | |
SD: | 1.75 | 1.37 | 1.77 | 1.38 | NS | |
Preimplantation Loss % | Mean: | 7.4 | 11.7 | 8.4 | 13.7 | |
SD: | 11.97 | 15.45 | 10.20 | 13.58 | NS | |
Implantation | Mean: | 12.5 | 11.4 | 11.3 | 11.0 | |
SD: | 2.23 | 2.35 | 1.79 | 1.71 | NS | |
Early Embryonic Death % | Mean: | 5.9 | 3.3 | 4.2 | 1.7 | |
SD: | 6.85 | 4.95 | 6.19 | 3.98 | NS | |
Late Embryonic Death % | Mean: | 1.3 | 1.0 | 0.8 | 11.8 | |
SD: | 4.58 | 3.13 | 2.40 | 14.00 ** | U | |
Dead Fetuses % | Mean: | 0.0 | 0.0 | 0.0 | 3.2 | |
SD: | 0.00 | 0.00 | 0.00 | 7.27 ** | DN | |
Postimplantation Loss % | Mean: | 7.2 | 4.4 | 5.0 | 16.8 | |
SD: | 8.71 | 5.99 | 6.47 | 17.44 ** | U | |
Total Intrauterine Mortality % | Mean: | 14.2 | 15.6 | 12.9 | 28.1 | |
SD: | 13.37 | 15.68 | 11.88 | 19 77 ** | DN | |
Viable fetuses | Mean: | 11.6 | 10.9 | 10.7 | 9.0 | |
SD: | 2.35 | 2.38 | 1.79 | 2.57 ** | DN | |
Male fetuses % | Mean: | 43.9 | 51.7 | 48.2 | 50.4 | |
SD: | 17.01 | 14.66 | 14.49 | 14.06 | NS | |
Female fetuses % | Mean: | 56.1 | 48.3 | 51.8 | 49.6 | |
SD: | 17.01 | 14.66 | 14.49 | 14.06 | NS |
RESULTS OF EXTERNAL, VISCERAL AND SKELETAL EXAMINATIONS (percentile litter means and SD) | ||||||
DOSE GROUPS (mg/kg bw/day) | ||||||
Control | 50 | 150 | 450 | |||
EXTERNAL EXAMINATION | ||||||
Litters examined | N | 23 | 20 | 21 | 17 | |
Fetuses examined | N | 266 | 218 | 225 | 153 | |
Fetuses | Mean | 2.5 | 2.3 | 3.5 | 26.2 ** | U |
with abnormalities | SD | 5.46 | 4.12 | 5.59 | 24.34 | |
Variation | Mean | 2.5 | 2.3 | 3.5 | 21.5 ** | U |
SD | 5.46 | 4.12 | 5.59 | 24.62 | ||
Malformation | Mean | 0.0 | 0.0 | 0.0 | 4.7 ** | DN |
SD | 0.00 | 0.00 | 0.00 | 9.03 | ||
Retarded in body weight | Mean | 2.5 | 2.3 | 3.5 | 22.2 ** | U |
SD | 5.46 | 4.12 | 5.59 | 23.72 | ||
VISCERAL EXAMINATION | ||||||
Litters examined | N | 23 | 20 | 21 | 17 | |
Fetuses examined | N | 133 | 109 | 111 | 77 | |
Fetuses | Mean | 1.3 | 2.0 | 1.0 | 2.0 | NS |
with abnormalities | SD | 4.47 | 8.94 | 4.36 | 5.78 | |
Variation | Mean | 0.0 | 2.0 | 0.0 | 2.0 | NS |
SD | 0.00 | 8.94 | 0.00 | 5.78 | ||
Malformation | Mean | 1.3 | 0.0 | 1.0 | 0.0 | NS |
SD | 4.47 | 0.00 | 4.36 | 0.00 | ||
SKELETAL EXAMINATION | ||||||
Litters examined | N | 23 | 20 | 21 | 17 | |
Fetuses examined | N | 133 | 109 | 114 | 76 | |
Fetuses | Mean | 19.4 | 15.0 | 22.7 | 61.4 ** | DN |
with abnormalities | SD | 21.32 | 24.29 | 31.81 | 30.69 | |
Variation | Mean | 17.8 | 15.0 | 19.9 | 39.8 ** | DN |
SD | 19.61 | 24.29 | 27.56 | 23.91 | ||
Malformation | Mean | 1.6 | 0.0 | 2.9 | 21.6 ** | U |
SD | 5.31 | 0.00 | 9.56 | 28.75 |
LITTER MEANS OF FETAL AND PLACENTAL WEIGHT | |||||||||||||
DOSE GROUPS (mg/kg bw/day) | |||||||||||||
Control | 50 | 150 | 450 | ||||||||||
M+F | M | F | M+F | M | F | M+F | M | F | M+F | M | F | ||
Fetal weight | MEAN | 3.3 | 3.4 | 3.2 | 3.3 | 3.3 | 3.2 | 3.3 | 3.4 | 3.2 | 2.9 | 3.0 | 2.9 |
(g) | SD | 0.18 | 0.16 | 0.20 | 0.19 | 0.24 | 0.19 | 0.19 | 0.18 | 0.23 | 0.29 | 0.29 | 0.32 |
n | 23 | 23 | 23 | 20 | 20 | 20 | 21 | 21 | 21 | Y]** | 17 ** | 17 ** | |
DN | U | DN | |||||||||||
Placental weight | MEAN | 717.0 | 721.7 | 713.3 | 699.9 | 699.0 | 698.7 | 690.1 | 695.3 | 681.8 | 690.6 | 693.6 | 686.1 |
(g) | SD | 48.84 | 64.10 | 51.88 | 56.31 | 59.40 | 68.85 | 45.72 | 55.68 | 43.55 | 90.37 | 120.89 | 90.17 |
n | 23 | 23 | 23 | 20 | 20 | 20 | 21 | 21 | 21 | 17 | 17 | 17 | |
Relative placental weight | MEAN | 219.7 | 213.1 | 224.5 | 214.4 | 211.2 | 218.0 | 212.3 | 206.5 | 217.4 | 236.5 | 233.7 | 238.6 |
(mg/g) | SD | 16.3 | 17.06 | 23.25 | 16.41 | 20.00 | 20.00 | 17.11 | 17.43 | 18.67 | 32.19 | 40.73 | 34.39 |
n | 23 | 23 | 23 | 20 | 20 | 20 | 21 | 21 | 21 | 17 | 17.0 | 17.0 |
Applicant's summary and conclusion
- Conclusions:
- Treatment with dicumyl peroxide resulted in maternal and developmental toxicity at a dose of 450 mg/kg bw/day when administered during days 5-19 of gestation to rats. The developmental effects are possibly secondary to maternal toxicity. This conclusion has been supported by an independent re-evaluation conducted by an external pathologist.
- Executive summary:
In a developmental toxicity study according to OECD 414, dicumyl peroxide was administered to 24 pregnant female Hsd. Brl. Han: WISTAR rats per dose by oral gavage at dose levels of 0, 50, 150 and 450 mg/kg bw/day from day 5 through 19 of gestation. The highest administered dose elicited pronounced maternal toxicity, including death, piloerection, reduced activity, coldness, paleness, vaginal bleeding and hypotonicity, enlarged adrenals and spleen and blood in the uterus, markedly reduced food consumption, lower body weight, markedly reduced body weight gain and weight loss as well as markedly reduced corrected body weight and body weight gain.
Effects of the highest dose on embryos included increased post implantation loss (and lower number of viable foetuses), a decreased foetal weight, an increased percentage of foetuses with body weight retardation, malrotated fore- and hindlimbs as well as skeletal malformations of the pectoral girdle and extremities, increase of skeletal variations and placentas with dark brownish discoloration or fibrinoid degeneration possibly due to the marked maternal toxicity.
The maternal LOAEL is 450 mg/kg bw/day. The maternal NOAEL is 150 mg/kg bw/day.
The developmental LOAEL is 450 mg/kg bw/day. The developmental NOAEL is 150 mg/kg bw/day.
The developmental toxicity study in the rat is classified as acceptable and satisfies the guideline requirement for a developmental toxicity study (OECD 414) in rats. Considering the high incidence of skeletal malformation in the high dose group and some ambiguous effects in the mid-dose group, the study results have been re-evaluated by an external pathologist. The result of the re-examination confirmed that the skeletal findings critical to the result of this study were essentially reliable. Thus, the previously set NOAEL for developmental toxicity at a dose of 150 mg/kg bw/day in the original report can be considered acceptable.
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