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EC number: 213-147-2 | CAS number: 927-07-1
- 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:
- 2015-03-20 to 2015-07-29
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 015
- Report date:
- 2015
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- 2001
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- 1998
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: OECD Guidance No. 43 on Mammalian Reproductive Toxicity Testing and Assessment (2008)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- tert-butyl peroxypivalate
- EC Number:
- 213-147-2
- EC Name:
- tert-butyl peroxypivalate
- Cas Number:
- 927-07-1
- Molecular formula:
- C9H18O3
- IUPAC Name:
- tert-butyl 2,2-dimethylpropaneperoxoate
- Reference substance name:
- 2,2,4,6,6-pentamethylheptane
- EC Number:
- 236-757-0
- EC Name:
- 2,2,4,6,6-pentamethylheptane
- Cas Number:
- 13475-82-6
- Molecular formula:
- C12H26
- IUPAC Name:
- isododecane
- Test material form:
- liquid
Constituent 1
additive 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Toxi-Coop Zrt. 1103 Budapest, Cserkesz u. 90, Hungary
- Age at study initiation: Young adult and nulliparous females, 12- 13 weeks; males: 18-21 weeks
-Body weight at study initiation: mean ca. 200 g
- Housing: Before mating: 1-3 females per cage, 1-2 males per cage; during mating: 1 male and 1-3 females / cage; during gestation: 2 sperm positive females per cage, if not possible 1 sperm positive female per cage; Type II polypropylene/polycarbonate
- Diet: ssniff® SM R/M-Z+H "Autoclavable complete feed for rats and mice – breeding and maintenance" produced by ssniff Spezialdiäten GmbH, D-59494 Soest, Germany, ad libitum
- Water: tap water ad libitum
- Acclimation period: 14 days females, 7 days males
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-22
- Humidity (%): 30 - 36
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12 / 12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: sunflower oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
Formulations were prepared in the formulation laboratory of the Test Facility not longer than for 3 days before the administration.
Analytical control of dosing solutions (control of concentration) was performed in the Analytical Laboratory of the Test Facility twice during the study. Concentrations of the test item in the dosing formulations varied in the acceptable range between 98 and 109 % of nominal concentrations at both analytical occasions confirming proper dosing. A sufficient stability and homogeneity in the chosen vehicle were verified over the range of relevant concentrations at the appropriate frequency of preparation.
VEHICLE
- Justification for use and choice of vehicle: The test item is not soluble in water therefore sunflower oil was used for preparing formulations appropriate for oral administration. Sunflower oil was a suitable vehicle to facilitate formulation analysis for the test item.
- Concentration in vehicle: 0, 25, 75, 225 mg/mL
- Amount of vehicle: treatment volume: 2 mL - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analytical control of dosing solutions (control of concentration) was performed in the Analytical Laboratory of Test Facility twice during the study. Concentrations of the test item in the dosing formulations varied in the acceptable range between 98 and 109 % of nominal concentrations at both analytical occasions confirming proper dosing. A sufficient stability and homogeneity in the chosen vehicle were verified over the range of relevant concentrations at the appropriate frequency of preparation.
The test item was analyzed using reverse phase HPLC method with UV detection. Five samples were taken from different places of each test concentration and from the vehicle. The samples were stored at 5 ± 3 °C until the analysis.
HPLC system: Hitachi LaChrom Elite,
L-2000 Organizer, No.: 18E32-083
L-2130 HPLC pump, No.: 18E17-015
L-2200 Autosampler, No.: 19E40-005
L-2400 UV Detector, No.: 18E33-030
L-2350 Column Oven, No.: 1831-023
HPLC Conditions:
Detector: 210 nm
Column: HyperPrep HS C18, 250 x 4.6 mm, 8 μm, No.: 10190790
Mobil Phase: Acetonitrile : water = 70 : 30 (v/v)
Flow Rate: 1 mL/min
Injection volume: 50 μL
Temperature: 25 °C
Retention time: 7 min ± 5 %
Run time: 10 minutes - Details on mating procedure:
- - Impregnation procedure: cohoused
- M/F ratio per cage: 1 male and 1-3 females / cage
- Length of cohabitation: The females were paired to males in the mornings for two to four hours (one male: one to three females) until the number of sperm positive females per group achieves at least twenty four.
- Proof of pregnancy: vaginal plug and/or sperm in vaginal smear referred to as day 0 of pregnancy - Duration of treatment / exposure:
- The sperm positive females were treated from gestational day 5 to 19.
- Frequency of treatment:
- daily, 7 days/week
- Duration of test:
- gestational day 5 to 19
Doses / concentrationsopen allclose all
- Dose / conc.:
- 50 mg/kg bw/day (nominal)
- Dose / conc.:
- 150 mg/kg bw/day (nominal)
- Dose / conc.:
- 450 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 24 females per dose
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The dose setting based on findings obtained in a Non GLP 14-Day Oral Gavage Dose Range Finding Study with TBPPI in the Rat.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily
BODY WEIGHT: Yes
- Time schedule for examinations: days 0-3, 3-5, 5-8, 8-11, 11-14, 14-17, 17-20, 0-20 of gestation
FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: uterus with cervix, ovaries - 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: Yes
- Number of late resorptions: Yes - Fetal examinations:
- - External examinations: Yes: all live fetuses per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: half per litter - Statistics:
- The homogeneity of variance between groups was checked by Bartlett’s homogeneity of variance test.
Where no significant heterogeneity is detected a one-way analysis of variance (ANOVA) is carried out. If the obtained result is significant Duncan’s Multiple Range test was used to access the significance of inter-group differences. If significance is the result of the Bartlett’s test, the Kruskal-Wallis analysis of variance was used and the inter-group comparisons were performed using Mann-Whitney U-test. - Historical control data:
- The results were compared to the laboratory's historical control data.
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Reduced activity, piloerection, hypotonicity and hyperventilation in the 450 mg/kg bw/day group
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- weight loss and lower body weight in the 450 mg/kg bw/day group
reduced body weight- and corrected body weight gain in the 150 mg/kg bw/day dose group - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- reduced food consumption in the 450 mg/kg bw/day group
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- no effects observed
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- maternal
- Effect level:
- 50 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- lower mean body weight in the 450 mg/kg bw/day group
- Reduction in number of live offspring:
- effects observed, treatment-related
- Description (incidence and severity):
- The increased late embryonic death in the 450 mg/kg bw/day group
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- effects observed, treatment-related
- Changes in postnatal survival:
- no effects observed
- External malformations:
- no effects observed
- Skeletal malformations:
- no effects observed
- Description (incidence and severity):
- No malformations but abnormalities: increased incidence of fetuses with delayed ossification of skeletons or bipartite ossification of sternebra in the 450 mg/kg bw/day group. Moderately increased incidence of split sternum (7 of 108 fetuses) in the 450 mg/kg bw/day dose group. Split sternum occurs however with low incidence also in control fetuses according to the Summary of Laboratory’s historical control data.
- Visceral malformations:
- no effects observed
- Description (incidence and severity):
- No malformations but abnormalities:
- Other effects:
- no effects observed
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:yes
Details on embryotoxic / teratogenic effects:
Moderately increased incidence of split sternum (7 of 108 fetuses) in the 450 mg/kg bw/day dose group might be a consequence of the treatment. Split sternum occurs however with low incidence also in control fetuses according to the Summary of Laboratory’s historical control data. The increased late embryonic death, lower mean body weight and the increased incidence of fetuses with delayed ossification of skeletons or bipartite ossification of sternebra in the 450 mg/kg bw/day group might be attributed to the clinical signs, the statistically significant reduced body weight from gestation day 11 up to the end of in-life phase, the weight loss on the first three days of treatment and the reduced body weight gain between gestation days 8 and 11 and 17 to 20 as well as the affected food intake in the entire treatment period at this dose level. The delayed ossification of the skull bones of the fetuses in the 150 mg/kg bw/day group might be attributed to the statistically significant reduced body weight gain between gestational day 5 and 8 and a lower corrected body weight gain of the dams at this dose level. Based on the maternal toxicity observed, and the assumptions in the international literature that retarded skull bone ossification is a relatively common observation and may not be a reliable indicator for developmental toxicity (Mylchreest, E., Munley, S.M., and Kennedy Jr., G.L. (2005) Evaluation of the Developmental Toxicity of 8-2 Telomer B Alcohol. Drug and Chemical Toxicology, 28:315-328.), the delay in ossification is considered to be non-adverse.
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- developmental
- Effect level:
- 150 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: soft tissue and skeletal abnormalities
Fetal abnormalities
- Key result
- Abnormalities:
- effects observed, non-treatment-related
Overall developmental toxicity
- Key result
- Developmental effects observed:
- yes
- Lowest effective dose / conc.:
- 150 mg/kg bw/day (actual dose received)
- Treatment related:
- yes
- Relation to maternal toxicity:
- developmental effects as a secondary non-specific consequence of maternal toxicity effects
- Dose response relationship:
- yes
- Relevant for humans:
- not specified
Applicant's summary and conclusion
- Conclusions:
- Based on the observations the No Observed Adverse Effect Level (NOAEL) was determined as follows:
NOAEL (maternal toxicity): 50 mg/kg bw/day
NOAEL (developmental toxicity): 150 mg/kg bw/day - Executive summary:
TBPPI was examined for its possible prenatal developmental toxicity. Groups of 24 sperm-positive female Hsd. Brl. Han: Wistar rats were treated with TBPPI by oral administration daily at three dose levels of 50, 150 and 450 mg/kg bw/day from day 5 up to and including day 19 post coitum. A control group of 24 sperm positive females was included and the animals were given the vehicle sunflower oil. The treatment volume was 2 mL/kg bw.
During the study, mortality was checked and clinical observations were performed. Body weight and food consumption of the dams were also recorded. The day, when sperm was detected in the vaginal smear, was regarded as day 0 of gestation. Caesarean section and gross pathology were performed on gestational day 20. The number of implantations, early and late resorptions, live and dead fetuses in each uterine horn and the number of corpora lutea were recorded. Each fetus was weighed and examined for sex and gross external abnormalities. The placentas were weighed and examined externally. About half of each litter was preserved for visceral examination and the other half of the litters were preserved for skeletal evaluation. At visceral examination the bodies were micro dissected by means of a dissecting microscope. The heads were examined by Wilson's free-hand razor blade method. After cartilage-bone staining the skeletons were examined by means of a dissecting microscope. All abnormalities found during the fetal examinations were recorded.Reduced activity, piloerection, hypotonicity and hyperventilation of the animals as well as reduced food consumption, weight loss and lower body weight in the 450 mg/kg bw/day group as well as reduced body weight- and corrected body weight gain in the 150 mg/kg bw/day dose group was in association with the test item.
TBPPI did not reveal any adverse effect on the preimplantation loss, early embryonic- and fetal death, number of implantation and the sex distribution of the fetuses moreover did not decrease the number of viable fetuses significantly. There was a scattered occurrence of few brain malformations (dilated lateral ventricles, deficient or misshapen brain tissue and enlarged perimeningeal space) in three fetuses, each one fetus in one litter, in the 450 mg/kg bw/day group. However, a test item relationship can neither be concluded nor excluded with certainty as according to the experience with this species and to the international literature similar findings occur spontaneously with low incidence in the rat strain used. Therefore it is finally considered as more likely that these single brain alterations in isolated fetuses are not caused by the treatment with the test item but as incidental in nature.
Moderately increased incidence of split sternum (7 of 108 fetuses) in the 450 mg/kg bw/day dose group is considered to be a consequence of the treatment. Split sternum occurs, however, with low incidence also in control fetuses according to the historical control data.
The increased late embryonic death, lower mean body weight and the increased incidence of fetuses with delayed ossification of skeletons or bipartite ossification of sternebra in the 450 mg/kg bw/day group are considered to be attributed to maternal toxicity, which occurred in the form of clinical signs, statistically significant reduced body weight from gestation day 11 up to the end of in-life phase, weight loss on the first three days of treatment and reduced body weight gain between gestation days 8 and 11 and 17 to 20 as well as affected food intake in the entire treatment period at this dose level. The delayed ossification of the skull bones of the fetuses in the 150 mg/kg bw/day group might be attributed to the statistically significant reduced body weight gain between gestational day 5 and 8 and a lower corrected body weight gain of the dams at this dose level. Based on the maternal toxicity observed, and the hind in the peer reviewed international literature that retarded skull bone ossification is a relatively common observation and may not be a reliable indicator for developmental toxicity, the delay in ossification is finally considered to be non-adverse.
Based on these observations the No Observed Adverse Effect Level (NOAEL) was determined as follows:
NOAEL (maternal toxicity): 50 mg/kg bw/day
NOAEL (developmental toxicity):150 mg/kg bw/day
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