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EC number: 258-469-4 | CAS number: 53306-54-0
- 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
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 003
- Report date:
- 2003
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- Bis(2-propylheptyl) phthalate
- EC Number:
- 258-469-4
- EC Name:
- Bis(2-propylheptyl) phthalate
- Cas Number:
- 53306-54-0
- Molecular formula:
- C28H46O4
- IUPAC Name:
- 1,2-bis(2-propylheptyl) benzene-1,2-dicarboxylate
- Test material form:
- other: clear colourless liquid
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Germany
- Strain: Wistar (CrIGIxBrlHan:WI)
- Age at study initiation: 70 - 84 at delivery
- Weight at study initiation: 146.3 - 188.6 g
- Housing: single, DK III stainless steel wire mesh cages (Becker, Castrop-Rauxel, Germany)
- Diet (e.g. ad libitum): ground Kliba laboratory diet rat/mouse/hamster, Provimi Kliba SA, Kaiseraugts, Switzerland, ad libitum
- Water (e.g. ad libitum): drinking water; ad libitum
- Acclimation period: between the supply on day 0 and the first administration on gestational day 6
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24
- Humidity (%): 30 - 70
- Photoperiod (hrs dark / hrs light): 12 / 12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- olive oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
The test substance solutions in olive 011 Ph.Eur./DAB were prepared at the beginning of the administration period and thereafter at intervals, which took into account the analytical results of the stability verification. For the preparation of the solutions, an appropriate amount of the test substance was weighed in a graduated beakers (depending on the dose group), topped up with olive oil Ph.Eur./DAB and subsequently thoroughly mixed using a magnetic stirrer.
VEHICLE
- Concentration in vehicle: 0.8, 4, 20%
- Amount of vehicle (if gavage): 5 ml/kg bw - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analytical verifications of the stability of the test substance in olive oil for a period of at least 7 days at room temperature were carried out by HPLC or GC.
- Details on mating procedure:
- Mating procedure: the animals were mated by the breeder (time-mated) and supplied on day 0 post coitum
- Impregnation procedure: purchased timed pregnant
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy - Duration of treatment / exposure:
- day 6 through day 19 of gestation
- Frequency of treatment:
- daily
- Duration of test:
- 20 days
Doses / concentrationsopen allclose all
- Dose / conc.:
- 40 mg/kg bw/day (nominal)
- Dose / conc.:
- 200 mg/kg bw/day (nominal)
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 25
- Control animals:
- yes, concurrent vehicle
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: a check was made twice a day on working days or once a day (Saturday, Sunday or on public holidays) (days 0 - 20 p.c.).
- Cage side observations checked in table were included.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: the animals were examined for clinical symptoms at least once a day, or more often when clinical signs of toxicity were elicited (days 0 - 20 p.c.).
BODY WEIGHT: Yes
- Time schedule for examinations: all animais were weighed on days 0, 1, 3, 6, 8, 10, 13, 15, 17, 19 and 20 p.c.. The body weight change of the animals was caiculated from these results.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20 p.c.
- Organs examined: uterus, 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
- Other: dead fetuses - Fetal examinations:
- - External examinations: Yes:
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: half per litter - Statistics:
- Statistical analysis: Dunnett's test (food consumption, body weight, body weight change, corrected body weight gain, weight of uterus (before opening), weights of fetuses, placentae, corpora lutea, implantations, pre- and post implantation losses, resorptions and live fetuses). KRUSKAL-WALLIS-test (weights of liver, kidneys, spleen). Fisher's exact test (conception rate, mortality of the dams, number of litter with fetal findings). Wilcoxon test (proportion of fetuses with malformations, variations and/or unclassified observation in each litter).
- Indices:
- - The conception rate (in %) was calculated according to the following formula: number of pregnant animals/number of fertilized animals x 100
- The preimpIantation loss (in %) was calculated according to the following formula: (number of corpora lutea - number of implantations) / number of corpora lutea x 100
- The postimplantation loss (in %) was calculated from the following formula: (number of implantations - number of live fetuses) / number of implantations x 100
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- In total 5 high dose dams showed urine-smeared fur occasionally, predominantly on the last days of the treatment period (days 16 - 20 p.c.).
The clinical finding "urine smeared fur" is a sign of discomfort of the rats and is probably substance-induced. There were no abnormal clinical findings in the other dams of this study. - Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- 1000 mg/kg bw/d: The mean body weights of the high dose rats were statistically significantly below control values between days 19 - 20 p.c.. On day 20 p.c., the mean body weight of these rats was about 6% below the mean value of the concurrent control females. There was a statistically significant body weight less at 1,000 mg/kg bw/d at initiation of treatment (days 6 - 8 p.c.). This is in-line with the reductions in food intake of these dams during this study phase. Thereafter, weight gains of the high dose dams were generally slightly below corresponding control values without attaining statistical significance. If calculated for the entire treatment period (days 6 - 19 p.c.), however, weight gain of the high dose dams was statistically significantly impaired and about 24% below the respective contral value. A reduction of about 18% occurred at 1,000 mg/kg bw/d, if weight gain was calculated for the total study phase (day 0 - 20 p.c.).
The corrected body weight gain (terminal body weight on day 20 p.c. minus weight of the unopened uterus minus body weight on day 6 p.c.) was distinctly and statistically significantly lower at 1,000 mg/kg bw/d (about 30% below the concurrent control
value). - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- 1000 mg/kg bw/d: mean food consumption was statistically significantly reduced (up to about 32% below the concurrent control value) on treatment days 6 - 13 p.c.. On the following days of the treatment period, food consumption reached or even exceeded control values. If calculated for the entire treatment phase (days 6 - 19 p.c.), food uptake of the 1,000 mg/kg bw/d dams was still about 11 % below the comparable control value. The transient reductions in food consumption at 1,000 mg/kg bw/d were accompanied by corresponding impairments in body weight gain of these dams at initiation of dosing. Therefore, this finding is considered to be substance-induced.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- UTERUS WEIGHT
1000 mg/kg bw/d: the mean gravid uterus weight of the high dose females, was about 19% below the control value, but the difference did not attain statistical significance due to the high standard deviation. The 3 dams of this group which had no live fetuses at all, but only early resorptions had very low uterus weights, whereas the uterus weights of the other dams of this group remained unaffected. - Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- no effects observed
Maternal developmental toxicity
- Number of abortions:
- not specified
- Pre- and post-implantation loss:
- effects observed, treatment-related
- Description (incidence and severity):
- 1000 mg/kg bw/day: the postimplantation lass value in the top dose was statistically significantly increased (23.1%) and distinctly outside the historical control range (mean value: 6.6%; range: 3.7 - 11.3%). The increased embryo-/fetolethality at 1,000 mg/kg was not equally distributed throughout the dams of this dose group, but was primarily induced by 3 high dose dams which had no live fetuses at all, but only very early resorptions. Thus, the 3 affected dams were only pregnant by stain and had a postimplantation lass of 100% each, whereas the postimplantation loss values of the other 1,000 mg/kg dams were generally similar to control values.
- Total litter losses by resorption:
- not specified
- Early or late resorptions:
- effects observed, treatment-related
- Description (incidence and severity):
- 1000 mg/kg bw/d: a statistically significant increase in resorption rate (especially early ones).
- Dead fetuses:
- not specified
- Changes in pregnancy duration:
- not specified
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified - Changes in number of pregnant:
- not specified
- Other effects:
- no effects observed
Effect levels (maternal animals)
- Dose descriptor:
- NOAEL
- Effect level:
- 200 mg/kg bw/day
- Basis for effect level:
- other: maternal toxicity
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed - Reduction in number of live offspring:
- not specified
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- not specified
- Changes in postnatal survival:
- not specified
- External malformations:
- no effects observed
- Description (incidence and severity):
- No external malformations or variations were seen in any of the fetuses of test groups, except two unclassified variations which were regarded as isolated and considered to be spontaneous in nature.
- Skeletal malformations:
- no effects observed
- Description (incidence and severity):
- Malformations of the skeletons were observed at low incidences in fetuses of the test groups 40 and 1,000 mg/kg bw/d. In total, none out of 115 control fetuses (from 24 litters), 2 out of 105 low dose fetuses (1.9%) in 2 out of 23 litters (8.7%), none out of 114 mid dose fetuses (from 25 litters) and 2 out of 77 high dose fetuses (2.6%) in one of 17 litters (5.9%) showed skeletal malformations. The mean percentages of affected fetuses/litter with skeletal malformations amounted to 0.0, 1.6, 0.0, and 2.4%. The noted skeletal malformations appeared without a clear relation to dosing, without biologically relevant differences between the groups and/or can be found at a comparable frequency in the historical control data
In all groups, signs of skeletal variations with or without involvement of corresponding cartilaginous structures elicited. The mean percentages of affected fetuses/litter with skeletal variations amounted to 96.0, 95.0, 97.4, and 100% at 0; 40; 200 or 1,000 mg/kg bw/d.
However, two skeletal variations, occurred at statistically significantly rates in the high fetuses (1,000 mg/kg bw/d). The increased occurrence of unossified sternebra and supernumerary rib (without cartilage) were clearly above the upper historical-control values. However, the overall rate of skeletal variations at this dose level was not statistically significantly elevated above the concurrent control value (affected fetuses/litter: 96.0, 95.0, 97.4 and 100.0% in all groups).
Also, unclassified cartliage observations, occurred in all groups including the controls. The mean percentages of affected fetuses/litter with these findings amounted to 38.6, 34.6, 47.2, and 63.5%** at 0; 40; 200 or 1,000 mg/kg bw/d (** = p< 0.01). A toxicological relevance for these findings could be excluded. - Visceral malformations:
- no effects observed
- Description (incidence and severity):
- No soft tissue malformations were recorded in any of the fetuses of all groups.
However, soft tissue variations were detected in each group including the control. Uni- or bilateral dilations of the renal pelvis occasionally in association with uni- or bilaterally dilated ureter(s) were found in fetuses of all groups. The mean percentages of affected fetuses/litter with total soft tissue variations were within the historical control range (4.0 - 22.2%) in test groups (8.5% (control), 9.1% (40 mg/kg bw/d) and 14.8% (200 mg/kg bw/d)), but were above the upper historical control value at 1,000 mg/kg bw/d (26.7%; p< 0.05).
No so-called unclassified soft tissue observation (like blood inhibition of kidneys) was recorded in any of the fetuses. - Other effects:
- no effects observed
- Details on embryotoxic / teratogenic effects:
- Details on embryotoxic / teratogenic effects:
WEIGHT
The mean fetal body weights in test groups were not influenced by the test substance administration and were very similar to or even identical with concurrent control values.
SEX DISTRIBUTION
The sex distribution of the fetuses in the test groups 1 - 3 was comparable with that of the control fetuses. The differences observed in comparison to the control were without any biological relevance.
EXTERNAL EXAMINATION
No external malformations or variations were seen in any of the fetuses of test groups, except two unclassified variations which were regarded as isolated and considered to be spontaneous in nature.
SOFT TISSUE EXAMINATION
No soft tissue malformations were recorded in any of the fetuses of all groups.
However, soft tissue variations were detected in each group including the control. Uni- or bilateral dilations of the renal pelvis occasionally in association with uni- or bilaterally dilated ureter(s) were found in fetuses of all groups. The mean percentages of affected fetuses/litter with total soft tissue variations were within the historical control range (4.0 - 22.2%) in test groups (8.5% (control), 9.1% (40 mg/kg bw/d) and 14.8% (200 mg/kg bw/d)), but were above the upper historical control value at 1,000 mg/kg bw/d (26.7%; p< 0.05).
No so-called unclassified soft tissue observation (like blood inhibition of kidneys) was recorded in any of the fetuses.
SKELETAL EXAMINATION
Malformations of the skeletons were observed at low incidences in fetuses of the test groups 40 and 1,000 mg/kg bw/d. In total, none out of 115 control fetuses (from 24 litters), 2 out of 105 low dose fetuses (1.9%) in 2 out of 23 litters (8.7%), none out of 114 mid dose fetuses (from 25 litters) and 2 out of 77 high dose fetuses (2.6%) in one of 17 litters (5.9%) showed skeletal malformations. The mean percentages of affected fetuses/litter with skeletal malformations amounted to 0.0, 1.6, 0.0, and 2.4%. The noted skeletal malformations appeared without a clear relation to dosing, without biologically relevant differences between the groups and/or can be found at a comparable frequency in the historical control data
In all groups, signs of skeletal variations with or without involvement of corresponding cartilaginous structures elicited. The mean percentages of affected fetuses/litter with skeletal variations amounted to 96.0, 95.0, 97.4, and 100% at 0; 40; 200 or 1,000 mg/kg bw/d.
However, two skeletal variations, occurred at statistically significantly rates in the high fetuses (1,000 mg/kg bw/d). The increased occurrence of unossified sternebra and supernumerary rib (without cartilage) were clearly above the upper historical-control values. However, the overall rate of skeletal variations at this dose level was not statistically significantly elevated above the concurrent control value (affected fetuses/litter: 96.0, 95.0, 97.4 and 100.0% in all groups).
Also, unclassified cartliage observations, occurred in all groups including the controls. The mean percentages of affected fetuses/litter with these findings amounted to 38.6, 34.6, 47.2, and 63.5%** at 0; 40; 200 or 1,000 mg/kg bw/d (** = p< 0.01). A toxicological relevance tor these findings could be excluded.
Effect levels (fetuses)
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 200 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: embryotoxicity
- Dose descriptor:
- NOAEL
- Effect level:
- 200 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: fetotoxicity
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: teratogenicity
Fetal abnormalities
- Abnormalities:
- not specified
Overall developmental toxicity
- Developmental effects observed:
- not specified
Any other information on results incl. tables
Maternal examination:
Dose (mg/kg bw/d) | 0 | 40 | 200 | 1000 |
Mated females | 25 | 25 | 25 | 25 |
Pregnant females | 24 | 23 | 25 | 20 |
Mortality of dams | 0 | 0 | 0 | 0 |
Pregnant on C-section | 24 | 23 | 25 | 20 |
Clinical symptoms: | - | - | - | + |
Food consumption day 6-19 p.c. g | 16.9 | 17.2 | 17.6 | 15.1 |
Mean body weight day 0 (g) | 169.2 | 170.7 | 173.2 | 171.9 |
Mean body weight day 6 (g) | 196.9 | 197.1 | 201.7 | 198.3 |
Mean body weight day19 (g) | 265.2 | 264.4 | 271.1 | 250.0* |
Mean body weight gain (days 6-19; (g)) | 68.4 | 67.4 | 69.4 | 51.7** |
Uterus weight (g) | 49.4 | 47 | 48.7 | 40.2 |
+ urine smeared fur
*p<0.05; ** p<0.01 (Dunnett test or Kruskal-Wallis and Wilcoxon)
Caesarian section/fetal examination:
Dose (mg/kg bw/d) | 0 | 40 | 200 | 1000 |
Corpora lutea (mean) | 10.1 | 9.8 | 10.5 | 10.6 |
Implantation sites (mean) | 9.6 | 9 | 9.4 | 9.4 |
Post-implantation loss (mean %) | 6.2 | 4.2 | 6.4 | 23.1** |
Dead fetuses/litter (mean %) | 0 | 0 | 0 | 0 |
Resorption sites/litter (mean) | 0.5 | 0.4 | 0.6 | 2.2** |
Mean No. of live fetuses/litter | 9 | 8.6 | 8.7 | 8.6 |
Mean fetal weights males (g) | 3.6 | 3.6 | 3.7 | 3.6 |
Mean fetal weights females (g) | 3.4 | 3.5 | 3.5 | 3.4 |
% of fetuses with external malformations | 0 | 0.5 | 0 | 0 |
% of fetuses with visceral malformations | 0 | 0 | 0 | 0 |
% of fetuses with skeletal malformations | 0 | 1.9 | 0 | 2.6 |
% of fetuses with external variations | 0 | 0 | 0 | 0 |
% of fetuses with visceral variations | 8.8 | 8.7 | 13 | 23 |
% of fetuses with skeletal variations | 96 | 96 | 97 | 100 |
** p<0.01 (Dunnett test or Kruskal-Wallis and Wilcoxon)
Applicant's summary and conclusion
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.