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EC number: 201-553-2 | CAS number: 84-69-5
- 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:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Non-GLP, near-guideline study, acceptable for assessment.
Data source
Reference
- Reference Type:
- publication
- Title:
- Developmental toxic effects of diisobutyl phthalate, the methyl-branched analogue of di-n-butyl phthalate, administered by gavage to rats
- Author:
- Saillenfait AM, Sabaté JP, Gallisot F
- Year:
- 2 006
- Bibliographic source:
- Toxicology Letters, 165, 39-46
Materials and methods
- Principles of method if other than guideline:
- Pre-natal developmental toxicity study. Dams were administered the test substance daily by gavage on GD 6-20, with foetuses subject to a standard developmental assessments on GD 21 (including degree of transabdominal testicular migration in males).
- GLP compliance:
- not specified
- Limit test:
- no
Test material
- Reference substance name:
- Diisobutyl phthalate
- EC Number:
- 201-553-2
- EC Name:
- Diisobutyl phthalate
- Cas Number:
- 84-69-5
- Molecular formula:
- C16H22O4
- IUPAC Name:
- 1,2-bis(2-methylpropyl) benzene-1,2-dicarboxylate
- Details on test material:
- Purity: ≥ 99%
Source: ACROS (Geel., Belgium)
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: IFFA CREDO Breeding Laboratories (Saint-Germain-sur-l'Arbresle, France)
- Age at study initiation: Not reported, dams were primiparous
- Weight at study initiation: 180-200 g
- Fasting period before study: No
- Housing: Single. Clear polycarbonate cages with stainless steel wire lids and corn cob granules as bedding.
- Diet (e.g. ad libitum): Food pellets (UAR Alimentation Villemoissonm France) ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 1-2 weeks
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 2°C
- Humidity (%): 50 ± 5%
- Air changes (per hr): Not reported
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- olive oil
- Details on exposure:
- No further details
- Analytical verification of doses or concentrations:
- not specified
- Details on analytical verification of doses or concentrations:
- No data
- Details on mating procedure:
- - Impregnation procedure: cohoused
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy - Duration of treatment / exposure:
- From GD 6 to 20 (termination on GD 21)
- Frequency of treatment:
- daily
- Duration of test:
- Termination on GD 21
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0 (olive oil), 250, 500, 750, 1000 mg/kg b.w./day
Basis:
nominal conc.
- No. of animals per sex per dose:
- 23-24 (20-22 pregnant)
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Based on range-finding study (0, 250, 500, 750 or 1000 mg/kg bw/d) in which maternal and foetal effects recorded at 750 mg/kg bw/d and above.
Examinations
- Maternal examinations:
- CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily
BODY WEIGHT: Yes
- Time schedule for examinations: Every 3 days
FOOD CONSUMPTION (if feeding study): Yes - 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:
- - Live foetal weight
- Sex ratio
- Trans-abdominal testicular migration
- External examinations: Yes: all per litter
- Visceral examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter - Statistics:
- Post-implantation loss, dead fetuses, resorptions, TTM and alterations among litters was evaluated by using the Kruskal-Wallis test followed by the Mann-Whitney test where appropriate.
Rates of pregnancy and incidences of fetal alterations per dose analysed by using Fisher's test.
p < 0.05 deemed significant - Indices:
- Maternal parameters: (corrected) body weight change, food consumption
Gestation parameters: Number of implantation sites per litter, post-implantation loss, dead/live foetuses, resporptions, sex distribution, foetal body weight
Various Malformations (external, visceral and skeletal)
Various Variations: (external, visceral and skeletal) - Historical control data:
- Not used
Results and discussion
Results: maternal animals
Maternal developmental toxicity
- Details on maternal toxic effects:
- Maternal toxic effects:yes
Details on maternal toxic effects:
Significant deviations in body-weight gain seen at dose levels of 500 mg/kg b.w./day and above
Effect levels (maternal animals)
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
- Dose descriptor:
- NOAEL
- Effect level:
- 250 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- other: developmental toxicity
Results (fetuses)
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:yes
Details on embryotoxic / teratogenic effects:
Significant decrease in fetal body weight and degree of trans-abdominal testicular migration at dose levels of 500 mg/kg b.w./day and above.
Wide-ranging embryotoxic/tetragenic effects seen at dose levels of 750 mg/kg b.w./day and above.
Fetal abnormalities
- Abnormalities:
- not specified
Overall developmental toxicity
- Developmental effects observed:
- not specified
Any other information on results incl. tables
Maternal parameters:
- no maternal deaths;
- body weight gain significantly reduced in high dose dams (GD 6-21), however weight gain after correction for gravid uterine weight unremarkable (i.e. weight gain reduction due to lower number of liver foetuses and foetal body weight);
- gravid uterine weight statistically significantly decreased in the 500, 750 and 1000 mg/kg bw/d groups (-19%, -27% and -61%, respectively);
Litter parameters:
- pregnancy rate and the number of implantations unaffected by treatment;
- incidence of resorptions statistically significantly increased at 750 mg/kg bw/d (28%) and 1000 mg/kg bw/d (59%) relative to controls (7%);
- number of liver foetuses per litter statistically significantly decreased at 750 mg/kg bw/d (-21%) and 1000 mg/kg bw/d (-51%);
- sex ratio unremarkable
Foetal parameters:
- mean foetal body weight statistically significantly reduced 7-24% at 500 mg/kg bw/d and above;
- external malformations (neural tube closure defects, anophthalmia) statistically significantly increased at 750 and 1000 mg/kg bw/d;
- skeletal malformations (primarily fused sternebrae) statistically significantly increased at 750 and 1000 mg/kg bw/d;
- skeletal variations (delayed ossification, supernumerary ribs) statistically significantly increased at 750 and 1000 mg/kg bw/d;
- total visceral malformations (urinary tract and vascular defects) were statistically significantly increased at 750 and 1000 mg/kg bw/d;
- visceral variations involved primarily the urinary tract, ureter and male reproductive system
- unilateral or bilateral undescended testes occurred in 3/55 male foetuses (2/20 litters) at 500 mg/kg bw/d, in 30/55 male foetuses (16/20 litters) at 750 mg/kg bw/d, and in 30/34 male foetuses (16/17 litters) at 1000 mg/kg;
- transabdominal testicular migration in relation to the bladder was significantly increased at 500 mg/kg bw/d and above, and in high dose males around two third of the testes (right and left) were located in the upper half of the abdominal cavity;
- alterations of the male reproductive system occurred at lower doses than those producing structural malformations/variations and embryotoxicity.
Applicant's summary and conclusion
- Conclusions:
- Diisobutyl phthalate was found to exhibit developmental toxicity in rats at dose rates of 500 mg/kg b.w./day and above. The overall NOEAL was 250 mg/kg b.w./day
- Executive summary:
The prenatal developmental toxicity of DIBP was investigated in pregnant Sprague-Dawley rats administered doses of 0 (olive oil), 250, 500, 750 and 1000 mg/kg bw/d by gavage on GD 6-20. Dams and foetuses were subject to a standard range of assessments on GD 21, with the degree of transabdominal testicular migration determined additionally in male foetuses. Maternal parameters were generally unremarkable, with an apparent reduction in body weight secondary to statistically significant reductions in gravid uterine weight in the 500, 750 and 1000 mg/kg bw/d groups. Pregnancy rate and the number of implantations were unaffected by treatment, however the incidence of resorptions was statistically significantly increased, and the number of liver foetuses per litter decreased, at 750 mg/kg bw/d and above. Foetal sex ratio was unremarkable, but mean foetal body weight was significantly reduced at 500 mg/kg bw/d and above. The incidence of external malformations, total visceral malformations, skeletal malformations and skeletal variations was significantly increased at 750 and 1000 mg/kg bw/d. Visceral variations involved primarily the urinary tract, ureter and male reproductive system, and included significantly increased incidences of unilateral or bilateral undescended testes and significantly increased transabdominal testicular migration relative to the bladder at 500 mg/kg bw/d and above. No evidence foetal effects was found at the 250 mg/kg dose level. The NOAEL for maternal toxicity was therefore 1000 mg/kg bw/d, and the NOAEL for foetal effects 250 mg/kg bw/d.
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