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EC number: 500-109-8 | CAS number: 43011-20-7
- 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:
- migrated information: read-across based on grouping of substances (category approach)
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Scientifically valid study, no information on GLP
Data source
Reference
- Reference Type:
- publication
- Title:
- Developmental toxicity evaluation of phthalic acid, one of the metabolites of phthalic acid esters, in rats
- Author:
- Ema M, Miyawaki E, Harazono A, Kawashima K
- Year:
- 1 997
- Bibliographic source:
- Toxicol. Letters 93: 109-115
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Deviations:
- yes
- Remarks:
- no data on dose validation
- GLP compliance:
- not specified
- Limit test:
- no
Test material
- Reference substance name:
- 1,3-dioxo-2-benzofuran-5-carboxylic acid
- IUPAC Name:
- 1,3-dioxo-2-benzofuran-5-carboxylic acid
- Reference substance name:
- Phthalic acid
- EC Number:
- 201-873-2
- EC Name:
- Phthalic acid
- Cas Number:
- 88-99-3
- IUPAC Name:
- phthalic acid
- Test material form:
- not specified
- Details on test material:
- obtained from Aldrich Chemicals, Milwaukee, WI, USA. 99.5% purity
Constituent 1
Constituent 2
Test animals
- Species:
- rat
- Strain:
- Wistar Kyoto (WKY)
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source:
- Age at study initiation: (P) 12 wks
- Fasting period before study: no
- Use of restrainers for preventing ingestion (if dermal): yes/no
- Diet (e.g. ad libitum): F-1 basal diet (Funabashi Farm, Funabashi, Japan), ad libitum
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 2 ± 1
- Humidity (%): 55 ± 5
Administration / exposure
- Route of administration:
- oral: feed
- Details on exposure:
- The administration in the feed was selected because of the necessity to expose to large amounts of phthalic acid (PA) and the slight solubility of PA in water and oil (Budavari, et al. 1996). The diet was prepared fresh weekly. A predetermined amount of PA was weighed and added to a small aliquot of ground basal diet and hand-blended. This premix was then added to a preweighed ground basal diet and blended with a mill for 30 min. The control rats were fed a basal diet only, ad libitum.
- Analytical verification of doses or concentrations:
- not specified
- Details on mating procedure:
- Virgin female rats were mated overnight with male rats. The day when sperm were detected in the vaginal smear was considered to be day 0 of pregnancy.
- Duration of treatment / exposure:
- GD 7-16
- Frequency of treatment:
- daily
- Duration of test:
- 20 days (gestation)
Doses / concentrations
- Remarks:
- Doses / Concentrations:
1.25%, 2.5% and 5.0%, equivalent to 1021 mg/kg, 1763 mg/kg and 2981 mg/kg, respectively
Basis:
nominal in diet
- No. of animals per sex per dose:
- 11
- Control animals:
- yes, plain diet
Examinations
- Maternal examinations:
- Clinical observations were made daily. Maternal body weight and food consumption were recorded daily and average daily intake calculated by the method of Tyl, et al, 1988. The pregnant rats were sacrificed on GD 20.
- Ovaries and uterine content:
- The peritoneal cavity and uterus were opened and the numbers of live and dead fetuses and resorptions were counted. The gravid uterus was removed and the rats weighed again.
- Fetal examinations:
- The live fetuses removed from the uterus were sexed, weighed and inspected for external malformations and malformations within the oral cavity. Approximately two-thirds of each litter, randomly selected, were fixed in 99% ethanol, stained with alizarin red S (Kawamura, et al, 1990) and examined for skeletal malformations. The remaining live fetuses in each litter were fixed in Bouin's solution and examined for internal malformations using the free-hand razor blad sectioning method of Wilson (1965).
- Statistics:
- The litter was the unit for statistical comparisons. Analysis of variance and Dunnett's multiple comparison test, Kruskal-Wallis test and Mann-Whitney test or Fisher's exact test were used as appropriate. The 0.05 level of probability was used as the criterion for significance.
Results and discussion
Results: maternal animals
Maternal developmental toxicity
- Details on maternal toxic effects:
- Maternal toxic effects:yes. Remark: Decreased food consumption (GD 7-16) and body weight gain in the mid and high dose group.
Details on maternal toxic effects:
No deaths or clinical signs of toxicity were observed in pregnant rats of any groups. The maternal body weight gain on days 7-16 in the 2.5 and 5.0% groups and the adjusted weight gain in the 5.0% group were significantly lower than those in the control group. The maternal body weight gain on days 16-20 in the 5.0% group was significantly higher than that in the control group. A significantly decreased food consumption on days 7-16 in the 2.5 and 5.0% groups and a significantly increased food consumption on days 16-20(no PA in diet) in the 1.25, 2.5 and 5.0% groups were found.
Effect levels (maternal animals)
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 1 021 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
- Dose descriptor:
- NOAEL
- Effect level:
- 1 763 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:no effects
Details on embryotoxic / teratogenic effects:
No significant differences between the PA-treated groups and the control group were detected in the numbers of corpora lutea per litter, implantations per litter, resorptions and dead fetuses per litter and live fetuses per litter, incidence of post-implantation loss per litter, and sex ratio of live fetuses. The weight of male fetuses in the 5.0% group was significantly lighter than that in the control group, although no significantly decreased weight of female fetuses was found in any PA-treated groups. No fetuses with external, skeletal and internal malformations were found in any groups. A few types of skeletal variations in the vertebrae and sternebrae were observed in the control and PA-treated groups. The incidence of fetuses with skeletal variations was not significantly different between the PA treated groups and the control group. The degree of ossification indicated by the number of the ossification centers of the caudal vertebrae in the 5.0% group was significantly lower than that in the control group.
Fetal abnormalities
- Abnormalities:
- not specified
Overall developmental toxicity
- Developmental effects observed:
- not specified
Any other information on results incl. tables
In this study, the dosage as high as possible, which should be expected to induce maternal toxicity, was given to pregnant rats to characterize the effects of PA on embryo-fetal development. The dosage level was determined based on the description of Arnold (1990) in which the highest dose level should not exceed 5% of diet because there is concern about nutrientdilution. According to expectation, the two higher dosage levels used in the present study were maternally toxic. Pronounced effects of PA on the maternal body weight and food consumption during pregnancy were observed and the decreased rate of these indexes was roughly proportional to the dose. Although significant decreases in the body weight gain and food consumption were foundat 2.5 and 5.0%, no significant changes in maternal parameters were detected at 1.25%. These findings suggest that maternal toxicity is induced by PA at dietary doses of 2.5% and above, but not at a dietary dose of 1.25%.
While no significant changes in the numbers of resorptions and dead fetuses per litter and live fetuses per litter were found in any PA-treated groups, significant decreases in the fetal weight and degree of ossification were detected at 5.0%. It seems likely that PA possesses adverse effects on prenatal development of rat offspring at a dietary dose of 5% and that PA has no adverse effects on fetal development at dietary doses of 2.5% and below.
No fetuses with malformations were found in any PA-treated groups. Although several typesof skeletal variations were observed after administration of PA, neither a significant difference between the PA-treated groups and the control group nor a consistent trend was detected in the incidence of these alterations. It is apparent that PA is not developmentally toxic in rats even at a dietary dose which induces maternal toxicity. The data of this study indicates that the no-observed adverse effect levels of PA for maternal and developmental toxicity under these experimental conditions are lower than 5.0 and 2.5%, respectively.
Applicant's summary and conclusion
- Conclusions:
- A teratology study was undertaken with phthalic acid in Wistar-KY rats at doses of 1.25, 2.5 and 5.0% in the diet during gestational days 7-16. Signs of maternal toxicity were observed in the mid and high dose groups, as decreased food consumption and decreased body weight gain. No external, skeletal or internal malformations were observed in any of the groups of fetuses. There was a decrease in the mean body weight of male fetuses in the high dose group. The maternal and fetal NOAELs were 1.25% and 2.5%, equivalent to 1021 and 1763 mg/kg bw, respectively. This study is informative for evaluation of the toxicity of members of the cyclic acid anhydride category, and is adequate for classification and risk assessment.
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