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EC number: 201-607-5 | CAS number: 85-44-9
- 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: No OECD guideline or GLP defined.
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 1 997
Materials and methods
Test guideline
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- other: Developmental toxicity study in rats.
- GLP compliance:
- not specified
- Limit test:
- no
Test material
- Reference substance name:
- Phthalic acid
- EC Number:
- 201-873-2
- EC Name:
- Phthalic acid
- Cas Number:
- 88-99-3
- Molecular formula:
- C8H6O4
- IUPAC Name:
- phthalic acid
- Details on test material:
- Test substance Phthalic Acid (PA) (99.5% pure, Aldrich, Milwaukee, WI).
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar Kyoto (WKY)
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Age at study initiation: about 12 weeks
- Weight at study initiation:
- Fasting period before study:
- Diet (e.g. ad libitum): basal diet ad libitum
- Water (e.g. ad libitum): tap water ad libitum
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 +- 1°C
- Humidity (%): 55 +-5%
- Air changes (per hr): air-conditioned room
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- other: diet
- Details on exposure:
- The pregnant rats were fed a diet containing phthalic acid (PA, 99.5% pure, Aldrich, Miwaukee, WI) at a dose of 1.25, 2.5, or 5.0% ad libitum on day 7 through to day 16 of pregnancy.
- Analytical verification of doses or concentrations:
- not specified
- Details on analytical verification of doses or concentrations:
- The diet containing PA was prepared fresh weekly. A predetermined amount of PA was weighed and added to a small aliquot of ground basal diet and handblended. This premix was then added to a preweighed ground basal diet and blended with mill (Irie Shokai, Tokyo, Japan) for 30 min. The control rats were fed a basal diet only ad libitum.
- Details on mating procedure:
- Virgin female rats, about 12 weeks old, were mated overnight with male rats. The day when sperm were detected in the vaginal smear was considered to be day 0 of pregnancy. The pregnant rats were distributed on a random basis into four groups of 11 pregnant rats each housed individually.
- Duration of treatment / exposure:
- The pregnant rats were fed a diet ad libitum on day 7 through to day 16 of pregnancy.
- Frequency of treatment:
- continuous via food
- Duration of test:
- The pregnant rats were sacrified on day 20 of pregnancy.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 1.25 other: % in diet
- Remarks:
- daily test material intake determined with 1021 +- 52 mg/kg bw/day
- Dose / conc.:
- 2.5 other: % in diet
- Remarks:
- daily test material intake determined with 1763 +- 163 mg/kg bw/day
- Dose / conc.:
- 5 other: %
- Remarks:
- daily test material intake determined with 2981 +- 270 mg/kg bw/day
- No. of animals per sex per dose:
- 11
- Control animals:
- yes
- Details on study design:
- The pregnant rats were fed a diet containing PA (99.5% pure, Aldrich, Milwaukee, WI) at a dose of 1.25, 2.5, or 5.0% ad libitum on day 7 through to day 16 of pregnancy. The administration in the feed was selected because of necessity to expose to large amount of PA and slight solubility of PA in water and oil (Budavari et al.,1996). This method for administration is useful with agents that are to be given in large amounts or are difficult to dissolve in vehicles that would be tolerated in other treatment routes (Wilson, 1965).
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily
BODY WEIGHT: Yes
- Time schedule for examinations: daily
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
Average daily intake of PA was calculated by the method described by Tyl et al. (1988).
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 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. The adjusted weight gain, i.e. maternal weight gain throughout pregnancy corrected for gravid uterine weight, was calculated. - 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 live fetuses in each litter, randomly selected, were fixed in 99% ethanol, stained 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 blade sectioning method of Wilson (1965).
- Statistics:
- Statistical analysis of the offspring data was carried out using the litter as a unit. 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
General toxicity (maternal animals)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- see Table 1
- Mortality:
- no mortality observed
- Description (incidence):
- see Table 1
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- see Table 1: The maternal body weight gain on days 7–16 in the 2.5 and 5.0% groups and the adjusted weight gain, which indicates the net weight gain of maternal rats, 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.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- see Table 1: 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 in the 1.25, 2.5 and 5.0% groups were found. The average daily intakes of PA were 1021 mg/kg for the 1.25% group, 1763 mg/kg for the 2.5% group, and 2981 mg/kg for the 5.0% group.
Maternal developmental toxicity
- Description (incidence and severity):
- The reproductive findings in rats given dietary phthalic acid (PA) on day 7 through day 16 of pregnancy are shown in Table 2. 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 postimplantation loss per litter, and sex ration of live fetuses.
Effect levels (maternal animals)
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- ca. 1 021 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
- Dose descriptor:
- NOAEL
- Effect level:
- ca. 1 763 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- other: developmental toxicity
Results (fetuses)
- Fetal body weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- see Table 2: 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.
- External malformations:
- no effects observed
- Skeletal malformations:
- no effects observed
- Description (incidence and severity):
- see Table 3: A few types of skeletal variations in the vertebrae and sternebrae were observed in the control and PA-treated groups.
- Visceral malformations:
- no effects observed
Effect levels (fetuses)
- Dose descriptor:
- NOAEL
- Effect level:
- 1 763 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: body weight male fetuses
Fetal abnormalities
- Abnormalities:
- not specified
Overall developmental toxicity
- Developmental effects observed:
- not specified
Any other information on results incl. tables
Table 1: Maternal findings in rats given dietary PA on days 7 -16 of pregnancy:
PA (%) | ||||
0 (control) | 1.25 | 2.5 | 5.0 | |
No. of pregnant rats | 11 | 11 | 11 | 11 |
No. of dead pregnant rats | 0 | 0 | 0 | 0 |
Initial body weight (g) | 242+10 | 243+16 | 243+12 | 244+16 |
Body weight gain during pregnancya) | ||||
Days 0 -7 | 24+6 | 26+10 | 31+6 | 27+7 |
Days 7 -16 | 49+8 | 54+8 | 40+5* | 20+12** |
Days 16 -20 | 41+9 | 40+8 | 47+11 | 57+16** |
adjusted weight gainb) | 50+11 | 47+10 | 42+10 | 30+12** |
Food consumption during pregnancy (g)a) | ||||
Days 0 -7 | 138+8 | 140+15 | 145+13 | 138+8 |
Days 7 -16 | 198+11 | 197+10 | 173+17** | 145+13** |
Days 16 -20 | 88+10 | 98+4** | 101+6** | 120+7** |
Daily intake of PA (mg/kg)a,c) | 0 | 1021+52 | 1763+163 | 2981+270 |
a)Values are given as mean+S.D:
b)Adjusted weight gain refers to maternal weight gain excluding the gravid uterus.
c)[Food consumotion on days 7 -16/9)x%PA]/body weight on day 7.
*,**Significantly different from the control, P<0.05 and P<0.0.1, respectively.
Table 2: Reproductive findings in rats given dietary PA on days 7 -16 of pregnancy:
PA (%) | ||||
0 (control) | 1.25 | 2.5 | 5.0 | |
No. of litters | 11 | 11 | 11 | 11 |
No. of corpora lutea per littera) | 14.3 +1.3 | 15.3 +1.6 | 15.7 +2.3 | 15.7 +1.5 |
No. of implantations per littera) | 13.1 +2.1 | 14.0 +1.7 | 14.3 +3.3 | 13.8 +3.4 |
No. of litters totally resorbed | 0 | 0 | 0 | 0 |
No. of resorbtions and dead fetuses per littera) | 1.6 +1.6 | 1.3 +1.1 | 0.9 +1.0 | 1.3 +1.4 |
% Postimplantation loss per litterb) | 14.2 | 9.3 | 5.8 | 8.7 |
No. of live fetuses per littera) | 11.5 +3.0 | 12.7 +2.2 | 13.4 +3.0 | 12.5 +3.4 |
Sex ratio of live fetuses (male/female) | 60/66 | 61/79 | 83/64 | 62/76 |
Body weight of live fetuses (g)a) | ||||
Male | 4.19 +0.13 | 4.15 +0.07 | 4.20 +0.18 | 4.03 +0.18* |
Female | 3.92 +0.16 | 3.95 +0.13 | 3.92 +0.15 | 3.82 +0.14 |
a) values are given as mean + S.D.
b) (No. of resorbtions and dead fetuses/no. of implantations)x100.
* Significantly different from the control, P<0.05.
Table 3: Morphological findings in fetuses of rats given dietary PA on days 7 -16 of pregnancy:
PA (%) | ||||
0 (control) | 1.25 | 2.5 | 5.0 | |
external examination | ||||
No. of fetuses (litters) examined | 126 (11) | 140 (11) | 147 (11) | 138 (11) |
No. of fetuses (litters) with malformations | 0 | 0 | 0 | 0 |
Skeletal examination | ||||
No. of fetuses (litters) examined | 84 (11) | 94 (11) | 97 (11) | 92 (11) |
No. of fetuses (litters) with malformations | 0 | 0 | 0 | 0 |
No. of fetuses (litters) with variations | 4 (3) | 5 (4) | 4 (3) | 10 (6) |
No. of fetuses (litters) with: | ||||
Splitting of thoracic vertebral bodies | 1 (1) | 0 | 0 | 0 |
Asymetric of sternebrae | 3 (3) | 4 (3) | 4 (3) | 7 (6) |
Splitting of sternebrae | 0 | 1 (1) | 0 | 5 (3) |
Degree of ossification | ||||
No. of ossification centers of caudal vertebraea) | 5.5 +0.3 | 5.3 +0.3 | 5.4 +0.3 | 5.1 +0.2* |
No. of sternebraea) | 5.9 +0.1 | 6.0 +0 | 6.0 +0.1 | 5.9 +0.1 |
Internal examination | ||||
No. of fetuses (litters) examined | 42 (11) | 46 (11) | 50 (11) | 46 (11) |
No. of fetuses (litters) with malformations | 0 | 0 | 0 | 0 |
a) Values are given as mean +S.D.
* Significantly different from the control, P<0.01.
Applicant's summary and conclusion
- Executive summary:
The developmental toxicity of phthalic acid was investigated in a developmental toxicity study. Groups of eleven pregnant Wistar rats were fed a diet containing phthalic acid at a dose of 0, 1.25, 2.5, or 5.0 % ad libitum on GD 7 - GD 16 ( average daily intake: 0, 1021, 1763, 2981 mg/kg bw/day). The pregnant rats were observed daily for evidence of clinical signs of toxicity, maternal body weight and food consumption, and were sacrificed on day 20 of pregnancy. 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. The adjusted weight gain, i.e. maternal weight gain throughout pregnancy corrected for gravid uterine weight, was calculated. 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 live fetuses in each litter, randomly selected, were stained with alizarin red S and examined for skeletal malformations. The remaining live fetuses in each litter were fixed in Bouin¿s solution and examined for internal malformations. Maternal toxicity occurred in the 2.5 and 5.0 % groups as demonstrated by decreases in the adjusted maternal bodyweight gain (maternal bw gain excluding the gravid uterus; 30, 42, or 50 g for the 5, 2.5, or control group, respectively) during the administration period. No significant changes in maternal parameters were found in the 1.25 % group (adjusted body weight gain 47 g). No deaths or clinical signs of toxicity were noted in any group. No significant changes induced by phthalic acid were detected in the incidence of postimplantation loss, number and sex ratio of live fetuses. No fetuses with external, skeletal and internal malformations were found in any group. Significant decreases in the weight of male fetuses and decreased numbers of ossified centers of the caudal vertebrae were found only in the 5.0 % group, where significant maternal toxicity also was observed. Morphological examinations of fetuses revealed no evidence of developmental toxicity (NOAEL, maternal toxicity: 1.25 % in feed = 1021 mg/kg bw/day; NOAEL, developmental toxicity: 2.5 % in feed = 1763 mg/kg bw/day).
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