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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
Toxicity to reproduction: other studies
Administrative data
- Endpoint:
- toxicity to reproduction: other studies
- Remarks:
- other: reproductive organs in a 2 years study were examined
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- other: well documented and scientifically acceptable
- Rationale for reliability incl. deficiencies:
- other: reproductive organs in a 2 years study were examined
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Reference
- Endpoint:
- chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: No hematology, urinalysis or clinical chemistry analyses were performed.
- Principles of method if other than guideline:
- 50 male and female rats each (20 male and 20 female rats as control) were fed doses of the test substance of 0, 7.500, or 15.000 ppm (ca. 0, 500, 1000 mg/kg bw/d for 102-106 consecutive weeks, followed by sacrifice, necropsy and histopathological examination of major organs and tissues.
- GLP compliance:
- not specified
- Specific details on test material used for the study:
- Elemental analysis was performed and showed, together with the infrared spectrum, an authentic standard.
- Species:
- rat
- Strain:
- Fischer 344
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: NCI Frederick Cancer Research Center animal farm, Maryland
- Age at study initiation: 6 weeks
- Weight at study initiation: males: 90-105 g; females: 80-95 g
- Fasting period before study: not adequate
- Housing: 4 rats per cage
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum, acidified to pH 2.5
- Acclimation period: 2 weeks
DETAILS OF FOOD AND WATER QUALITY:
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-24°C
- Humidity (%): 45-55%
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 hr per day cycle
- Route of administration:
- oral: feed
- Vehicle:
- other: diet
- Details on oral exposure:
- Based on prelimary studies with 7 week exposure via food, the doses for the chronic studies were determined. 10% depression in body weight was taken as the major criterion for the extimation of MTD's.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analyses by Frederick Cancer Research Center indicated that when phthalic anhydride was mixed with Lab Meal at a concentration of 15,000 ppm and stored at room temperature for 2 weeks, the loss was 2.59% (372 ppm) per day. Test diets containing phthalic anhydride were thus prepared fresh every 1 to 1.5 weeks. The diets were routinely stored at 5°C until used.
- Duration of treatment / exposure:
- 105 week
- Frequency of treatment:
- daily
- Dose / conc.:
- 0 ppm
- Dose / conc.:
- 7 500 ppm
- Remarks:
- ca. 500 mg/kg bw/d
- Dose / conc.:
- 15 000 ppm
- Remarks:
- ca. 1000 mg/kg bw/d
- No. of animals per sex per dose:
- 50 male and 50 female rats
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- Post-exposure period: no
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
Daily observations for sick, tumour bearing and moribund animals, twice daily checked for deaths.
Clinical examination and palpation for masses were performed each month.
BODY WEIGHT: Yes
- Time schedule for examinations: at least once per month - Sacrifice and pathology:
- At the end all animals were killed using CO2 inhalation and necropsied. Necropsies were also performed on all animals found dead, unless precluded by autolysis or severe cannibalization.
gross and microscopic examination of: skin, lungs and bronchi, trachea, bone marrow (femur), spleen, lymph nodes (mesenteric and submandibular), thymus, heart, salivary glands (patrotid, sublingual, and submaxillary), liver, pancreas, esophagus, stomach (glandular and nonglandular), small and large intestines, kidneys, urinary bladder, pituitary, adrenal, thyroid, parathyroid, pancreatic islets, testis, prostate, mammary gland, uterus, ovary, brain (cerebrum, and cerebellum), and all tissue masses. Peripheral blood smears were made for all animals, whenever possible. - Statistics:
- Data recorded in an automatic data processing system, the Carcinogenesis Bioassay Data System.
Probabilities of survival were estimated by the product-limit procedure of Kaplan and Meyer (1958). A possible dose-related effect on survival was investigated with teh method of Cox (1972 and Tarone's (1975) extensions.
Incidence of neoplastic or nonneoplastic lesions is given as the ratio of animals bearing such lesions to the number without. As part of this analysis the one-tailed Fischer exact test (Cox, 1975) and other tests were used. - Description (incidence and severity):
- Arched back, rough hair coat, ulceration, and corneal opacity occurred only in dosed groups, but at low incidences.
- Description (incidence):
- No statistical significant difference in mortality was observed in any group. Survival male rats: high-dose group 36/50 (72 %) low-dose group 44/50 (88), control group 14/20 (70 %) Survival female rats: high-dose group 41/50 (82 %), low-dose group 42/50 (84 %), control group 17/20 (85 %)
- Description (incidence and severity):
- The mean body weights of the high-dose males were lower than the controls from week 13 to the end of the study, but the decrease was never more than 10%. Mean body weights of the low-dose males and both the low- and high-dose females were essentially unaffected by the test compound.
- Description (incidence and severity):
- Severe chronic inflammatory, degenerative, or proliferative lesions frequently seen in aged rats occurred with approx. equal frequency and severity in the dosed and control groups of animals.
- Description (incidence and severity):
- By inspection, there appeared to be no difference between the dosed and control groups in frequency or distribution of neoplasms, except for malignant lymphoma in the female rats. The incidence in the control females was 1/20; in low-dose females 11/50; in high-dose females 4/50. Due to the high and fluctuating incidence of this type of malignant lymphoma in control F344 rats, the apparent differences in incidences of the tumor in the dosed and control groups were not considered to be compound related.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 500 mg/kg bw/day (nominal)
- Sex:
- male/female
- Basis for effect level:
- other: The NOAEL = 500 mg/kg/day, based on the reduced body-weight gain (<10%).
- Critical effects observed:
- no
- Executive summary:
50 male and female rats each (20 male and 20 female rats as control) were fed daily doses of the test substance of 0, 7.500, or 15.000 ppm (ca. 0, 500, 1000 mg/kg bw/d for 102-106 consecutive weeks, followed by sacrifice, necropsy and histopathological examination of major organs and tissues.
The NOAEL = 500 mg/kg/day, based on the reduced body-weight gain (<10%).
reference: Huff, 1984; Kluwe, 1986; NCI, 1979
F344 rats (50/sex/group) were fed diets containting 7500 or 15,000 ppm
phthalic anhydride for 105 weeks (approx. 500 and 1,000 mg/kg bw/day).
The observation that the test compound is unstable (2.59% loss of
activity per day at room temperature) has to be noted, although this is
of minor relevance because the diet was prepared fresh every 1 to 1-1/2
weeks and the diet was stored at 5 degree Celsius, consequently the
hydrolysis is assumed to be lower than 26%.
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 1 979
Materials and methods
- Principles of method if other than guideline:
- Groups of 50 rats of each sex were administered phthalic anhydride at one of 2 doses, either 7.500 or 15.000 ppm (ca. 500, 1000 mg/kg bw/d) for 105 weeks. Matched controls consisted of 20 untreated rats of each sex
At the end all animals were killed using CO2 inhalation and necropsied; gross and microscopic examination of: all major organs, including reproductive organs; in male rats preputial gland, prostate, seminal vesicle, testis and epididymis, and the mammary gland; in female rats mammary gland, uterus, endothelial gland, and ovary. - GLP compliance:
- not specified
- Type of method:
- in vivo
Test material
- Reference substance name:
- Phthalic anhydride
- EC Number:
- 201-607-5
- EC Name:
- Phthalic anhydride
- Cas Number:
- 85-44-9
- Molecular formula:
- C8H4O3
- IUPAC Name:
- 1,3-dihydro-2-benzofuran-1,3-dione
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Fischer 344
- Sex:
- male/female
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- other: diet
- Analytical verification of doses or concentrations:
- yes
- Duration of treatment / exposure:
- Exposure period: 105 w
- Frequency of treatment:
- daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 7 500 ppm
- Remarks:
- ca. 500 mg/kg bw/day
- Dose / conc.:
- 15 000 ppm
- Remarks:
- ca.1000 mg/kg bw/day
- No. of animals per sex per dose:
- 50 male and 50 female animals
- Control animals:
- yes, concurrent vehicle
Results and discussion
Effect levels
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 000 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- other:
- Remarks:
- Pathological examination revealed no difference between the dosed and control groups including reproductive organs; in male rats preputial gland, prostate, seminal vesicle, testis and epididymis, and the mammary gland; in female rats mammary gland, uterus, endothelial gland, and ovary.
Any other information on results incl. tables
SURVIVAL:
reduced from week 75 onwards in dosed male and female rats as well as in controls:
high-dose males: 36/50, and females: 41/50
low-dose males: 44/50, and females: 42/50
control males: 14/20, and females: 17/20
MEAN BODYWEIGHTS (no data given):
high dose males lower than controls
high dose females and low dose males and females comparable with controls
CLINICAL SIGNS:
dosed groups: low incidences: arched back, rough hair coat, ulceration and corneal opacity (no further details given)
PATHOLOGICAL EXAMINATION:
by inspection: no difference between the dosed and control groups
Nonneoplastic lesions on reproductive organs:
Organ control (20) low dose (50) high dose (50)
Males:
preputial gland
cyst 0/20 1/50 (2%) 0/50
prostate
calculus 0/20 0/48 2/45 (4%)
inflammation, suppurative
0/20 2/48 (4%) 1/45 (2%)
abscess 0/20 0/48 1/45 (2%)
Inflammation, chronic
1/20 (5%) 0/48 0/45
inflammation, chronic suppurative
1/20 (5%) 0/48 0/45
fibrosis 0 1/48 (2%) 0/45
hyperblasia, focal1/20 (5%) 0/48 0/45
seminal vesicle
inflammation, suppurative
1/20 (5%) 0/50 0/50
testis
hemorrhage 0/20 0/50 1/50 (2%)
infarct 0/20 1/50 (2%) 0/50
atrophy 0/20 3/50 (6%) 2/50 (4%)
epididymis
inflammation, chronic
0/20 0/50 1/50 (2%)
mammary gland
dilatation/ducts 5/20 (25%) 12/50 (24%) 12/50 (24%)
Females:
mammary gland 20 50 50
dilatation/ducts 13 (65%) 33 (66%) 24 (48%)
galactccele 1 (5%) 4 (8%) 1 (2%)
inflammation, granulomatous 0 1 (2%) 0
fibrosis 0 0 1 (2%)
hyperplasia, Nos 0 0 1 (2%)
hyperplasia, focal 1 (5%) 0 0
hyperplasia, cystic 0 0 1 (2%)
uterus 19 47 50
hematoma 0 0 1 (2%)
dilatation, nos 0 1 (2%) 0
necrosis, nos 1 (5%) 0 0
uterus/endometrium 19 47 50
dilatation, nos 0 1 (2%) 1 (2%)
cysti, nos 0 1 (2%) 0
hyperplasia, epithelial 1 (2%) 0
endothelial gland 19 47 50
dilatation, nos 3 (16%) 0 0
ovary 19 47 50
cyst, nos 1 (5%) 3 (6%) 1 (2%)
inflamation, chronic 1 (5%) 0 0
hypoplasia, nos 0 1 (2%) 0
NOAEL: 15000 ppm.
Applicant's summary and conclusion
- Conclusions:
- Groups of 50 rats of each sex were administered phthalic anhydride at one of 2 doses, either 7.500 or 15.000 ppm (ca. 500, 1000 mg/kg bw/d) for 105 weeks. Matched controls consisted of 20 untreated rats of each sex
At the end all animals were killed using CO2 inhalation and necropsied; gross and microscopic examination of: all major organs, including reproductive organs; in male rats preputial gland, prostate, seminal vesicle, testis and epididymis, and the mammary gland; in female rats mammary gland, uterus, endothelial gland, and ovary.
The NOAEL = 1000 mg/kg bw/day (rats, m+f), the pathological examination revealed no difference between the dosed and control groups
Reference: Huff, 1984; Kluwe, 1986; NCI, 1979 - Executive summary:
Groups of 50 rats of each sex were administered phthalic anhydride at one of 2 doses, either 7.500 or 15.000 ppm (ca. 500, 1000 mg/kg bw/d) for 105 weeks. Matched controls consisted of 20 untreated rats of each sex
At the end all animals were killed using CO2 inhalation and necropsied; gross and microscopic examination of: all major organs, including reproductive organs; in male rats preputial gland, prostate, seminal vesicle, testis and epididymis, and the mammary gland; in female rats mammary gland, uterus, endothelial gland, and ovary.
The NOAEL = 1000 mg/kg bw/day (rats, m+f), the pathological examination revealed no difference between the dosed and control groups
Reference: Huff, 1984; Kluwe, 1986; NCI, 1979
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