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Diss Factsheets

Toxicological information

Repeated dose toxicity: oral

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Administrative data

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.

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Phthalate esters carcinogenicity in F344/N rats and B6C3F1 mice
Author:
Huff JE, Kluwe WM
Year:
1984
Bibliographic source:
Ind. Hazards Plastics Synthetic Elastomers, 137-154.
Reference Type:
publication
Title:
Carcinogenic potential of phthalic acid esters and related compounds: structure-activity relationships
Author:
Kluwe WM (1986). Carcinogenic potential of phthalic acid esters and related compounds: structure-activity relationships. Environ. Health Perspect 65, 271-278.
Year:
1986
Bibliographic source:
Environ. Health Perspect 65, 271-278.
Reference Type:
publication
Title:
Unnamed
Year:
1979
Title:
No information
Author:
U.S. EPA Integrated Risk Information System (IRIS)
Year:
2004
Bibliographic source:
http://www.epa.gov/IRIS/subst/0308.htm (December 15, 2004).
Report date:
2004

Materials and methods

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

Test material

Constituent 1
Chemical structure
Reference substance name:
Phthalic anhydride
EC Number:
201-607-5
EC Name:
Phthalic anhydride
Cas Number:
85-44-9
Molecular formula:
C8H4O3
IUPAC Name:
2-benzofuran-1,3-dione
Specific details on test material used for the study:
Elemental analysis was performed and showed, together with the infrared spectrum, an authentic standard.

Test animals

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

Administration / exposure

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
Doses / concentrationsopen allclose all
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

Examinations

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.

Results and discussion

Results of examinations

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.

Effect levels

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%).

Target system / organ toxicity

Critical effects observed:
no

Any other information on results incl. tables

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%.

Applicant's summary and conclusion

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