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Toxicological information

Carcinogenicity

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Administrative data

Description of key information

In comprehensive chronic (105-week) feeding studies no tumors occurred in the rats or mice of either sex at incidences that could be clearly related to the administration of the test chemical. It is concluded that under the conditions of this bioassay, phthalic anhydride was not carcinogenic for F344 rats or B6C3F1 mice of either sex.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records
Reference
Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: well documented study from the NCI (National Cancer Institute)
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. All surviving rats were killed at the end of the period of administration of the test chemical. All animals were checked twice daily for deaths. Observations for sick, tumor-bearing, and moribund animals were recorded daily. Clinical examination and palpation for massess were performed each month, and the animals were weighed at least once per month. The pathologic evaluation consisted of gross and microscopic examination of major tissues, major organs, and all gross lesions.
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, 3 mice 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 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 w
Frequency of treatment:
continuously via food
Post exposure period:
none
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 animals
Control animals:
yes, concurrent no treatment
Details on study design:
Post-exposure period: no
Statistics:
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.
Details on results:
Result (carcinogenicity): negative
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Sex:
male/female
Remarks on result:
other: phthalic anhydride was not carcinogenic for F344 rats of either sex.
F344 rats (50/sex/group) were fed diets contenting 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%.

Survival and non-carcinogenic effects see robust summary chapter repeated dose toxicity.

Animal disposition summary
Control low-dose high dose
Animals initial in study: males (females)
20(20) 50(50) 50(50)
Natural death 3(2) 4(6) 9(2)
Moribund sacrifice
3(1) 2(2) 5(7)
Terminal sacrifice 14(17) 44(42) 36(41)

Tumor summary:
Total animals with primary tumors
19(13) 47(37) 46(36)
Total primary tumors
37(18) 101(58) 84(53)
Total animals with benign tumors
18(12) 45(27) 43(32)
Total benign tumors
28(15) 77(38) 63(44)
Total animals with malignant tumors
7(3) 20(16) 21(8)
Total malignant tumors
7(3) 24(20) 21(9)

Total animals with secondary tumors
0(0) 0(1) 3(1)
Total secondary tumors
0(0) 0(1) 3(1)
Total animals with tumors uncertain
benign or malignant
2(0) 0(0) 0(0)
Total uncertain tumors
2(0) 0(0) 0(0)
Total animals with tumors uncertain
primary or metastatic
0(0) 0(0) 0(0)
Total uncertain tumors
0(0) 0(0) 0(0)

PATHOLOGICAL EXAMINATION:
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 of malignant lymphoma in the control females was 1/20 (5%) in low-dose females, 11/50 (22%), and in high-dose females, 4/50 (8%). Due to the high and fluctuating incidence of this type of malignant lymphoma in control F344 rats, the apparent differences incidences of the tumor in the dosed and control groups were not considered to be compound related. Statistical analysis revealed that a departure from linear trend (P = 0.019) is found in the incidence of lymphoma in female rats, due to the relatively large proportion of 11/50 (22%) in the low-dose group compared with 4/50 (8%) in the high-dose group and 1/20 (5%) in the control group. The results of the Fisher exact test are not significant.
Current historical records at this laboratory indicate an incidence of lymphoma in female rats of 14/285 (4.9%), and, although the majority of the control groups had incidences of less than 5%, one control group was observed to have an incidence as high as 4/20 (20%). Since the results of the Fisher exact test were not significant and since the historical data concerning lymphoma indicates the possibility of an occasional high spontaneous rate of lymphoma, the evidence of association of the lymphomas in the dosed group of female rats with the chemical is questionable.

Further statistical analysis:
In female rats, the result of the Cochran-Armi tage test positive dose-related trend in the incidence of alveolar/ bronchiolar adenomas is significant (P = 0.020), but the results of the Fisher exact test are not significant. The results of the statistical tests on the incidences of alveolar/bronchiolar carcinomas and of alveolar/bronchiolar adenomas or carcinomas are not significant. In male rats, the results of the statistical tests on the incidences of lung tumors are not significant.

A significant dose-related trend (P = 0.037) in the negative direction is observed in the incidence of pheochromocytomas of the adrenal in male rats.

Incidence of primary tumors (%) in selected tissues:

Organ control low-dose high-dose

Male rats

Lung: Alveolar/Bronchiolar Adenoma
1/20 (5%) 4/50 (8%) 1/50 (2%)
Hematopoietic System: Lymphomas
4/20 (20%) 11/50 (22%) 12/50 (24%)
Hematopoietic System: Lymphomas or Leukemias
5/20 (25%) 12/50 (24%) 15/50 (30%) Adrenal: Pheochromocytoma
6/20 (30%) 8/48 (17%) 5/49 (10%)

Female rats

Lung: Alveolar/Bronchiolar Adenoma 0/20 (0%) 0/50 (0%) 5/50 (10%)
Carcinoma 1/20 (5%) 3/50 (6%) 1/50 (2%)
Carcinoma or Adenoma
1/20 (5%) 3/50 (6%) 6/50 (12%)
Hematopoietic System: Lymphomas
1/20 (5%) 11/50 (22%) 4/50 (8%)
Adrenal: Pheochromocytoma
0/20 (0%) 0/49 (0%) 3/49 (6%)

Severe chronic inflammatory, degenerative, or proliferative lesions frequently seen in aged rats occurred with approximately equal frequency and severity in the dosed and control groups of animals.

Conclusion: No tumors occurred in the rats of either sex at incidences that could be clearly related to the administration of the test compound. It is concluded that under the conditions of this bioassay, phthalic anhydride was not carcinogenic for F344 rats of either sex.
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. All surviving rats were killed at the end of the period of administration of the test chemical. All animals were checked twice daily for deaths. Observations for sick, tumor-bearing, and moribund animals were recorded daily. clinical examination and palpation for massess were performed each month, and the animals were weighed at least once per month. the pathologic evaluation consisted of gross and microscopic examination of major tissues, major organs, and all gross lesions.

The NOAEL = 1000 mg/kg bw/d for cancerogenicity (rat, m+f)

No tumors occurred in the rats of either sex at incidences that could be clearly related to the administration of the test compound. It is concluded that under the conditions of this bioassay, phthalic anhydride was not carcinogenic for F344 rats of either sex.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
Scientifically acceptable and well documented.

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Based on the available studies a classification for carcinogenicity is not warranted.

Additional information

A bioassay of phthalic anhydride for possible carcinogenicity was conducted by administering the test chemical in feed to F344 rats and B6C3F1 mice. Groups of 50 rats of each sex were administered the test chemical at one of two doses, initially either 25,000 or 50,000 ppm, for 32 weeks. Because of excessive depressions in the amount of body weight gained in the dosed groups, the doses for the males were then reduced to 12,500 and 25,000 ppm, respectively, and the doses for the females were reduced to 6,250 and 12,500 ppm. Administration of the test chemical at the lowered doses was continued for 72 weeks. The time-weighted average doses for the males were either 16,346 or 32,692 ppm, and those for the females were either 12,019 or 24,038 ppm. Matched controls consisted of 20 untreated mice of eachsex. All surviving mice were killed at the end of the period of administration of the test chemical. Mean body weights of the high-dose male rats and of the lowand high-dose mice of each sex were lower than those of the corresponding controls; mean body weights of the low-dose male rats and of both the low- and high-dose female rats were essentially unaffected by administration of the test chemical.

Depressions in the amount of body weight gained in the male and female mice were dose related throughout the bioassay.

Survivals of the rats and mice were not affected by administration of the test chemical. No tumors occurred in the rats or mice of either sex at incidences that could be clearly related to the administration of the test chemical. It is concluded that under the conditions of this bioassay, phthalic anhydride was not carcinogenic for F344 rats or B6C3F1 mice of either sex.