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Carcinogenicity

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Description of key information

An EPA OPPTS 870.430 study was conducted using phthalic anhydride, an analogue substance for PMDA, by administering the test chemical in feed to F344 rats and B6C3F1 mice.  

 

Groups of 50 rats of each sex were administered phthalic anhydride at one of two doses, either 7,500 or 15,000 ppm, 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.

 

 Groups of 50 mice 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. 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 low- and 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.

 

Rats: LOAEL = 15,000 ppm (1000 mg mg/kg bw/day) based on reduced body weight gain (males); NOAEL = 7500 ppm (500 mg/kg bw/day); no conclusive evidence for carcinogenicity in this bioassay.

 

Mice: LOAEL (males) = 16,346 ppm (approx. 2340 mg/kg bw/day) and NOAEL (males) = Not established; LOAEL (females) = 12,019 ppm (approx. 1717 mg/kg bw/day ) and NOAEL (females) = Not established.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Remarks:
Analog substance
Adequacy of study:
key study
Study period:
1979
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
Analogue substance. Well documented study from Carcinogenesis Testing Program, Division of Cancer Cause and Prevention, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20014, USA
Qualifier:
equivalent or similar to
Guideline:
EPA OPPTS 870.4300 (Combined Chronic Toxicity / Carcinogenicity)
Deviations:
not specified
GLP compliance:
not specified
Specific details on test material used for the study:
Phthalic anhydride
Species:
other: Rat and Mouse
Strain:
other: Male and female F344 rats and B6C3F1 mice
Remarks:
See attached report
Sex:
male/female
Details on test animals and environmental conditions:
See attached report
Route of administration:
oral: feed
Vehicle:
not specified
Remarks:
See attached report
Details on exposure:
Via diet for 105 weeks for rats and 32 or 72 weeks for mice.
Analytical verification of doses or concentrations:
not specified
Remarks:
See attached report
Details on analytical verification of doses or concentrations:
See attached report
Duration of treatment / exposure:
Via diet for 105 weeks for rats and 32 or 72 weeks for mice.
Frequency of treatment:
Daily in diet
Dose / conc.:
7 500 ppm (nominal)
Remarks:
Rats
Dose / conc.:
15 000 ppm (nominal)
Remarks:
Rats
Dose / conc.:
6 250 ppm (nominal)
Remarks:
Mice
Dose / conc.:
12 500 ppm (nominal)
Remarks:
Mice
Dose / conc.:
25 000 ppm (nominal)
Remarks:
Mice
No. of animals per sex per dose:
50
Control animals:
not specified
Details on study design:
See attached report
Positive control:
No
Observations and examinations performed and frequency:
See attached report
Sacrifice and pathology:
See attached report
Other examinations:
See attached report
Statistics:
See attached report
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
See attached report
Mortality:
mortality observed, non-treatment-related
Description (incidence):
See attached report; as expected in the aging rat or mouse
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
See attached report; impaired body weights in both species.
Food consumption and compound intake (if feeding study):
not specified
Description (incidence and severity):
See attached report
Food efficiency:
not specified
Description (incidence and severity):
See attached report
Water consumption and compound intake (if drinking water study):
not specified
Description (incidence and severity):
See attached report
Ophthalmological findings:
not specified
Description (incidence and severity):
See attached report
Haematological findings:
not specified
Description (incidence and severity):
See attached report
Clinical biochemistry findings:
not specified
Description (incidence and severity):
See attached report
Urinalysis findings:
not specified
Description (incidence and severity):
See attached report
Behaviour (functional findings):
not specified
Description (incidence and severity):
See attached report
Immunological findings:
not specified
Description (incidence and severity):
See attached report
Organ weight findings including organ / body weight ratios:
not specified
Description (incidence and severity):
See attached report
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
See attached report
Neuropathological findings:
not specified
Description (incidence and severity):
See attached report
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
See attached report; no abnormalities
Histopathological findings: neoplastic:
effects observed, treatment-related
Description (incidence and severity):
See attached report; no neoplasms
Other effects:
not specified
Description (incidence and severity):
See attached report
Details on results:
See attached report
Key result
Dose descriptor:
LOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
body weight and weight gain
Remarks on result:
other: Rats
Key result
Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
Remarks on result:
other: Rats
Key result
Dose descriptor:
LOAEL
Effect level:
2 340 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
body weight and weight gain
Remarks on result:
other: Mice
Key result
Dose descriptor:
LOAEL
Effect level:
1 717 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
body weight and weight gain
Remarks on result:
other: Mice
Critical effects observed:
no

See attached report

Conclusions:
It is concluded that under the conditions of this bioassay that phthalic anhydride was not carcinogenic for F344 rats or B6C3F1 mice of either sex.
Executive summary:

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 phthalic anhydride at one of two doses, either 7,500 or 15,000 ppm, 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.

 

Groups of 50 mice 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 each sex. 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 low- and 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.

 

Rats: LOAEL = 15,000 ppm (1000 mg mg/kg bw/day) based on reduced body weight gain (males); NOAEL = 7500 ppm (500 mg/kg bw/day); no conclusive evidence for carcinogenicity in this bioassay.

 

Mice: LOAEL (males) = 16,346 ppm (approx. 2340 mg/kg bw/day) and NOAEL (males) = Not established; LOAEL (females) = 12,019 ppm (approx. 1717 mg/kg bw/day ) and NOAEL (females) = Not established.

 

It is concluded that under the conditions of this bioassay that phthalic anhydride was not carcinogenic for F344 rats or B6C3F1 mice of either sex.

Endpoint:
carcinogenicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reason / purpose:
read-across source
Key result
Dose descriptor:
LOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
body weight and weight gain
Remarks on result:
other: Rats
Key result
Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
Remarks on result:
other: Rats
Key result
Dose descriptor:
LOAEL
Effect level:
2 340 mg/L air (nominal)
Based on:
test mat.
Sex:
male
Remarks on result:
other: Mice
Key result
Dose descriptor:
LOAEL
Effect level:
1 717 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
body weight and weight gain
Remarks on result:
other: Mice
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
500 mg/kg bw/day
Study duration:
chronic
Species:
other: Rats and mice: NOAEL for rats given
Quality of whole database:
Reliability 1
System:
other: body weights
Organ:
other:

Additional information

Justification for classification or non-classification

Based on the data available the substance is not classified or labelled according to Regulation 1272/2008/EC (CLP).