Benzene-1,2,4-tricarboxylic acid 1,2-anhydride, oligomeric reaction products with ethane- l,2-diol

Repeated dose toxicity: oral

Administrative data

Endpoint:

chronic toxicity: oral

Remarks:

combined repeated dose and carcinogenicity

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Guideline study but predates OECD guidelines and GLP

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1979

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)

Deviations:

yes

Remarks:

precedes establishment of guideline

GLP compliance:

no

Remarks:

precedes establishment of GLP

Test material

Test material information

Constituent 1

Reference substance name:

Phthalic anhydride

EC Number:

201-607-5

EC Name:

Phthalic anhydride

Cas Number:

85-44-9

IUPAC Name:

2-benzofuran-1,3-dione

Test material form:

other: granular solid

Details on test material:

White granular solid, obtained from Koppers Co. Purity 98.8% with one impurity, via HPLC. Melting point = 131 degrees C.

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 farm, Frederick, MD.
- Age at study initiation: 6 weeks
- Weight at study initiation:
- Fasting period before study: no
- Housing: Housed 4/cage in polycarbonate cages, suspended from aluminum racks and covered by nonwoven polyester0fiber 12 mm thick filter paper (Hoeltge, Inc., Cincinnati, OH). The bedding was Absorb-dri (R) hardwood chips (Northeastern Products, Inc, Warrensburg, NY). Cages were sanited twice weekly in a tunnel-type cagewasher using detergents Clout (R), Pharmacal Research Laboratories, Greenwich, CT or Oxford d'Chlor (Oxford Chemicals, Atlanta, GA).
- Diet (e.g. ad libitum): presterilized Wayne Sterilizable Lab meal, ad libitum. Suspended in steel hoppers and replendished three times weekly. Hoppers and sippers were sanitized twice monthlyusing Calgen Commercial Division detergen (St. Louis, MO)
- Water (e.g. ad libitum): acidified to pH 2.5, ad libitum from glass bottles, via sipper tubes through the tops of the cages.
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-24
- Humidity (%): 45-55
- Air changes (per hr): 15. Fresh air was filtered prior to delivery and not recirculated. Air pressure was maintained negative to a clean hallway and positive to a return hallway.
- Photoperiod (hrs dark / hrs light): 12/12, Fluorescent light.

Administration / exposure

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Analysis by the 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.

Duration of treatment / exposure:

8 weeks (7 weeks of adminstration of test chemical and 1 week of further observation)

Frequency of treatment:

daily in feed

Doses / concentrations

Remarks:

Doses / Concentrations:
6200, 12500, 25000 and 50000 ppm
Basis:
nominal in diet

No. of animals per sex per dose:

5

Control animals:

yes, plain diet

Positive control:

no

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: no data

BODY WEIGHT: Yes
- Time schedule for examinations: twice weekly

Sacrifice and pathology:

Animals were euthanized using CO2.

Other examinations:

Pathology evaluation consisted of gross and microscopic examination of major tissues, major organs and all gross lesions.

Statistics:

The maximally tolerated dose was determined by least squares regressions of mean body weights vs days on study (49). Probits of the percent weights at day 49 relative to weights in corresponding controls were plotted against the log of the doses, and least squares regressions were fitted to the data. The dose associated with a 10% depression in body weight was identified.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

The MTD was set at 15000 ppm, based on a 10% weight depression at higher doses.

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

Hepatic centrilobular cytoplasmic vacuolation in male rats

Details on results:

Mean body weights of males were lower than those of controls from weeks 1-8 at 25000 ppm and higher. There were no effects of phthalic anhydride on the survival of rats for 8 weeks. In males at 25000 ppm, there were trace amounts of hepatic centrilobular cytoplasmic vacuolation; however, this was not seen in animals dosed at 50000 ppm. No other adverse effects were noted. The MTD was less than 25000 ppm. The doses for the chronic bioassay were set at 7500 ppm and 15000 ppm.

Effect levels

Dose descriptor:

LOAEL

Effect level:

25 000 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: The lowest dose at which histopathologic findings were observed in male/females at 25000 ppm.

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

An 8 week repeated dose toxicity assay was undertaken in F344 rats with phthalic anhydride in the feed, at doses of 6200, 12500, 25000 and 50000 ppm. The test material was administered for 7 weeks with a 1 week recovery period. The MTD was less than 25000 ppm. In males at 25000 ppm, hepatic centrilobular cytoplasmic vacuolation was observed, but this was not dose related. The doses for the chronic bioassay were set at 7500 ppm and 15000 ppm. This study is informative for evaluation of the toxicity of members of the selected cyclic acid anhydride category.