Tetrachlorophthalic anhydride

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study with acceptable restrictions

Data source

Reference

Reference Type:

publication

Title:

Toxicity studies of tetrachlorophthalic anhydride (CAS No. 117-08-8) administered by gavage to F344/N Rats and B6C3F1 Mice.

Author:

NTP

Year:

1993

Bibliographic source:

NTP Technical Report Series No 28.

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Deviations:

yes

Remarks:

No functional observations and ophthalmological examinations

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Tetrachlorophthalic anhydride

EC Number:

204-171-4

EC Name:

Tetrachlorophthalic anhydride

Cas Number:

117-08-8

Molecular formula:

C8Cl4O3

IUPAC Name:

tetrachloro-1,3-dihydro-2-benzofuran-1,3-dione

Details on test material:

- Name of test material (as cited in study report): Tetrachlorophthalic anhydride
- Analytical purity: 99%

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Simonsen Laboratorles
- Age at study initiation: 3-4 weeks
- Housing: 5 per cage
- Diet (e.g. ad libitum): NIH-07 Open Formula mash diet
- Water (e.g. ad libitum): city water
- Acclimation period: 12-16 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25
- Humidity (%): 30-70
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS: Dose formulations were prepared weekly by mixing TCPA in corn oil (w/w). Before mixing, TCPA was ground and sieved, then weighed and added to a beaker containing the required amount of corn oil, the corn oil was magnetically stirred during the addition. Formulations were stored at approximately 4±3 °C and were discarded 7 days after the date of preparation.

VEHICLE
- Justification for use and choice of vehicle (if other than water): because of limited solubility of TCPA in water
- Concentration in vehicle: 0, 20.3, 40.1, 78.6, 15 1.2, or 280.9 mg/g in corn oil
- Amount of vehicle (if gavage): 5 ml/kg bw

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

5 days/week

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 94, 187, 375, 750, 1500 mg/kg bw
Basis:
actual ingested

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily


BODY WEIGHT: Yes
- Time schedule for examinations: at study initiation, weekly thereafter, and at necropsy


FOOD CONSUMPTION:
- Food consumption for each cage (5 rats/cage): at weekly interval

HAEMATOLOGY: Yes
- Time schedule for collection of blood: end of the study
- Anaesthetic used for blood collection: Yes (CO2)
- Animals fasted: No data
- How many animals: all
- Parameters checked: Erythrocyte count (RBC), hematocrit, hemoglobin concentration (HGB), mean cell hemoglobin (MCH), mean cell hemoglobin concentration (MCHC), mean cell volume (MCV), and leukocyte count (WBC), leukocyte differential counts, platelet counts


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: days 6, 20, and at study termination
- Animals fasted: No data
- How many animals: animals in the 0, 94, 375 and 1500 mg/kg bw
- Parameters checked: alanine
aminotransferaso (ALT). albumin, creatinine, y-glutamyltransterase (GGT), glucose, and urea nitrogen (UN).


OTHER: Male rats dosed with 0, 94, 375, or 750 mg/kg bw were evaluated for necropsy body and reproductive tissue weights and spermatozoal data. Female rats dosed with 0, 94, 375, or 1500 mg/kg bw were evaluated for necropsy body weight, estrous cycle length, and the percent of cycle spent in the various stages.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
In addition to detailed necropsy examination, following tissues were examined microscopically: adrenal glands, bone (femur, sternebrae, or vertebrae with marrow) brain (3 sections), clitoral and preputial glands, esophagus, heart, intestine (large cecum, colon, rectum, small duodenum, jejunumn, ileum), kidneys, liver, lungs and mainstem bronchi, lymph nodes (mandibular and mesenteric), mammary glands (including surface skin), nasal cavity and turbinates (3 sections), ovaries, pancreas, parathyroid glands, pituitary gland, prostate gland, salivary glands, seminal vesicles, spinal cord and sciatic nerve (if neurologic signs were present), spleen, stomach (forestomach and glandular stomach), testis with epididymis, thymus, thyroid gland, trachea, urinary bladder, and uterus.

Results and discussion

Results of examinations

Details on results:

CLINICAL SIGNS AND MORTALITY: Treatment-related deaths occurred at 1500 mg/kg bw (5/10 males; 1/10 females) and 750 mg/kg bw (1/10 females). No compound-specific clinical signs of toxicity were observed at any test level in male animals. Urine staining in most females in the 750 and 1500 mg/kg bw groups and diarrhea in all females in the 1500 mg/kg bw group were attributed to treatment with TCPA.


BODY WEIGHT AND WEIGHT GAIN: Mean final body weights and weight gains were notably reduced in groups of male rats given 375, 750 and 1500 mg/kg bw and in all female treated groups. Final weight relative to vehicle controls in the males of the 94, 187, 375, 750, 1500 mg/kg bw dose groups were 94, 97, 89, 90 and 86 %. Similarly, final weight relative to vehicle controls in the females of the 94, 187, 375, 750, 1500 mg/kg bw dose groups were 91, 92, 90, 90 and 90 %.


FOOD CONSUMPTION : All groups (males and females) at all treatment levels exhibited decreased feed consumption compared to controls. In males, these decreases were dose related, and the average feed consumption of the 1500 mg/kg bw group was 12% lower than that of the controls.


HAEMATOLOGY: no clinical significant effects were observed


CLINICAL CHEMISTRY: no clinical significant effects were observed


ORGAN WEIGHTS: Absolute and relative kidney weights were increased in a dose-dependent manner to female rats while males were significantly increased (relative wt) at 187 mg/kg bw and higher. Other changes (spleen, thymus and liver) were either small, inconsistent or attributed to the marked decrease in body weights exhibited, and thus were not considered treatment-related


GROSS PATHOLOGY: No gross lesions attributable to treatment were observed at necrospy.


HISTOPATHOLOGY: NON-NEOPLASTIC: Treatment-related microscopic lesions were identified in the kidney of male and female rats from all test groups, and consisted of renal tubular degenerative changes. These changes involved epithelial necrosis at higher dose levels and tubular dilation at lower dose levels. No other microscopic findings attributable to treatment were found.

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

< 94 mg/kg bw/day (nominal)

Sex:

male/female

2

Dose descriptor:

LOAEL

Effect level:

94 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: microscopic changes in kidney

Target system / organ toxicity

Critical effects observed:

not specified