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Repeated dose toxicity: inhalation

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repeated dose toxicity: inhalation
other: Carcinogenicity study
Type of information:
experimental study
Adequacy of study:
key study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Non-GLP, near guideline study, published study report, fully adequate for assessment

Data source

Reference Type:
study report

Materials and methods

Principles of method if other than guideline:
Carcinogenicity study, which was conducted to modern regulatory standards
GLP compliance:
not specified
Limit test:

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
Details on test material:
- Name of test material (as cited in study report): tetrachloroethylene- Analytical purity: 99.9%- Lot/batch No.: two batches: TA03116F-01 and TA08190D- Stability under test conditions: yes. Tetrachloroethylene was found to be stable for 2 weeks at 60ºC- Storage condition of test material: stored at 0ºC

Test animals

Details on test animals or test system and environmental conditions:
TEST ANIMALS- Source: Charles River Breeding Laboratories (Kingston, NY)- Age at study initiation: 8-9 weeks- Housing: stainless steel wire, 1 animal per cage- Diet: ad libitum, except during inhalation exposure- Water: ad libitum, also during inhalation exposure- Acclimation period: 21 daysENVIRONMENTAL CONDITIONS- Temperature (°F): 67-83- Humidity (%): 20-83 - Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
other: unchanged (no vehicle)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTIONTetrachloroethylene was pumped from a stainless steel reservoir to a vaporizer by a stable micrometering pump. Tetrachloroethylene was vaporized at 100ºC-110ºC, diluted with air, and introduced into the chambers. The tetrachloroethylene vapor entered the fresh air duct and was led directly into the exposure chamber.
Analytical verification of doses or concentrations:
Details on analytical verification of doses or concentrations:
Concentrations in the exposure chambers were monitored 8-12 times per exposure period by a gas chromatograph. Mean concentrations measured in the exposure chambers were 99.5 ± 6.6, and 201 ± 11 ppm for target concentrations 100 and 200 ppm, respectively.
Duration of treatment / exposure:
103 weeks
Frequency of treatment:
6 hours per day, 5 days per week
Doses / concentrationsopen allclose all
Doses / Concentrations:100, 200 ppmBasis:nominal conc.
Doses / Concentrations:99.5 +/- 6.6, 201 +/- 11 ppm (mean +/- SD)Basis:analytical conc.
No. of animals per sex per dose:
Control animals:
yes, concurrent no treatment
Details on study design:
The exposure concentrations used were selected on the basis of results from 13-week inhalation studies in which groups of 10 mice of each sex were exposed to tetrachloroethylene at 100-1600 ppm for 6 hours per day, 5 days per week. During the 13-week study, 1600 ppm tetrachloroethylene was lethal to 20-70% of the animals and reduced the final body weights of the survivors. In dosed male and female mice, minimal to mild hepatic leukocytic infiltration, centilobular necrosis, bile stasis (400-1600 ppm), and mitotic alteration (200-1600ppm) were produced. Tetrachloroethylene exposure also caused minimal renal tubular cell karyomegaly in mice at concentrations as low as 200 ppm.


Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes, two times per dayDETAILED CLINICAL OBSERVATIONS: Yes, clinical signs recorded at least once per monthBODY WEIGHT: Yes, individual body weights were recorded once per week for the first 13 weeks of the study and once per month thereafter. FOOD CONSUMPTION: No data (ad libitum) WATER CONSUMPTION: No data (ad libitum)
Sacrifice and pathology:
Necropsy was performed on all animals, including those found dead, unless they were excessively autolyzed, or cannibalized, missexed, or found missing. During necropsy, all organs and tissues were examined for grossly visible lesions. Tissues were preserved in 10% neutral buffered formalin, embedded in paraffin, sectioned and stained with hematoxylin and eosin.NOTE: nonneoplastic lesions are not examined routinely unless they are considered part of the toxic effect of the chemical.
- Survival analyses: product-limit procedure of Kaplan and Meier (1958)- Calculation of incidence: incidence of neoplastic of nonneoplastic lesions is given as the ratio of the number of animals bearing such lesions at a specific anatomic site to the number of animals in which that site was examined. - Analysis of tumor incidence: three methods were used: life table analyses (Cox, 1972 and Tarone, 1975 / incidental tumor analyses (Haseman, 1984) / unadjusted analyses (Fisher exact test for pairwise comparisons and the exact Cochran-Armitage linear trend test (Armitage, 1971; Gart et al, 1979)).

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
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:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
effects observed, treatment-related
Details on results:
CLINICAL SIGNS AND MORTALITYSurvival was decreased in males (control 46/49; low dose 25/50; high dose 32/50) and in females (control 36/49; low dose 31/50; high dose 19/50).The survival of the low dose (after week 74) and high dose (after week 78) male groups and the high dose female group (after week 90) was signifcantly lower than that of the controls. BODY WEIGHT AND WEIGHT GAINMean body weights and weight gain of dosed and control groups were comparable throughout the study.GROSS PATHOLOGY AND HISTOPATHOLOGYKidney: - Concentration-related increases in renal tubular cell karyomegaly were obtained in the exposed males (control 4/49; low dose 17/49; high dose 46/50) and females (control 0/48; low dose 16/49; high dose 38/50).- The incidence of nephrosis was also increased in the exposed females (control 5/48; low dose 14/49; high dose 25/50), and tubular cell casts were observed at higher incidences in test males (control 3/49; low dose 9/49; high dose 15/50) and females (control 4/48; low dose 4/49; high dose 15/50). Liver: - Degeneration, characterised by hepatocellular necrosis, cytoplasmic vacuolation, inflammatory infiltration and regenerative foci, showed increased incidence in males (control 2/49; low dose 8/49; high dose 14/50) and females (control 1/49; low dose 2/50; high dose 13/50).- Necrosis: 1/49; 6/49; 15/50 (males) and 3/48; 5/50; 9/50 (females).- Nuclear inclusions: 2/49; 5/49; 9/50 (males).Lung: The number of mice with (acute passive) congestion of the lungs was increased in the exposed males (control 1/49; low dose 8/49; high dose 10/50) and females (control 1/48; low dose 5/50; high dose 6/50).

Effect levels

Dose descriptor:
Effect level:
100 ppm
Basis for effect level:
other: liver lesions (degeneration, characterised by hepatocellular necrosis, cytoplasmic vacuolation, inflammatory infiltration and regenerative foci), kidney damage (tubular cell karyomegaly, nephrosis and casts) and congestion of the lungs

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion