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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Non-GLP, non-guideline study, however well documented and scientifically acceptable.

Data source

Reference
Reference Type:
publication
Title:
Experimental research on trichloroethylene carcinogenesis.
Author:
Maltoni C, Lefermine G and Cotti G
Year:
1986
Bibliographic source:
Archives of Research on Industrial Carcinogenesis (Eds: Maltoni C, Mehlman MA) Vol. 5; 1-393. Pub: Princeton Scientific, Princeton, NJ.

Materials and methods

Principles of method if other than guideline:
Although the project was started in 1976, and most of the experiments were performed from the beginning of 1979, the methodological protocol was considered acceptable.
GLP compliance:
no
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Trichloroethylene
EC Number:
201-167-4
EC Name:
Trichloroethylene
Cas Number:
79-01-6
Molecular formula:
C2HCl3
IUPAC Name:
1,1,2-trichloroethene
Constituent 2
Reference substance name:
Trichloroethene
IUPAC Name:
Trichloroethene
Details on test material:
TCE was supplied and analysed by Montedison. The tested compound was highly purified and epoxide-free. As a stabiliser, butil-hydroxy-toluene at 20 ppm was used. All shipments of TCE were examined to determine whether they had met the required standards.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
Sprague-Dawly rats were of the breed routinely employed in the Bentivoglio Laboratory. The room temperature varied from 19-22 degrees and was checked 3 times daily. Animals were fed an adequate commercial diet and recieved water, ad libitum.

Administration / exposure

Route of administration:
inhalation
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
The chambers for inhalation exposure are made of stainless steel (210 x 206 x 200 cm), for exposure of 10 animals simulaneously. Continuous air flow provided 12-15 air changes per hour. Before its introduction the air was filtered, and the chamber arrangement was such that air flowed from the top of the chamber to its bottom without recirculation. The internal pressure was about 1 mm Hg less than that of the room where the chamber was situated to avoid any possible contamination of the outside environment. Lighting was provided by room light. Exposure chambers were equipped with 5 fixed-point matrixes for checking the distribution of the test substance. The fallout from the chambers was decontaminated before being dispersed into the external atmosphere to avoid general pollution and, as far as the experiments are concerned, to avoid any remote possibility of reintroducing into exposure chambers air with any trace of the test compound.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The concentrations in air were checked by continuous gas-chromatographic monitoring.
Duration of treatment / exposure:
104 weeks
Frequency of treatment:
5 days/week, 7 hour/day
Doses / concentrations
Remarks:
Doses / Concentrations:
100, 300, 600 ppm
Basis:
other: target concentrations
No. of animals per sex per dose:
generally at least 90 of each sex
Control animals:
yes
Details on study design:
The animals were allowed to live until spontaneous death.
Positive control:
None

Examinations

Observations and examinations performed and frequency:
The status and behavior of the animals were examined at least three times daily. Every two weeks, the animals were submitted to an examination for the detection of the gross changes, which were registeredd in the experimental records. The animals were weighed every two weeks during the treatment period and then every eight weeks.
Sacrifice and pathology:
A complete necropsy was performed on each animal. All of the different parts of the body were explored, including the central nervous system. Specimens for histology included: skin, mammary gland, subcutaneous lymph nodes, brain, pituitary gland, Zymbal glands, salivary glands, Harderian glands, eyeballs, thyroid, tongue, thymus and mediastinal lymph nodes, larynx, lungs, heart, aorta, esophagus, diaphragm, liver, kidneys, adrenals, spleen, pancreas, mesenteric lymph nodes, stomach, various segments of intestine (3 levels), urinary bladder, uterus, ovaries, seminal vesicles, prostate gland, testes and epididymes, right thigh muscle, interscapular brown fat, bone marrow (femur) and any other organ or tissue with gross pathological lesions.
The histological specimens were fixed in 70% ethyl alcohol. Once fixed, they were trimmed in a highly standardized way. A higher number of samples was taken when particular pathological lesions were seen. Sections were routinely stained with hematoxilin-eosin, and, when necessary, with other techniques. The bone marrow smears were stained with May-Grunwald-Giemsa and with the Papanicolaou technique. All slides were screened by a junior pathologist, and then reviewed by a senior pathologist.
Other examinations:
Not specified.
Statistics:
When necessary, data from the experiments were submitted to statistical analysis. The following statistical methods are routinely employed:
- Analysis of variance is used for the statistical evaluation of body weights
- For different survival rates the Log rank test has been used
- The non-neoplastic, pre-neoplastic and neoplastic lesions were evaluated by using the Chi-square or Fishers exact test
- The effect of different doses is evaluated by using the Cochran-Armitage test for linear trends in proportions and frequencies.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
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:
not specified
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
effects observed, treatment-related
Details on results:
Evidence of non-cancer toxicity was limited to the observation of kidney tubule meganucleocytosis in male rats of the 300 (incidence 20%) and 600 (78%) ppm groups. A NOAEL for kidney toxicity of 100 ppm can be identified from these data.

Effect levels

Dose descriptor:
NOAEL
Effect level:
100 ppm
Sex:
male
Basis for effect level:
other: kidney tubule meganucleocytosis

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion