Registration Dossier

Toxicological information

Repeated dose toxicity: oral

Currently viewing:

Administrative data

Endpoint:
chronic toxicity: oral
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

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
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 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:
oral: gavage
Vehicle:
olive oil
Details on oral exposure:
For ingestion treatment by stomach tube, glass syringes with a stainless steel needle provided with a round tip were used. The ingestion was done from Monday to Friday, usually early in the morning.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The TCE concentration in oil was periodically checked.
Duration of treatment / exposure:
52 weeks
Frequency of treatment:
4 or 5 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
50 or 250 mg/kg/day
Basis:
actual ingested
No. of animals per sex per dose:
30
Control animals:
yes
Details on study design:
Animals were observed 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 registered 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 general toxicity was limited to the observation of kidney tubule meganucleocytosis in 47% of males at 250 mg/kg/day only; females were not affected.

Effect levels

Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw (total dose)
Sex:
male
Basis for effect level:
other: kidney toxicity, characterised by tubular cytomegaly and dilatation

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion