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Administrative data

Description of key information

Regarding inhalation exposure, based on human data an OEL (TWA) of 10 ppm (54.7 mg/m3) is proposed as a human NOAEL (which is related to the avoidance of renal toxicity) for trichloroethylene. Furthermore, a NOAEL of 50 ppm was established for CNS disturbance in humans.
With regard to animals (rats), a NOAEL of 100 ppm (547 mg/m3) for kidney toxicity and a NOAEL for neurotoxicity of 200 ppm have been reported for long-term inhalation exposure to trichloroethylene.
After oral exposure (only animal data available), evidence of general toxicity has been observed as kidney tubule meganucleocytosis in male rats dosed at 250 mg/kg bw/day, 4 or 5 days/week for 52 weeks. Subsequently, a NOAEL for systemic toxicity after oral administration was set at 50 mg/kg bw/day.
The kidney toxicity appears to be the most sensitive repeated dose toxicity endpoint, however it should be noted that the onset of this effect occurs late (> 1 year of exposure).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
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.
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
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.
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
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
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.
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.
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
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
50 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
good

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
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.
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
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.
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
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
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.
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.
Dose descriptor:
NOAEL
Effect level:
100 ppm
Sex:
male
Basis for effect level:
other: kidney tubule meganucleocytosis
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
547 mg/m³
Study duration:
chronic
Species:
rat
Quality of whole database:
good

Additional information

There is an extensive database on repeated dose toxicity of trichloroethylene in humans. However, most studies can not be used for quantitative evaluation. In limited volunteer studies no evidence of toxicity was seen following repeated short-term exposure of up to 200 ppm for up to 7.5 hours/day. There are numerous reports of health surveys being carried out on workers occupationally exposed to trichloroethylene, where exposure is primarily by inhalation, although some dermal exposure is also likely. Unfortunately, the value of these studies is severely limited by the lack of any detailed information on the atmospheric trichloroethylene levels, the possibility of exposure to other chemicals including alcohol and other potential confounding factors. Furthermore, in many studies, no control group was used. Consequently, it is difficult to assess either the qualitative or quantitative relationship that any observed health effects or symptoms may have with trichloroethylene exposure based on these studies.

Although open questions still remain, it is apparent that a target of human trichloroethylene toxicity and carcinogenesis is the kidney, notably the proximal tubule. Based on several recent studies, human renal cell cancer has been observed in highly and repetitively exposed workers, having used trichloroethylene mostly in metal degreasing activities. Observations in experimental systems, as well as in occupationally exposed and diseased persons, lead to the conclusion that human renal cell cancer risk is minimised if exposure to nephrotoxic concentrations of trichloroethylene is avoided, including trichloroethylene concentrations leading to sub-clinical renal changes that can be monitored by urinary excretion of suitable marker proteins. In the occupational field study by Green et aI. (2004) on 70 workers, the mean trichloroethylene exposure was 32 ppm (range 0.5-252 ppm). In this cohort some minor sub-clinical alterations in renal functional parameters were observed. This is corroborated by data of Seldén et al. (1993), who found no increase in urinary excretion of the NAG marker protein (N-acetyl-beta-D-glucosaminidase; a marker for kidney disorder) in workers exposed to a range of 6-10 ppm trichloroethylene. Based on these studies, an OEL (TWA) of 10 ppm (54.7 mg/m3) is therefore proposed as a human NOAEL (which is related to the avoidance of renal toxicity) for trichloroethylene. Since the SCOEL assessment Vermeulen et al (2012) performed a study assessing renal damage by measuring the levels of several kidney damage biomarkers in the urine of exposed workers in China. An increased excretion of Kidney Injury Molecule 1 (KIM-1) was observed in workers with an average exposure of 22ppm. An increased excretion of this biomarker was observed at TWA exposure levels of approximately 12 ppm. The KIM-1 marker is a sensitive biomarker for kidney injury, and it is not clear whether the relatively small increases observed at exposure levels of approximately 12ppm were indicative of kidney injury, particularly since other markers such as NAG were not increased. As such a leel of between 12 and 22 ppm represents a potentially non-adverse effect level for human kidney damage in this population of workers. This is consistent with the current SCOEL OEL of 10ppm indicating that this level can still be considered to be protective of human kidney toxicity on occupatioanlly exposed workers.

A lot of studies report the presence of subjective symptoms of CNS disturbance in exposed workers. Consistently reported symptoms include fatigue, vertigo, dizziness, headaches, memory loss and impaired ability to concentrate. Also, there are a number of reports of skin and eye irritation. The consistency of the reports lends support to the view that these symptoms were related to trichloroethylene exposure and therefore functional CNS disturbance is regarded as a relevant endpoint in humans, although the available data do not allow conclusive judgments to be made regarding causal or dose-response relationships. Notwithstanding the dose-response uncertainties it is concluded that there appears to be an absence of CNS effects associated with exposure levels of around 50 ppm. However, it is noted that in animal studies, a clear NOAEL for neurotoxicity of 200 ppm has been identified for long-term inhalation exposure to trichloroethylene. In view of this, and given the uncertainties surrounding the identification of a reliable NOAEL for humans from the available data, it is possible that NOAEL for neurotoxicity in humans may be higher than 50 ppm and is therefore less critical compared to the NOAEL for kidney effects.

 

In animals, the main toxic effects which have been observed following repeated inhalation exposure to trichloroethylene are on the liver, kidney, CNS, pulmonary system and hearing. Liver and kidney toxicity have also been reported following oral administration. Overall, in animals, kidney toxicity appears to be the most sensitive endpoint for both long-term repeated inhalation and oral exposure. However it should be noted that the onset of this effect occurs late (> 1 year of exposure). NOAELs of 100 ppm and 50 mg/kg bw/day were identified in rodents for inhalation and oral exposure, respectively.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
reasonably well conducted study identifying a clear NOEL for the critical effect

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
reliable study

Repeated dose toxicity: via oral route - systemic effects (target organ) urogenital: kidneys

Repeated dose toxicity: inhalation - systemic effects (target organ) urogenital: kidneys

Justification for classification or non-classification

The available data on repeated dose toxicity do not trigger classification according to EU Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.