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Administrative data

Description of key information

The critical effects of tetrachloroethylene are kidney, liver and central nervous system effects. Based on all available data, there is no clear evidence from studies in humans for repeated dose effects of tetrachloroethylene at exposure levels up to a level of 20 ppm (138 mg/m3) (8 hr TWA).
Regarding oral exposure, no human data are available. Regarding animal data, an oral LOAEL of 390 mg/kg bw/day has been identified from the mouse oral cancer bioassay based on kidney damage.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: oral
Remarks:
other: Carcinogenicity bioassay
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, available as published report, adequate for assessment
Principles of method if other than guideline:
The bioassay was conducted according to a protocol of the National Cancer Institute
GLP compliance:
not specified
Limit test:
no
Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS- Source: Charles River Breeding Laboratories, Inc., Wilmington, Massachusetts- Age at study initiation: approximately 5 weeks. The vehicle control mice were approximately 2 weeks older than the other rats and were started on test correspondingly earlier.- Housing: by sex in groups of 10 in solid-bottom polypropylene cages equipped with filter tops. - Food: ad libitum - Water: ad libitum- Acclimation period: quarantined for at least 10 daysENVIRONMENTAL CONDITIONS- Temperature (°C): 20-24- Humidity (%): 45-55- Air changes (per hr): 12- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:Fresh solutions of tetrachloroethylene and corn oil were prepared weekly, sealed, and stored at 34°F. These tetrachloroethylene solutions were considered generally stable for 10 days under the indicated storage conditions.VEHICLE:- Concentration in vehicle: 6, 8, 9 and 11% tetrachloroethylene in corn oil
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
no data
Duration of treatment / exposure:
78 weeks, followed by a 12-week observation period.
Frequency of treatment:
five consecutive days per week
Remarks:
Doses / Concentrations:Males: low dose: 450 mg/kg bw/day (initially) to 550 mg/kg bw/day (maximum low dose); high dose 900 mg/kg bw/day (initially) to 1100 mg/kg bw/day (maximum high dose)Basis:actual ingested
Remarks:
Doses / Concentrations:Females: low dose 300 mg/kg bw/day (initially) to 400 mg/kg bw/day (maximum low dose); high dose 600 mg/kg bw/day (initially) to 800 mg/kg bw/day (maximum high dose)Basis:actual ingested
Remarks:
Doses / Concentrations:Males: 540 and 1070 mg/kg bw/dayBasis:other: time-weighted average dose
Remarks:
Doses / Concentrations:Females: 390 and 770 mg/kg bw/dayBasis:other: time-weighted average dose
No. of animals per sex per dose:
treatment groups: 50 animals per sex/groupcontrol group: 20 animals per sex/group
Control animals:
yes, concurrent no treatment
yes, concurrent vehicle
Details on study design:
Dose selection rationale: subchronic toxicity tests were conducted to establish maximum tolerated dosages. Six groups, each consisting of five males and five females, were utilized and were administered tetrachloroethylene in corn oil at dosages 316, 562, 1000, 1780 and 3160 mg/kg/day; the sixth group served as control (corn oil). The male mice receiving 562 mg/kg/day experienced no reduction in weight gain relative to controls, while male mice receiving 1000 mg/kg/day experienced a 22 percent reduction in weight gain relative to controls. An initial high dose of 900 mg/kg/day was selected for the chronic bioassay of male mice. Female mice receiving 562 mg/kg/day gained 70 percent of the weight gained by controls, while the female mice receiving 1000 mg/kg/day gained 85 percent of the weight gained by controls. An initial high dose of 600 mg/kg/day was selected for the chronic bioassay of female mice.The high and low doses initially utilized for males and females, respectively were 900 and 450 mg/kg/day and 600 and 300 mg/kg/day. After 11 weeks, the animals appeared to be tolerating the chemical, so the high and low doses were, respectively, increased to 1100 and 550 mg/kg/day for male mice and 800 and 400 mg/kg/day for female mice. Treatment continued at this level for the remainder of the 78-week treatment period and was followed by approximately 12 weeks of observation.
Positive control:
no data
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes - Time schedule: cage side observations (appearance, behavior, signs of toxic effects) were recorded at weekly intervals for the first 10 weeks and at monthly intervals thereafter. The incidence, size and location of tissue masses were recorded at weekly intervals for the first 10 weeks and at monthly intervals thereafter and were determined by observation and palpation of each animal. DETAILED CLINICAL OBSERVATIONS: Yes- Time schedule: clinical observations (see above) were recorded at weekly intervals for the first 10 weeks and at monthly intervals thereafter. BODY WEIGHT: Yes - Time schedule for examinations: animals were weighed immediately prior to initiation of the experiment. Body weights were recorded at weekly intervals for the first 10 weeks and at monthly intervals thereafter. FOOD CONSUMPTION: Yes- Food consumption was recorded at weekly intervals for the first 10 weeks and at monthly intervals thereafter.
Sacrifice and pathology:
A necropsy was performed on each animal regardless of whether it died, was killed when moribund, or was sacrificed at the end of the bioassay. the animals were euthanized by exsanguination under sodium pentobarbital anesthesia, and were immediately necropsied. The histopatholic examinationconsisted of gross and microscopic examination of matjor tissues, organs, or gross lesions taken from sacrificed animals and, whenever possible, from animals found dead. Slides were prepared from the following tissues: skin, subcuteaneous tissue, lungs and bronchi, trachea, bone marrow, spleen, lymph nodes, thymus, heart, salivary gland, liver, gallbladder and bile duct, pancreas, esophagus, stomach, small intestine, large intestine, kidney, urinary bladder, pituitary, adrenal, thyroid, parathyroid, pancreatic islets, testis, prostate, brain, uterus, mammary gland, and ovary. A few tissues were not examined for some animals, particularly those that died early. Also, some animals were missing, cannibalized, or judged to be in such an advanced state of autolysis as to preclude histopathologic interpretation.
Statistics:
Several statistical techniques among which: Cochran-Armitage test for linaer trend in proportion, Fisher exact test (Cox, 1970) for the incidence of tumors; product-limit procedure of Kaplan and Meier (1958) for probabilities of survival; method of Cox (1972) for testing two groups for equality and Tarone's (1975) extensions of Cox's methods for testing a dose-related trend for possible dose-related effects on survival.
Clinical signs:
effects observed, treatment-related
Mortality:
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:
not specified
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 MORTALITYAppearance and behavior were generally similar for control and treated mice during the first 26 weeks of the study. Signs often observed in group-housed laboratory mice were noted with a slightly greater frequency in the treated mice of both sexes than in the respective control animals during the remainder of the first year. These signs included body sores, anal or penile irritation, rough or stained rfur, and generalized or localize alopecia. A number of treated mice of both sexed showed a hunched appearance from week 42 through 62. Furthermore, low incidence of bloating or abdominal distension and palpable nodules were observed in treated animals. Survival was markedly lower in both high dose groups and in the female low dose group, compared with the control groups, from about week 40. At least 50% of each of the four control groups survived to the end of the study at 90 weeks, compared with median survivals in the groups treated with tetrachloroethylene of 78 weeks for males and 62 weeks for females at the low dose, and respectively 43 and 50 weeks at the high dose.BODY WEIGHT AND WEIGHT GAINDosed male mice did gain less weight than vehicle control males after the first three months, and dosed female mice did gain less than vehicle control females during the second year of the bioassay. HISTOPATHOLOGY: NON-NEOPLASTICToxic nephropathy (degenerative changes in the proximal convoluted tubules, with cloudy swelling, fatty degeneration and necrosis of the epithelium) similar to that apparent in the rat NCI cancer bioassay, was seen in the majority of males (low dose 40/49; high dose 45/48) and females (low dose 46/48; high dose 48/48) receiving tetrachloroethylene, but was not found in controls.HISTOPATHOLOGY: NEOPLASTICIncidence of hepatocellular carcinomas exhibited a significant positive dose-related trend in mice of both sexes. Hepatocellular carcinomas appeared early in dosed mice. The first hepatocellular carcinoma observed at necropsy occurred in a male low dose mouse that died during week 27. No hepatocellular carcinomas were observed in control mice dying before week 90. A small number o hepatocellular carcinomas in treated mice of both sexes metastasized to the lung, while a single hepatocellular carcinoma in an untreated control male metastasized to the kidney.
Dose descriptor:
LOAEL
Effect level:
390 mg/kg bw/day (actual dose received)
Sex:
female
Basis for effect level:
other: kidney lesions (degeneration of the proximal convoluted tubules with cloudy swelling, fatty degeneration and necrosis)
Dose descriptor:
LOAEL
Effect level:
540 mg/kg bw/day (actual dose received)
Sex:
male
Basis for effect level:
other: kidney lesions (degeneration of the proximal convoluted tubules with cloudy swelling, fatty degeneration and necrosis)
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
390 mg/kg bw/day
Study duration:
chronic
Species:
mouse
Quality of whole database:
Non-GLP, non-guideline study, available as published report, adequate for assessment

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
138 mg/m³
Quality of whole database:
Good

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available (further information necessary)

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available (further information necessary)

Additional information

There is a relatively large amount of information on the potential repeated dose effects of tetrachloroethylene from studies in humans and from inhalation and oral studies in animals.

 

In relation to the studies in humans, there are general worker health surveys and studies specifically investigating potential effects on the liver, kidney, nervous system and colour vision. Variable results and interpretational difficulties have arisen in surveys of workers exposed to lower (below 100 ppm, 690 mg/m3) concentrations of tetrachloroethylene, with a study finding no effects on the frequency of subjective symptoms, psychomotor test results and markers of liver and kidney toxicity in dry-cleaners with a mean 8-hour TWA exposure of 21 ppm (145 mg/m3for 6 years) compared with an unexposed control group (Lauwerys et al., 1983). Two specific hepatotoxicity studies (Gennari et al., 1992 and Brodkin et al., 1995) have provided no clear evidence for tetrachloroethylene-induced liver toxicity at exposure concentrations below 50 ppm (339mg/m3; mean 8h TWA). Similarly, the specific six nephrotoxicity studies (Trevisan et al., 2000; Verplanke et al., 1999; Mutti et al., 1992; Solet and Robins, 1991; Vyskocil et al., 1990; Franchini et al., 1983) have provided no convincing evidence for tetrachloroethylene-induced kidney toxicity at mean exposure levels in the range 1.2 – 23 ppm (8.3 – 156 mg/m3). From the studies that have specifically investigated the potential effects of tetrachloroethylene on the nervous system (Echeverria et al., 1995; Ferroni et al., 1992; Seeber, 1989; Tuttle et al., 1977; Stewart et al., 1977; Altmann et al., 1990; Altmann et al., 1992; Altmann et al., 1995), a clear association between neurobehavioural/neurological deficits and repeated exposure to tetrachloroethylene in the workplace (dry-cleaners) at exposure levels up to 67 ppm (462 mg/m3for 10 years) or in volunteers at concentrations up to 150 ppm (1035 mg/m3for 7.5 hours/day for 5 days) has not been established. There are very few studies that have specifically investigated the effects of tetrachloroethylene on colour discrimination, such that no reliable conclusions can be drawn.

 

In relation to the animal studies, the liver, kidneys and lungs have been shown to be the main target organs of tetrachloroethylene-induced toxicity. Liver damage seen in mice following either inhalation exposure or oral administration has been shown to involve peroxisomal proliferation, an effect to which humans are not responsive. No liver toxicity was observed in rats. For kidney damage, which was observed in both rats and mice following either inhalation or oral exposure, an inhalation LOAEC of 100 ppm, 690 mg/m3(equivalent to an internal dose of 345 mg/kg/day) and an oral LOAEL of 390 mg/kg/day have been identified from the mouse inhalation (National Toxicology Programme, 1986) and oral cancer (National Cancer Institute, 1977; Weisburger, 1977) bioassays respectively. Evidence of hyaline droplet nephropathy was found in male rats following either inhalation or oral exposure, but the data indicate that this phenomenon, which is male rat-specific and hence not relevant to humans, only occurs at relatively high levels of exposure (1000 ppm, 6900 mg/m3and 1000 -1500 mg/kg/day) when relatively short exposure durations are employed. Congestion of the lungs was seen in mice following inhalation exposure at 100 ppm (690 mg/m3) for 2 years. One hundred ppm (690 mg/m3) is therefore also the LOAEC for this effect in the lungs.

 

Based on all available data, there is no clear evidence from studies in humans for repeated dose effects of tetrachloroethylene at exposure levels up to a level of 20 ppm (138 mg/m3). This concentration can be regarded to be a NOAEL in humans as an 8 hours TWA value.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
See discussion below

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Based on all available data, there is no clear evidence from studies in humans for repeated dose effects of tetrachloroethylene at exposure levels up to a level of 20 ppm (138 mg/m3). This concentration can be regarded to be a NOAEL in humans as an 8 hours TWA value.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
See discussion below

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
In accordance with column 2 of REACH Annex IX-X, testing shall be performed using the most appropriate route of administration. Testing by the inhalation route is appropriate if exposure of humans is likely to occur via inhalation; this is the main route of exposure to tetrachloroethylene and inhalation repeated dose toxicity studies are available. Therefore, no study for the dermal route is needed.

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
In accordance with column 2 of REACH Annex IX-X, testing shall be performed using the most appropriate route of administration. Testing by the inhalation route is appropriate if exposure of humans is likely to occur via inhalation; this is the main route of exposure to tetrachloroethylene and inhalation repeated dose toxicity studies are available. Therefore, no study for the dermal route is needed.

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

Repeated dose toxicity: inhalation - systemic effects (target organ) neurologic: central nervous system

Justification for classification or non-classification

Based on the available data, tetrachloroethylene does not need to be classified for repeated dose toxicity according to Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.